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brca1
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brca1
|
[
"BRCA1- and BRCA2-Associated HBOC",
"BRCA1- and BRCA2-Associated HBOC",
"Breast cancer type 1 susceptibility protein",
"Breast cancer type 2 susceptibility protein",
"BRCA1",
"BRCA2",
"BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer"
] |
Nancie Petrucelli, Mary B Daly, Tuya Pal
|
Summary The diagnosis of
|
## Diagnosis
Breast cancer diagnosed at or before age 50 years
Ovarian cancer
Multiple (i.e., >1) primary breast cancers in either one or both breasts
Male breast cancer
Triple-negative (estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2-negative) breast cancer
The combination of pancreatic cancer and/or prostate cancer (metastatic or Gleason score ≥7) with breast cancer and/or ovarian cancer
Breast cancer diagnosed at any age in an individual of Ashkenazi Jewish ancestry
Two or more relatives with breast cancer, one diagnosed at or before age 50 years
Three or more relatives with breast cancer at any age
A family member with a known
Note: (1) "Breast cancer" includes both invasive cancer and ductal carcinoma in situ. (2) "Ovarian cancer" includes epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.
Several models have been developed to estimate the likelihood that an individual or family has a germline pathogenic variant in
The diagnosis of
Note: (1) Molecular testing is most likely to be informative in an individual with a
Molecular testing approaches can include a
Targeted analysis can be considered in individuals of Ashkenazi Jewish ancestry by starting with targeted testing for three
Note: In a family known to have a
Individuals of Ashkenazi Jewish descent should consider testing for all three founder pathogenic variants because of the high population frequency of these variants as well as reports of the coexistence of more than one founder variant in some families. They may also consider multigene panel testing, depending on their personal and family history.
Individuals with a familial
A
For an introduction to multigene panels click
Molecular Genetic Testing Used in
HBOC = hereditary breast and ovarian cancer
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Breast cancer diagnosed at or before age 50 years
• Ovarian cancer
• Multiple (i.e., >1) primary breast cancers in either one or both breasts
• Male breast cancer
• Triple-negative (estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2-negative) breast cancer
• The combination of pancreatic cancer and/or prostate cancer (metastatic or Gleason score ≥7) with breast cancer and/or ovarian cancer
• Breast cancer diagnosed at any age in an individual of Ashkenazi Jewish ancestry
• Two or more relatives with breast cancer, one diagnosed at or before age 50 years
• Three or more relatives with breast cancer at any age
• A family member with a known
• Targeted analysis can be considered in individuals of Ashkenazi Jewish ancestry by starting with targeted testing for three
• Note: In a family known to have a
• Individuals of Ashkenazi Jewish descent should consider testing for all three founder pathogenic variants because of the high population frequency of these variants as well as reports of the coexistence of more than one founder variant in some families. They may also consider multigene panel testing, depending on their personal and family history.
• Individuals with a familial
• Individuals of Ashkenazi Jewish descent should consider testing for all three founder pathogenic variants because of the high population frequency of these variants as well as reports of the coexistence of more than one founder variant in some families. They may also consider multigene panel testing, depending on their personal and family history.
• Individuals with a familial
• A
• For an introduction to multigene panels click
• Individuals of Ashkenazi Jewish descent should consider testing for all three founder pathogenic variants because of the high population frequency of these variants as well as reports of the coexistence of more than one founder variant in some families. They may also consider multigene panel testing, depending on their personal and family history.
• Individuals with a familial
## Suggestive Findings
Breast cancer diagnosed at or before age 50 years
Ovarian cancer
Multiple (i.e., >1) primary breast cancers in either one or both breasts
Male breast cancer
Triple-negative (estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2-negative) breast cancer
The combination of pancreatic cancer and/or prostate cancer (metastatic or Gleason score ≥7) with breast cancer and/or ovarian cancer
Breast cancer diagnosed at any age in an individual of Ashkenazi Jewish ancestry
Two or more relatives with breast cancer, one diagnosed at or before age 50 years
Three or more relatives with breast cancer at any age
A family member with a known
Note: (1) "Breast cancer" includes both invasive cancer and ductal carcinoma in situ. (2) "Ovarian cancer" includes epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.
Several models have been developed to estimate the likelihood that an individual or family has a germline pathogenic variant in
• Breast cancer diagnosed at or before age 50 years
• Ovarian cancer
• Multiple (i.e., >1) primary breast cancers in either one or both breasts
• Male breast cancer
• Triple-negative (estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2-negative) breast cancer
• The combination of pancreatic cancer and/or prostate cancer (metastatic or Gleason score ≥7) with breast cancer and/or ovarian cancer
• Breast cancer diagnosed at any age in an individual of Ashkenazi Jewish ancestry
• Two or more relatives with breast cancer, one diagnosed at or before age 50 years
• Three or more relatives with breast cancer at any age
• A family member with a known
## Probability Models for
Several models have been developed to estimate the likelihood that an individual or family has a germline pathogenic variant in
## Establishing the Diagnosis
The diagnosis of
Note: (1) Molecular testing is most likely to be informative in an individual with a
Molecular testing approaches can include a
Targeted analysis can be considered in individuals of Ashkenazi Jewish ancestry by starting with targeted testing for three
Note: In a family known to have a
Individuals of Ashkenazi Jewish descent should consider testing for all three founder pathogenic variants because of the high population frequency of these variants as well as reports of the coexistence of more than one founder variant in some families. They may also consider multigene panel testing, depending on their personal and family history.
Individuals with a familial
A
For an introduction to multigene panels click
Molecular Genetic Testing Used in
HBOC = hereditary breast and ovarian cancer
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Targeted analysis can be considered in individuals of Ashkenazi Jewish ancestry by starting with targeted testing for three
• Note: In a family known to have a
• Individuals of Ashkenazi Jewish descent should consider testing for all three founder pathogenic variants because of the high population frequency of these variants as well as reports of the coexistence of more than one founder variant in some families. They may also consider multigene panel testing, depending on their personal and family history.
• Individuals with a familial
• Individuals of Ashkenazi Jewish descent should consider testing for all three founder pathogenic variants because of the high population frequency of these variants as well as reports of the coexistence of more than one founder variant in some families. They may also consider multigene panel testing, depending on their personal and family history.
• Individuals with a familial
• A
• For an introduction to multigene panels click
• Individuals of Ashkenazi Jewish descent should consider testing for all three founder pathogenic variants because of the high population frequency of these variants as well as reports of the coexistence of more than one founder variant in some families. They may also consider multigene panel testing, depending on their personal and family history.
• Individuals with a familial
## Clinical Characteristics
Risk of Malignancy in Individuals with a Germline
The histologic characteristics of
The evidence that a germline
Studies on ovarian cancer survival in women with a germline
No associated benign tumors or physical abnormalities are presently known to be associated with pathogenic variants in
Ovarian cancer and primary papillary serous carcinoma of the peritoneum are considerably more common and tend to develop at an earlier age in women with a germline
An ovarian cancer cluster region (OCCR) in or near exon 11 in both
In
The penetrance of breast, ovarian, and other cancers associated with pathogenic variants in
The prevalence of
Individuals of Ashkenazi Jewish descent: prevalence of 1:40 [
Inuit from Ammassalik (Greenland): prevalence of 1:10 to 1:100 [
Founder variants in
• Individuals of Ashkenazi Jewish descent: prevalence of 1:40 [
• Inuit from Ammassalik (Greenland): prevalence of 1:10 to 1:100 [
## Clinical Description
Risk of Malignancy in Individuals with a Germline
The histologic characteristics of
The evidence that a germline
Studies on ovarian cancer survival in women with a germline
No associated benign tumors or physical abnormalities are presently known to be associated with pathogenic variants in
## Phenotype Correlations by Gene
Ovarian cancer and primary papillary serous carcinoma of the peritoneum are considerably more common and tend to develop at an earlier age in women with a germline
## Genotype-Phenotype Correlations
An ovarian cancer cluster region (OCCR) in or near exon 11 in both
In
##
##
An ovarian cancer cluster region (OCCR) in or near exon 11 in both
In
## Penetrance
The penetrance of breast, ovarian, and other cancers associated with pathogenic variants in
## Prevalence
The prevalence of
Individuals of Ashkenazi Jewish descent: prevalence of 1:40 [
Inuit from Ammassalik (Greenland): prevalence of 1:10 to 1:100 [
Founder variants in
• Individuals of Ashkenazi Jewish descent: prevalence of 1:40 [
• Inuit from Ammassalik (Greenland): prevalence of 1:10 to 1:100 [
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Genes Associated with Cancer Susceptibility to Consider in the Differential Diagnosis of
AD = autosomal dominant; ER = estrogen receptor; GI = gastrointestinal; MOI = mode of inheritance; PR = progesterone receptor; SCTAT = sex cord tumor with annular tubules
NCCN Guidelines,
The
Note regarding
## Management
Individuals who have a germline pathogenic variant in
PARP inhibitors have emerged as a promising treatment in individuals with
Consider prophylactic bilateral mastectomy.
Given the conflicting data on the degree of risk reduction of breast cancer associated with prophylactic oophorectomy, consider discussing the risks and benefits of this approach with a genetics specialist.
Chemoprevention. In a retrospective study tamoxifen reduced the risk for breast cancer by 62% among healthy women with a
Note: Significant adverse consequences of tamoxifen treatment included higher rates of endometrial cancer and thromboembolic episodes (including pulmonary embolism) in those individuals who took the medication than in those who did not. Women with a history of thromboembolic disease or with a coagulation disorder should avoid taking tamoxifen. Women on tamoxifen should be counseled to report any abnormal vaginal bleeding immediately to their gynecologist.
Breast feeding for a cumulative total of more than one year reduced the risk for breast cancer [
Consider prophylactic salpingo-oophorectomy, recognizing that completion of childbearing may factor into this decision. A prospective cohort study of 2,482 women with
With the realization that the fallopian tube is frequently the site of serous ovarian cancer and its precursor lesions, a new paradigm of prophylactic salpingectomy after childbearing followed by delayed oophorectomy at the time of menopause has been suggested. While theoretically offering protection against ovarian cancer, this approach would also avoid the adverse consequences of premature menopause. Currently studies are under way to determine its feasibility, safety, and efficacy [
Tubal ligation. A meta-analysis of 13 studies showed a reduction in risk for ovarian cancer of 34% in the general population after tubal ligation [
A meta-analysis of 18 studies including 13,677 women with
Note: There is no evidence that use of current (after 1975) oral contraceptive formulations increases the risk for early-onset breast cancer for women with a germline
Recommended Surveillance for Women with
EUS = endoscopic ultrasound; MRCP = magnetic resonance cholangiopancreatography
For women who have not elected to undergo prophylactic bilateral salpingo-oophorectomy: while some clinicians conduct annual transvaginal ultrasound and/or CA-125 concentration, these modalities have not been effective in detecting early-stage ovarian cancer, either in high-risk or in average-risk women.
Recommended Surveillance for Men with
EUS = endoscopic ultrasound; MRCP = magnetic resonance cholangiopancreatography; PSA = prostate-specific antigen
Men with a
No data specific to individuals with
Once a cancer-predisposing
See
Several ongoing studies are investigating novel approaches to the treatment of
Several prospective and randomized clinical trials are investigating PARP inhibitor treatment of metastatic pancreatic cancer [
Studies to identify biomarkers of disease resistance and expected treatment toxicity are also under way [
Additional clinical trials are exploring the use of other PARP inhibitors alone or in combination with other systemic treatments.
Search
Three observational studies on the impact of HRT on breast cancer risk in
• Consider prophylactic bilateral mastectomy.
• Given the conflicting data on the degree of risk reduction of breast cancer associated with prophylactic oophorectomy, consider discussing the risks and benefits of this approach with a genetics specialist.
• Chemoprevention. In a retrospective study tamoxifen reduced the risk for breast cancer by 62% among healthy women with a
• Note: Significant adverse consequences of tamoxifen treatment included higher rates of endometrial cancer and thromboembolic episodes (including pulmonary embolism) in those individuals who took the medication than in those who did not. Women with a history of thromboembolic disease or with a coagulation disorder should avoid taking tamoxifen. Women on tamoxifen should be counseled to report any abnormal vaginal bleeding immediately to their gynecologist.
• Breast feeding for a cumulative total of more than one year reduced the risk for breast cancer [
• Consider prophylactic salpingo-oophorectomy, recognizing that completion of childbearing may factor into this decision. A prospective cohort study of 2,482 women with
• With the realization that the fallopian tube is frequently the site of serous ovarian cancer and its precursor lesions, a new paradigm of prophylactic salpingectomy after childbearing followed by delayed oophorectomy at the time of menopause has been suggested. While theoretically offering protection against ovarian cancer, this approach would also avoid the adverse consequences of premature menopause. Currently studies are under way to determine its feasibility, safety, and efficacy [
• Tubal ligation. A meta-analysis of 13 studies showed a reduction in risk for ovarian cancer of 34% in the general population after tubal ligation [
• A meta-analysis of 18 studies including 13,677 women with
• Note: There is no evidence that use of current (after 1975) oral contraceptive formulations increases the risk for early-onset breast cancer for women with a germline
## Evaluations Following Initial Diagnosis
Individuals who have a germline pathogenic variant in
## Treatment of Manifestations
PARP inhibitors have emerged as a promising treatment in individuals with
## Prevention of Primary Manifestations
Consider prophylactic bilateral mastectomy.
Given the conflicting data on the degree of risk reduction of breast cancer associated with prophylactic oophorectomy, consider discussing the risks and benefits of this approach with a genetics specialist.
Chemoprevention. In a retrospective study tamoxifen reduced the risk for breast cancer by 62% among healthy women with a
Note: Significant adverse consequences of tamoxifen treatment included higher rates of endometrial cancer and thromboembolic episodes (including pulmonary embolism) in those individuals who took the medication than in those who did not. Women with a history of thromboembolic disease or with a coagulation disorder should avoid taking tamoxifen. Women on tamoxifen should be counseled to report any abnormal vaginal bleeding immediately to their gynecologist.
Breast feeding for a cumulative total of more than one year reduced the risk for breast cancer [
Consider prophylactic salpingo-oophorectomy, recognizing that completion of childbearing may factor into this decision. A prospective cohort study of 2,482 women with
With the realization that the fallopian tube is frequently the site of serous ovarian cancer and its precursor lesions, a new paradigm of prophylactic salpingectomy after childbearing followed by delayed oophorectomy at the time of menopause has been suggested. While theoretically offering protection against ovarian cancer, this approach would also avoid the adverse consequences of premature menopause. Currently studies are under way to determine its feasibility, safety, and efficacy [
Tubal ligation. A meta-analysis of 13 studies showed a reduction in risk for ovarian cancer of 34% in the general population after tubal ligation [
A meta-analysis of 18 studies including 13,677 women with
Note: There is no evidence that use of current (after 1975) oral contraceptive formulations increases the risk for early-onset breast cancer for women with a germline
• Consider prophylactic bilateral mastectomy.
• Given the conflicting data on the degree of risk reduction of breast cancer associated with prophylactic oophorectomy, consider discussing the risks and benefits of this approach with a genetics specialist.
• Chemoprevention. In a retrospective study tamoxifen reduced the risk for breast cancer by 62% among healthy women with a
• Note: Significant adverse consequences of tamoxifen treatment included higher rates of endometrial cancer and thromboembolic episodes (including pulmonary embolism) in those individuals who took the medication than in those who did not. Women with a history of thromboembolic disease or with a coagulation disorder should avoid taking tamoxifen. Women on tamoxifen should be counseled to report any abnormal vaginal bleeding immediately to their gynecologist.
• Breast feeding for a cumulative total of more than one year reduced the risk for breast cancer [
• Consider prophylactic salpingo-oophorectomy, recognizing that completion of childbearing may factor into this decision. A prospective cohort study of 2,482 women with
• With the realization that the fallopian tube is frequently the site of serous ovarian cancer and its precursor lesions, a new paradigm of prophylactic salpingectomy after childbearing followed by delayed oophorectomy at the time of menopause has been suggested. While theoretically offering protection against ovarian cancer, this approach would also avoid the adverse consequences of premature menopause. Currently studies are under way to determine its feasibility, safety, and efficacy [
• Tubal ligation. A meta-analysis of 13 studies showed a reduction in risk for ovarian cancer of 34% in the general population after tubal ligation [
• A meta-analysis of 18 studies including 13,677 women with
• Note: There is no evidence that use of current (after 1975) oral contraceptive formulations increases the risk for early-onset breast cancer for women with a germline
## Surveillance
Recommended Surveillance for Women with
EUS = endoscopic ultrasound; MRCP = magnetic resonance cholangiopancreatography
For women who have not elected to undergo prophylactic bilateral salpingo-oophorectomy: while some clinicians conduct annual transvaginal ultrasound and/or CA-125 concentration, these modalities have not been effective in detecting early-stage ovarian cancer, either in high-risk or in average-risk women.
Recommended Surveillance for Men with
EUS = endoscopic ultrasound; MRCP = magnetic resonance cholangiopancreatography; PSA = prostate-specific antigen
Men with a
## Agents/Circumstances to Avoid
No data specific to individuals with
## Evaluation of Relatives at Risk
Once a cancer-predisposing
See
## Therapies Under Investigation
Several ongoing studies are investigating novel approaches to the treatment of
Several prospective and randomized clinical trials are investigating PARP inhibitor treatment of metastatic pancreatic cancer [
Studies to identify biomarkers of disease resistance and expected treatment toxicity are also under way [
Additional clinical trials are exploring the use of other PARP inhibitors alone or in combination with other systemic treatments.
Search
## Other
Three observational studies on the impact of HRT on breast cancer risk in
## Genetic Counseling
The vast majority of individuals with a germline pathogenic variant in
Penetrance of the variant
Sex of the parent
Age of the parent
Cancer risk reduction in the parent as a result of screening or prophylactic surgeries
Early death of the parent
It is appropriate to offer molecular genetic testing to both parents of an individual with a
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the
If one parent has the
The risk of developing cancer in a sib who inherits the familial
The offspring of an individual identified as having a
The risk of developing cancer in offspring who inherit the
See Management,
The optimal time for the determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
At-risk adult relatives who have not inherited the cancer-predisposing germline variant identified in the proband are presumed to be at or above the general population risk of developing cancer, depending on personal risk factors. For example, a female at-risk relative who does not have the family-specific
For family members determined to be at general population risk of developing cancer, appropriate cancer screening such as that recommended by the
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The vast majority of individuals with a germline pathogenic variant in
• Penetrance of the variant
• Sex of the parent
• Age of the parent
• Cancer risk reduction in the parent as a result of screening or prophylactic surgeries
• Early death of the parent
• Penetrance of the variant
• Sex of the parent
• Age of the parent
• Cancer risk reduction in the parent as a result of screening or prophylactic surgeries
• Early death of the parent
• It is appropriate to offer molecular genetic testing to both parents of an individual with a
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the
• Penetrance of the variant
• Sex of the parent
• Age of the parent
• Cancer risk reduction in the parent as a result of screening or prophylactic surgeries
• Early death of the parent
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• If one parent has the
• The risk of developing cancer in a sib who inherits the familial
• The offspring of an individual identified as having a
• The risk of developing cancer in offspring who inherit the
• The optimal time for the determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
## Risk to Family Members
The vast majority of individuals with a germline pathogenic variant in
Penetrance of the variant
Sex of the parent
Age of the parent
Cancer risk reduction in the parent as a result of screening or prophylactic surgeries
Early death of the parent
It is appropriate to offer molecular genetic testing to both parents of an individual with a
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the
If one parent has the
The risk of developing cancer in a sib who inherits the familial
The offspring of an individual identified as having a
The risk of developing cancer in offspring who inherit the
• The vast majority of individuals with a germline pathogenic variant in
• Penetrance of the variant
• Sex of the parent
• Age of the parent
• Cancer risk reduction in the parent as a result of screening or prophylactic surgeries
• Early death of the parent
• Penetrance of the variant
• Sex of the parent
• Age of the parent
• Cancer risk reduction in the parent as a result of screening or prophylactic surgeries
• Early death of the parent
• It is appropriate to offer molecular genetic testing to both parents of an individual with a
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the
• Penetrance of the variant
• Sex of the parent
• Age of the parent
• Cancer risk reduction in the parent as a result of screening or prophylactic surgeries
• Early death of the parent
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• If one parent has the
• The risk of developing cancer in a sib who inherits the familial
• The offspring of an individual identified as having a
• The risk of developing cancer in offspring who inherit the
## Related Genetic Counseling Issues
See Management,
The optimal time for the determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
At-risk adult relatives who have not inherited the cancer-predisposing germline variant identified in the proband are presumed to be at or above the general population risk of developing cancer, depending on personal risk factors. For example, a female at-risk relative who does not have the family-specific
For family members determined to be at general population risk of developing cancer, appropriate cancer screening such as that recommended by the
• The optimal time for the determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
National Human Genome Research Institute (NHGRI)
670 North Clark Street
Suite 2
Chicago IL 60654
48 Wall Street
11th Floor
New York NY 10005
6116 Executive Boulevard
Suite 300
Bethesda MD 20892-8322
2501 Oak Lawn Avenue
Suite 435
Dallas TX 75219
National Breast Cancer Coalition
National Cancer Institute Public Inquiries Office
6116 Executive Boulevard
Suite 300
Bethesda MD 20892-8322
Facing Hereditary Cancer Empowered
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo NY 14263
•
•
• National Human Genome Research Institute (NHGRI)
•
•
• 670 North Clark Street
• Suite 2
• Chicago IL 60654
•
•
• 48 Wall Street
• 11th Floor
• New York NY 10005
•
•
•
•
• 6116 Executive Boulevard
• Suite 300
• Bethesda MD 20892-8322
•
•
• 2501 Oak Lawn Avenue
• Suite 435
• Dallas TX 75219
•
•
• National Breast Cancer Coalition
•
•
•
•
• National Cancer Institute Public Inquiries Office
• 6116 Executive Boulevard
• Suite 300
• Bethesda MD 20892-8322
•
•
•
•
•
•
•
•
•
•
•
• Facing Hereditary Cancer Empowered
•
•
•
•
•
•
• Roswell Park Cancer Institute
• Elm and Carlton Streets
• Buffalo NY 14263
•
## Molecular Genetics
BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer (
The BRCA1/BARD1 protein complex enhances ubiquitin ligase activity, which is associated with the regulation of centrosome function and involved in DNA repair and cell cycle regulation [
BRCA1 colocalizes with BRCA2 and RAD51 at sites of DNA damage and activates RAD51-mediated homologous recombination repair of DNA double-strand breaks [
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
See
## Molecular Pathogenesis
The BRCA1/BARD1 protein complex enhances ubiquitin ligase activity, which is associated with the regulation of centrosome function and involved in DNA repair and cell cycle regulation [
BRCA1 colocalizes with BRCA2 and RAD51 at sites of DNA damage and activates RAD51-mediated homologous recombination repair of DNA double-strand breaks [
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
See
## Chapter Notes
Julie O Bars Culver, MS; Fred Hutchinson Cancer Research Center (1998-2011) Wylie Burke, MD, PhD; University of Washington (1998-2005) Mary B Daly, MD, PhD (1998-present) Gerald L Feldman, MD, PhD; Wayne State University School of Medicine (2002-2016) Judith L Hull, MS; Memorial Sloan-Kettering Cancer Center (1998-2005) Ephrat Levy-Lahad, MD; Sharre Zedek Medical Center (1998-2007) Tuya Pal, MD (2016-present)Nancie Petrucelli, MS (2002-present)
20 March 2025 (np,sw) Revision: surveillance recommendations for prostate cancer; prevalence
21 September 2023 (np,sw) Revision: cancer risk in individuals who are heterozygous for a pathogenic variant in
26 May 2022 (mbd,tp) Revision: recommended surveillance for ovarian and pancreatic cancer (
3 February 2022 (sw) Comprehensive update posted live
15 December 2016 (sw) Comprehensive update posted live
26 September 2013 (me) Comprehensive update posted live
20 January 2011 (me) Comprehensive update posted live
19 June 2007 (me) Comprehensive update posted live
29 March 2004 (ca) Comprehensive update posted live
4 March 2000 (me) Comprehensive update posted live
4 September 1998 (pb) Review posted live
January 1998 (jbc) Original submission
• 20 March 2025 (np,sw) Revision: surveillance recommendations for prostate cancer; prevalence
• 21 September 2023 (np,sw) Revision: cancer risk in individuals who are heterozygous for a pathogenic variant in
• 26 May 2022 (mbd,tp) Revision: recommended surveillance for ovarian and pancreatic cancer (
• 3 February 2022 (sw) Comprehensive update posted live
• 15 December 2016 (sw) Comprehensive update posted live
• 26 September 2013 (me) Comprehensive update posted live
• 20 January 2011 (me) Comprehensive update posted live
• 19 June 2007 (me) Comprehensive update posted live
• 29 March 2004 (ca) Comprehensive update posted live
• 4 March 2000 (me) Comprehensive update posted live
• 4 September 1998 (pb) Review posted live
• January 1998 (jbc) Original submission
## Author History
Julie O Bars Culver, MS; Fred Hutchinson Cancer Research Center (1998-2011) Wylie Burke, MD, PhD; University of Washington (1998-2005) Mary B Daly, MD, PhD (1998-present) Gerald L Feldman, MD, PhD; Wayne State University School of Medicine (2002-2016) Judith L Hull, MS; Memorial Sloan-Kettering Cancer Center (1998-2005) Ephrat Levy-Lahad, MD; Sharre Zedek Medical Center (1998-2007) Tuya Pal, MD (2016-present)Nancie Petrucelli, MS (2002-present)
## Revision History
20 March 2025 (np,sw) Revision: surveillance recommendations for prostate cancer; prevalence
21 September 2023 (np,sw) Revision: cancer risk in individuals who are heterozygous for a pathogenic variant in
26 May 2022 (mbd,tp) Revision: recommended surveillance for ovarian and pancreatic cancer (
3 February 2022 (sw) Comprehensive update posted live
15 December 2016 (sw) Comprehensive update posted live
26 September 2013 (me) Comprehensive update posted live
20 January 2011 (me) Comprehensive update posted live
19 June 2007 (me) Comprehensive update posted live
29 March 2004 (ca) Comprehensive update posted live
4 March 2000 (me) Comprehensive update posted live
4 September 1998 (pb) Review posted live
January 1998 (jbc) Original submission
• 20 March 2025 (np,sw) Revision: surveillance recommendations for prostate cancer; prevalence
• 21 September 2023 (np,sw) Revision: cancer risk in individuals who are heterozygous for a pathogenic variant in
• 26 May 2022 (mbd,tp) Revision: recommended surveillance for ovarian and pancreatic cancer (
• 3 February 2022 (sw) Comprehensive update posted live
• 15 December 2016 (sw) Comprehensive update posted live
• 26 September 2013 (me) Comprehensive update posted live
• 20 January 2011 (me) Comprehensive update posted live
• 19 June 2007 (me) Comprehensive update posted live
• 29 March 2004 (ca) Comprehensive update posted live
• 4 March 2000 (me) Comprehensive update posted live
• 4 September 1998 (pb) Review posted live
• January 1998 (jbc) Original submission
## References
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Cancer. Available
Robson ME, Bradbury AR, Arun B, Domchek SM, Ford JM, Hampel HL, Lipkin SM, Syngal S, Wollins DS, Lindor NM. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2015;33:3660-7. [
• National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Cancer. Available
• Robson ME, Bradbury AR, Arun B, Domchek SM, Ford JM, Hampel HL, Lipkin SM, Syngal S, Wollins DS, Lindor NM. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2015;33:3660-7. [
## Published Guidelines / Consensus Statements
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Cancer. Available
Robson ME, Bradbury AR, Arun B, Domchek SM, Ford JM, Hampel HL, Lipkin SM, Syngal S, Wollins DS, Lindor NM. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2015;33:3660-7. [
• National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Cancer. Available
• Robson ME, Bradbury AR, Arun B, Domchek SM, Ford JM, Hampel HL, Lipkin SM, Syngal S, Wollins DS, Lindor NM. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2015;33:3660-7. [
## Literature Cited
|
[] |
4/9/1998
|
3/2/2022
|
20/3/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
brugada
|
brugada
|
[
"Sudden Unexpected Nocturnal Death Syndrome",
"Sudden Unexpected Nocturnal Death Syndrome",
"ATP-binding cassette sub-family C member 9",
"ATP-sensitive inward rectifier potassium channel 8",
"A-type voltage-gated potassium channel KCND2",
"A-type voltage-gated potassium channel KCND3",
"Fibroblast growth factor 12",
"Glycerol-3-phosphate dehydrogenase 1-like protein",
"Plakophilin-2",
"Potassium voltage-gated channel subfamily E member 2",
"Potassium voltage-gated channel subfamily E member 3",
"Potassium voltage-gated channel subfamily E regulatory beta subunit 5",
"Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4",
"Ran guanine nucleotide release factor",
"Sarcolemmal membrane-associated protein",
"Semaphorin-3A",
"Sodium channel protein type 10 subunit alpha",
"Sodium channel protein type 5 subunit alpha",
"Sodium channel regulatory subunit beta-1",
"Sodium channel regulatory subunit beta-2",
"Sodium channel regulatory subunit beta-3",
"Transient receptor potential cation channel subfamily M member 4",
"Voltage-dependent calcium channel subunit alpha-2/delta-1",
"Voltage-dependent L-type calcium channel subunit alpha-1C",
"Voltage-dependent L-type calcium channel subunit beta-2",
"Voltage-gated inwardly rectifying potassium channel KCNH2",
"ABCC9",
"CACNA1C",
"CACNA2D1",
"CACNB2",
"FGF12",
"GPD1L",
"HCN4",
"KCND2",
"KCND3",
"KCNE2",
"KCNE3",
"KCNE5",
"KCNH2",
"KCNJ8",
"PKP2",
"RANGRF",
"SCN10A",
"SCN1B",
"SCN2B",
"SCN3B",
"SCN5A",
"SEMA3A",
"SLMAP",
"TRPM4",
"Brugada Syndrome"
] |
Brugada Syndrome
|
Ramon Brugada, Oscar Campuzano, Georgia Sarquella-Brugada, Pedro Brugada, Josep Brugada, Kui Hong
|
Summary Brugada syndrome is characterized by cardiac conduction abnormalities (ST segment abnormalities in leads V The diagnosis of Brugada syndrome is established clinically in an individual with characteristic EKG findings and suggestive clinical history and/or family history. A molecular diagnosis can be established in an individual with characteristic features and identification of a heterozygous pathogenic variant in In most instances Brugada syndrome is inherited in an autosomal dominant manner; the exception is
|
## Diagnosis
Brugada syndrome is a channelopathy, caused by genetic changes in transmembrane ion channels that create action potentials, in this case leading to an increased risk of cardiac arrhythmia [
Brugada syndrome
Recurrent syncope
Ventricular fibrillation
Self-terminating polymorphic ventricular tachycardia
Cardiac arrest
Family history of sudden cardiac death
* No other factor(s) should account for the EKG abnormality.
The clinical diagnosis of Brugada syndrome can be
Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
The clinical diagnosis of Brugada syndrome can be
* No other factor(s) should account for the EKG abnormality.
Documented ventricular fibrillation
Self-terminating polymorphic ventricular tachycardia
A family history of sudden cardiac death
Coved-type EKGs in family members
Electrophysiologic inducibility
Syncope or nocturnal agonal respiration
Note: In approximately 75% of persons affected by Brugada syndrome the diagnosis is established based on clinical history and EKG results. Molecular genetic testing confirms the diagnosis and may complement clinical testing [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Brugada Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Recurrent syncope
• Ventricular fibrillation
• Self-terminating polymorphic ventricular tachycardia
• Cardiac arrest
• Family history of sudden cardiac death
• * No other factor(s) should account for the EKG abnormality.
• * No other factor(s) should account for the EKG abnormality.
• Documented ventricular fibrillation
• Self-terminating polymorphic ventricular tachycardia
• A family history of sudden cardiac death
• Coved-type EKGs in family members
• Electrophysiologic inducibility
• Syncope or nocturnal agonal respiration
• Documented ventricular fibrillation
• Self-terminating polymorphic ventricular tachycardia
• A family history of sudden cardiac death
• Coved-type EKGs in family members
• Electrophysiologic inducibility
• Syncope or nocturnal agonal respiration
• Documented ventricular fibrillation
• Self-terminating polymorphic ventricular tachycardia
• A family history of sudden cardiac death
• Coved-type EKGs in family members
• Electrophysiologic inducibility
• Syncope or nocturnal agonal respiration
## Suggestive Findings
Brugada syndrome
Recurrent syncope
Ventricular fibrillation
Self-terminating polymorphic ventricular tachycardia
Cardiac arrest
Family history of sudden cardiac death
* No other factor(s) should account for the EKG abnormality.
• Recurrent syncope
• Ventricular fibrillation
• Self-terminating polymorphic ventricular tachycardia
• Cardiac arrest
• Family history of sudden cardiac death
• * No other factor(s) should account for the EKG abnormality.
## Establishing the Diagnosis
The clinical diagnosis of Brugada syndrome can be
Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
The clinical diagnosis of Brugada syndrome can be
* No other factor(s) should account for the EKG abnormality.
Documented ventricular fibrillation
Self-terminating polymorphic ventricular tachycardia
A family history of sudden cardiac death
Coved-type EKGs in family members
Electrophysiologic inducibility
Syncope or nocturnal agonal respiration
Note: In approximately 75% of persons affected by Brugada syndrome the diagnosis is established based on clinical history and EKG results. Molecular genetic testing confirms the diagnosis and may complement clinical testing [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Brugada Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• * No other factor(s) should account for the EKG abnormality.
• Documented ventricular fibrillation
• Self-terminating polymorphic ventricular tachycardia
• A family history of sudden cardiac death
• Coved-type EKGs in family members
• Electrophysiologic inducibility
• Syncope or nocturnal agonal respiration
• Documented ventricular fibrillation
• Self-terminating polymorphic ventricular tachycardia
• A family history of sudden cardiac death
• Coved-type EKGs in family members
• Electrophysiologic inducibility
• Syncope or nocturnal agonal respiration
• Documented ventricular fibrillation
• Self-terminating polymorphic ventricular tachycardia
• A family history of sudden cardiac death
• Coved-type EKGs in family members
• Electrophysiologic inducibility
• Syncope or nocturnal agonal respiration
## Clinical Diagnosis
The clinical diagnosis of Brugada syndrome can be
* No other factor(s) should account for the EKG abnormality.
Documented ventricular fibrillation
Self-terminating polymorphic ventricular tachycardia
A family history of sudden cardiac death
Coved-type EKGs in family members
Electrophysiologic inducibility
Syncope or nocturnal agonal respiration
Note: In approximately 75% of persons affected by Brugada syndrome the diagnosis is established based on clinical history and EKG results. Molecular genetic testing confirms the diagnosis and may complement clinical testing [
• * No other factor(s) should account for the EKG abnormality.
• Documented ventricular fibrillation
• Self-terminating polymorphic ventricular tachycardia
• A family history of sudden cardiac death
• Coved-type EKGs in family members
• Electrophysiologic inducibility
• Syncope or nocturnal agonal respiration
• Documented ventricular fibrillation
• Self-terminating polymorphic ventricular tachycardia
• A family history of sudden cardiac death
• Coved-type EKGs in family members
• Electrophysiologic inducibility
• Syncope or nocturnal agonal respiration
• Documented ventricular fibrillation
• Self-terminating polymorphic ventricular tachycardia
• A family history of sudden cardiac death
• Coved-type EKGs in family members
• Electrophysiologic inducibility
• Syncope or nocturnal agonal respiration
## Molecular Genetic Testing
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Brugada Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
Affected individuals in whom sustained ventricular arrhythmias are easily induced and who have a spontaneously abnormal EKG have a 45% likelihood of having an arrhythmic event at any time during life [
Brugada syndrome can occur in conjunction with conduction disease. The presence of first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome in Brugada syndrome is not unusual [
Clinical presentations of Brugada syndrome may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) [
Sodium channelopathies exhibited typical Brugada-type EKG and frequent arrhythmogenesis during bradycardia [
Few studies have investigated genotype-phenotype correlations [
In general, the
By restoring (at least partially) sodium current defects, the common
Brugada syndrome occurs worldwide. The prevalence of the disease in endemic areas (South Asia) is on the order of 1:2,000 persons. In countries in Southeast Asia in which SUNDS is endemic, it is the second leading cause of death (following accidents) of men under age 40 years.
Data from published studies indicate that Brugada syndrome is responsible for 4%-12% of unexpected sudden deaths and for up to 20% of all sudden death in individuals with an apparently normal heart [
A prospective study of an adult Japanese population (22,027 individuals) showed 12 individuals (prevalence of 0.05%) with EKGs compatible with Brugada syndrome [
• In general, the
• By restoring (at least partially) sodium current defects, the common
## Clinical Description
Affected individuals in whom sustained ventricular arrhythmias are easily induced and who have a spontaneously abnormal EKG have a 45% likelihood of having an arrhythmic event at any time during life [
Brugada syndrome can occur in conjunction with conduction disease. The presence of first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome in Brugada syndrome is not unusual [
Clinical presentations of Brugada syndrome may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) [
Sodium channelopathies exhibited typical Brugada-type EKG and frequent arrhythmogenesis during bradycardia [
## Phenotype Correlations by Gene
## Genotype-Phenotype Correlations
Few studies have investigated genotype-phenotype correlations [
In general, the
By restoring (at least partially) sodium current defects, the common
• In general, the
• By restoring (at least partially) sodium current defects, the common
## Penetrance
## Nomenclature
## Prevalence
Brugada syndrome occurs worldwide. The prevalence of the disease in endemic areas (South Asia) is on the order of 1:2,000 persons. In countries in Southeast Asia in which SUNDS is endemic, it is the second leading cause of death (following accidents) of men under age 40 years.
Data from published studies indicate that Brugada syndrome is responsible for 4%-12% of unexpected sudden deaths and for up to 20% of all sudden death in individuals with an apparently normal heart [
A prospective study of an adult Japanese population (22,027 individuals) showed 12 individuals (prevalence of 0.05%) with EKGs compatible with Brugada syndrome [
## Genetically Related (Allelic) Disorders
Disorders known to be caused by germline pathogenic variants in Brugada syndrome-related genes are summarized in
Note: Data on genetic modifiers (e.g., susceptibility loci / polymorphisms identified through genome-wide association studies) in Brugada syndrome-related genes that may contribute in small ways to risk of a given phenotype are not included in
Disorders Caused by Germline Pathogenic Variants in Brugada Syndrome-Related Genes
## Differential Diagnosis
Brugada syndrome should always be considered in the differential diagnosis of the following:
Other conditions that can be associated with ST segment elevation in right precordial leads include the following (adapted from
Right or left bundle branch block, left ventricular hypertrophy
Acute myocardial ischemia or infarction
Acute myocarditis
Hypothermia, causing Osborn wave in EKGs and sometimes resembling Brugada syndrome
Right ventricular ischemia or infarction
Dissecting aortic aneurysm
Acute pulmonary thromboemboli
Various central and autonomic nervous system abnormalities
Heterocyclic antidepressant overdose
Thiamine deficiency
Hypercalcemia
Hyperkalemia
Cocaine intoxication
Mediastinal tumor compressing the right ventricular outflow tract
Early repolarization syndrome
Other normal variants (particularly in males)
Most of the above conditions can give rise to a type 1 EKG, whereas ARVC and Brugada syndrome can both give rise to type 2 and type 3 EKGs. Therefore, it is important to distinguish between these two disorders.
• Right or left bundle branch block, left ventricular hypertrophy
• Acute myocardial ischemia or infarction
• Acute myocarditis
• Hypothermia, causing Osborn wave in EKGs and sometimes resembling Brugada syndrome
• Right ventricular ischemia or infarction
• Dissecting aortic aneurysm
• Acute pulmonary thromboemboli
• Various central and autonomic nervous system abnormalities
• Heterocyclic antidepressant overdose
•
•
• Thiamine deficiency
• Hypercalcemia
• Hyperkalemia
• Cocaine intoxication
• Mediastinal tumor compressing the right ventricular outflow tract
•
• Early repolarization syndrome
• Other normal variants (particularly in males)
## Management
To establish the extent of disease and needs in an individual diagnosed with Brugada syndrome, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Electrocardiogram (EKG)
Induction with sodium blockers (ajmaline, procainamide, pilsicainide, flecainide) in persons with a type 2 EKG or type 3 EKG and suspicion of the disease
Electrophysiologic study to assess risk of sudden cardiac death. Although the data are controversial, no other risk stratification parameter is presently available for asymptomatic individuals [
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of Brugada syndrome to facilitate medical and personal decision making
Brugada syndrome is characterized by the presence of ST segment elevation in leads V
Electrical storms respond well to infusion of isoproterenol (1-3 µg/min), the first line of therapy before other antiarrhythmics [
It is important to:
Eliminate/treat
AND
Hospitalize the patient at least until the EKG pattern has normalized.
Controversy exists regarding the treatment of asymptomatic individuals. Recommendations vary [
Observation until the first symptom develops (Note: The first symptom can also be sudden cardiac death.)
Placement of an ICD if the family history is positive for sudden cardiac death
Use of electrophysiologic study (EPS) to identify those most likely to experience arrhythmias and thus benefit the most from placement of an ICD
During surgery and in the postsurgical recovery period persons with Brugada syndrome should be monitored by EKG.
Quinidine (1-2 g daily) has been shown to restore ST segment elevation and decrease the incidence of arrhythmias [
At-risk individuals with a family history of Brugada syndrome or a known pathogenic variant should undergo EKG monitoring every one to two years beginning at birth [
The following can unmask the Brugada syndrome EKG [
Febrile state
Vagotonic agents
Alpha-adrenergic agonists [
Beta-adrenergic antagonists
Tricyclic antidepressants
First-generation antihistamines (dimenhydrinate)
Cocaine toxicity
The following should be avoided [
Class 1C antiarrhythmic drugs including flecainide and propafenone
Class 1A agents including procainamide and disopyramide
If the Brugada syndrome-related pathogenic variant has been identified in an affected family member, molecular genetic testing of at-risk relatives (including children) is appropriate because:
EKG changes have low sensitivity in establishing the diagnosis [
Identification of individuals at risk allows preventive measures such as fever control and avoidance of medications that can induce ventricular arrhythmias;
Cardiac surveillance can be limited to family members who have the familial Brugada syndrome-related pathogenic variant [
Individuals with a known pathogenic variant should undergo EKG monitoring every one to two years beginning at birth (see
If the pathogenic variant has not been identified in the family, relatives should undergo EKG monitoring every one to two years beginning at birth (see
See
Hormonal changes during pregnancy can precipitate arrhythmic events in women with Brugada syndrome. Recurrent ventricular tachyarrhythmia can be inhibited, and the electrocardiographic pattern can normalize following IV infusion of low-dose isoproterenol followed by oral quinidine [
Quinidine is not known to be teratogenic to the developing fetus and is a preferred drug to treat arrhythmia in pregnancy. See
Search
• Electrocardiogram (EKG)
• Induction with sodium blockers (ajmaline, procainamide, pilsicainide, flecainide) in persons with a type 2 EKG or type 3 EKG and suspicion of the disease
• Electrophysiologic study to assess risk of sudden cardiac death. Although the data are controversial, no other risk stratification parameter is presently available for asymptomatic individuals [
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of Brugada syndrome to facilitate medical and personal decision making
• Eliminate/treat
• AND
• Hospitalize the patient at least until the EKG pattern has normalized.
• Observation until the first symptom develops (Note: The first symptom can also be sudden cardiac death.)
• Placement of an ICD if the family history is positive for sudden cardiac death
• Use of electrophysiologic study (EPS) to identify those most likely to experience arrhythmias and thus benefit the most from placement of an ICD
• Febrile state
• Vagotonic agents
• Alpha-adrenergic agonists [
• Beta-adrenergic antagonists
• Tricyclic antidepressants
• First-generation antihistamines (dimenhydrinate)
• Cocaine toxicity
• Class 1C antiarrhythmic drugs including flecainide and propafenone
• Class 1A agents including procainamide and disopyramide
• EKG changes have low sensitivity in establishing the diagnosis [
• Identification of individuals at risk allows preventive measures such as fever control and avoidance of medications that can induce ventricular arrhythmias;
• Cardiac surveillance can be limited to family members who have the familial Brugada syndrome-related pathogenic variant [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Brugada syndrome, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Electrocardiogram (EKG)
Induction with sodium blockers (ajmaline, procainamide, pilsicainide, flecainide) in persons with a type 2 EKG or type 3 EKG and suspicion of the disease
Electrophysiologic study to assess risk of sudden cardiac death. Although the data are controversial, no other risk stratification parameter is presently available for asymptomatic individuals [
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of Brugada syndrome to facilitate medical and personal decision making
• Electrocardiogram (EKG)
• Induction with sodium blockers (ajmaline, procainamide, pilsicainide, flecainide) in persons with a type 2 EKG or type 3 EKG and suspicion of the disease
• Electrophysiologic study to assess risk of sudden cardiac death. Although the data are controversial, no other risk stratification parameter is presently available for asymptomatic individuals [
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of Brugada syndrome to facilitate medical and personal decision making
## Treatment of Manifestations
Brugada syndrome is characterized by the presence of ST segment elevation in leads V
Electrical storms respond well to infusion of isoproterenol (1-3 µg/min), the first line of therapy before other antiarrhythmics [
It is important to:
Eliminate/treat
AND
Hospitalize the patient at least until the EKG pattern has normalized.
Controversy exists regarding the treatment of asymptomatic individuals. Recommendations vary [
Observation until the first symptom develops (Note: The first symptom can also be sudden cardiac death.)
Placement of an ICD if the family history is positive for sudden cardiac death
Use of electrophysiologic study (EPS) to identify those most likely to experience arrhythmias and thus benefit the most from placement of an ICD
During surgery and in the postsurgical recovery period persons with Brugada syndrome should be monitored by EKG.
• Eliminate/treat
• AND
• Hospitalize the patient at least until the EKG pattern has normalized.
• Observation until the first symptom develops (Note: The first symptom can also be sudden cardiac death.)
• Placement of an ICD if the family history is positive for sudden cardiac death
• Use of electrophysiologic study (EPS) to identify those most likely to experience arrhythmias and thus benefit the most from placement of an ICD
## Prevention of Primary Manifestations
Quinidine (1-2 g daily) has been shown to restore ST segment elevation and decrease the incidence of arrhythmias [
## Surveillance
At-risk individuals with a family history of Brugada syndrome or a known pathogenic variant should undergo EKG monitoring every one to two years beginning at birth [
## Agents/Circumstances to Avoid
The following can unmask the Brugada syndrome EKG [
Febrile state
Vagotonic agents
Alpha-adrenergic agonists [
Beta-adrenergic antagonists
Tricyclic antidepressants
First-generation antihistamines (dimenhydrinate)
Cocaine toxicity
The following should be avoided [
Class 1C antiarrhythmic drugs including flecainide and propafenone
Class 1A agents including procainamide and disopyramide
• Febrile state
• Vagotonic agents
• Alpha-adrenergic agonists [
• Beta-adrenergic antagonists
• Tricyclic antidepressants
• First-generation antihistamines (dimenhydrinate)
• Cocaine toxicity
• Class 1C antiarrhythmic drugs including flecainide and propafenone
• Class 1A agents including procainamide and disopyramide
## Evaluation of Relatives at Risk
If the Brugada syndrome-related pathogenic variant has been identified in an affected family member, molecular genetic testing of at-risk relatives (including children) is appropriate because:
EKG changes have low sensitivity in establishing the diagnosis [
Identification of individuals at risk allows preventive measures such as fever control and avoidance of medications that can induce ventricular arrhythmias;
Cardiac surveillance can be limited to family members who have the familial Brugada syndrome-related pathogenic variant [
Individuals with a known pathogenic variant should undergo EKG monitoring every one to two years beginning at birth (see
If the pathogenic variant has not been identified in the family, relatives should undergo EKG monitoring every one to two years beginning at birth (see
See
• EKG changes have low sensitivity in establishing the diagnosis [
• Identification of individuals at risk allows preventive measures such as fever control and avoidance of medications that can induce ventricular arrhythmias;
• Cardiac surveillance can be limited to family members who have the familial Brugada syndrome-related pathogenic variant [
## Pregnancy Management
Hormonal changes during pregnancy can precipitate arrhythmic events in women with Brugada syndrome. Recurrent ventricular tachyarrhythmia can be inhibited, and the electrocardiographic pattern can normalize following IV infusion of low-dose isoproterenol followed by oral quinidine [
Quinidine is not known to be teratogenic to the developing fetus and is a preferred drug to treat arrhythmia in pregnancy. See
## Therapies Under Investigation
Search
## Genetic Counseling
Brugada syndrome is inherited in an autosomal dominant manner with the exception of one family with Brugada syndrome associated with a pathogenic variant in
Most individuals diagnosed with Brugada syndrome have an affected parent or another affected close relative.
A proband with Brugada syndrome may have the disorder as the result of a
If a diagnosis of Brugada syndrome has not already been established in the mother or the father of the proband, recommendations for the evaluation of parents of a proband include electrocardiographic analysis, attention to a family history of sudden death, and (if the pathogenic variant in the proband has been identified) molecular genetic testing.
If the proband has a known pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
Although most individuals diagnosed with Brugada syndrome have inherited the pathogenic variant from a parent, the family history may appear to be negative because of failure to recognize the disorder in family members, incomplete penetrance, early death of the parent before the onset of symptoms, or late onset of the symptoms in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless the proband has a known Brugada syndrome-related pathogenic variant that is not identified in either parent.
If a parent of the proband is affected, or unaffected but known to be heterozygous for the pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
The risk that a sib will inherit the familial pathogenic variant and develop Brugada syndrome may be less than 50% because of reduced penetrance and the possibility of other genetic and environmental factors (see
Sibs who do not inherit the variant identified in the proband are at approximately the same risk for Brugada syndrome as the general population due to the possibility of other genetic variants.
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs of inheriting the pathogenic variant is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
If the parents are clinically unaffected but their genetic status is unknown (because the parents have not undergone molecular genetic testing and/or a causative pathogenic variant has not been identified in the proband), sibs are still at increased risk for Brugada syndrome because of the possibility of reduced penetrance in a parent (i.e., a clinically unaffected parent may be heterozygous for a pathogenic variant) and the theoretic possibility of parental germline mosaicism.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the Brugada syndrome-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Brugada syndrome are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals diagnosed with Brugada syndrome have an affected parent or another affected close relative.
• A proband with Brugada syndrome may have the disorder as the result of a
• If a diagnosis of Brugada syndrome has not already been established in the mother or the father of the proband, recommendations for the evaluation of parents of a proband include electrocardiographic analysis, attention to a family history of sudden death, and (if the pathogenic variant in the proband has been identified) molecular genetic testing.
• If the proband has a known pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• Although most individuals diagnosed with Brugada syndrome have inherited the pathogenic variant from a parent, the family history may appear to be negative because of failure to recognize the disorder in family members, incomplete penetrance, early death of the parent before the onset of symptoms, or late onset of the symptoms in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless the proband has a known Brugada syndrome-related pathogenic variant that is not identified in either parent.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected, or unaffected but known to be heterozygous for the pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
• The risk that a sib will inherit the familial pathogenic variant and develop Brugada syndrome may be less than 50% because of reduced penetrance and the possibility of other genetic and environmental factors (see
• Sibs who do not inherit the variant identified in the proband are at approximately the same risk for Brugada syndrome as the general population due to the possibility of other genetic variants.
• The risk that a sib will inherit the familial pathogenic variant and develop Brugada syndrome may be less than 50% because of reduced penetrance and the possibility of other genetic and environmental factors (see
• Sibs who do not inherit the variant identified in the proband are at approximately the same risk for Brugada syndrome as the general population due to the possibility of other genetic variants.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs of inheriting the pathogenic variant is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
• If the parents are clinically unaffected but their genetic status is unknown (because the parents have not undergone molecular genetic testing and/or a causative pathogenic variant has not been identified in the proband), sibs are still at increased risk for Brugada syndrome because of the possibility of reduced penetrance in a parent (i.e., a clinically unaffected parent may be heterozygous for a pathogenic variant) and the theoretic possibility of parental germline mosaicism.
• The risk that a sib will inherit the familial pathogenic variant and develop Brugada syndrome may be less than 50% because of reduced penetrance and the possibility of other genetic and environmental factors (see
• Sibs who do not inherit the variant identified in the proband are at approximately the same risk for Brugada syndrome as the general population due to the possibility of other genetic variants.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Brugada syndrome is inherited in an autosomal dominant manner with the exception of one family with Brugada syndrome associated with a pathogenic variant in
## Risk to Family Members (Autosomal Dominant Inheritance)
Most individuals diagnosed with Brugada syndrome have an affected parent or another affected close relative.
A proband with Brugada syndrome may have the disorder as the result of a
If a diagnosis of Brugada syndrome has not already been established in the mother or the father of the proband, recommendations for the evaluation of parents of a proband include electrocardiographic analysis, attention to a family history of sudden death, and (if the pathogenic variant in the proband has been identified) molecular genetic testing.
If the proband has a known pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
Although most individuals diagnosed with Brugada syndrome have inherited the pathogenic variant from a parent, the family history may appear to be negative because of failure to recognize the disorder in family members, incomplete penetrance, early death of the parent before the onset of symptoms, or late onset of the symptoms in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless the proband has a known Brugada syndrome-related pathogenic variant that is not identified in either parent.
If a parent of the proband is affected, or unaffected but known to be heterozygous for the pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
The risk that a sib will inherit the familial pathogenic variant and develop Brugada syndrome may be less than 50% because of reduced penetrance and the possibility of other genetic and environmental factors (see
Sibs who do not inherit the variant identified in the proband are at approximately the same risk for Brugada syndrome as the general population due to the possibility of other genetic variants.
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs of inheriting the pathogenic variant is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
If the parents are clinically unaffected but their genetic status is unknown (because the parents have not undergone molecular genetic testing and/or a causative pathogenic variant has not been identified in the proband), sibs are still at increased risk for Brugada syndrome because of the possibility of reduced penetrance in a parent (i.e., a clinically unaffected parent may be heterozygous for a pathogenic variant) and the theoretic possibility of parental germline mosaicism.
• Most individuals diagnosed with Brugada syndrome have an affected parent or another affected close relative.
• A proband with Brugada syndrome may have the disorder as the result of a
• If a diagnosis of Brugada syndrome has not already been established in the mother or the father of the proband, recommendations for the evaluation of parents of a proband include electrocardiographic analysis, attention to a family history of sudden death, and (if the pathogenic variant in the proband has been identified) molecular genetic testing.
• If the proband has a known pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• Although most individuals diagnosed with Brugada syndrome have inherited the pathogenic variant from a parent, the family history may appear to be negative because of failure to recognize the disorder in family members, incomplete penetrance, early death of the parent before the onset of symptoms, or late onset of the symptoms in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless the proband has a known Brugada syndrome-related pathogenic variant that is not identified in either parent.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected, or unaffected but known to be heterozygous for the pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
• The risk that a sib will inherit the familial pathogenic variant and develop Brugada syndrome may be less than 50% because of reduced penetrance and the possibility of other genetic and environmental factors (see
• Sibs who do not inherit the variant identified in the proband are at approximately the same risk for Brugada syndrome as the general population due to the possibility of other genetic variants.
• The risk that a sib will inherit the familial pathogenic variant and develop Brugada syndrome may be less than 50% because of reduced penetrance and the possibility of other genetic and environmental factors (see
• Sibs who do not inherit the variant identified in the proband are at approximately the same risk for Brugada syndrome as the general population due to the possibility of other genetic variants.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs of inheriting the pathogenic variant is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
• If the parents are clinically unaffected but their genetic status is unknown (because the parents have not undergone molecular genetic testing and/or a causative pathogenic variant has not been identified in the proband), sibs are still at increased risk for Brugada syndrome because of the possibility of reduced penetrance in a parent (i.e., a clinically unaffected parent may be heterozygous for a pathogenic variant) and the theoretic possibility of parental germline mosaicism.
• The risk that a sib will inherit the familial pathogenic variant and develop Brugada syndrome may be less than 50% because of reduced penetrance and the possibility of other genetic and environmental factors (see
• Sibs who do not inherit the variant identified in the proband are at approximately the same risk for Brugada syndrome as the general population due to the possibility of other genetic variants.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the Brugada syndrome-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Brugada syndrome are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Spain
Canada
•
• Spain
•
•
•
•
• Canada
•
•
•
## Molecular Genetics
Brugada Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Brugada Syndrome (
Ion Channels and Associated Brugada Syndrome Phenotype Designations, Genes, and Proteins
BrS = Brugada syndrome
Author, personal communication
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Ion Channels and Associated Brugada Syndrome Phenotype Designations, Genes, and Proteins
BrS = Brugada syndrome
Author, personal communication
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
Research support is provided by CIBERCV and Fundació Obra Social La Caixa.
25 August 2022 (sw) Comprehensive update posted live
17 November 2016 (ma) Comprehensive update posted live
10 April 2014 (me) Comprehensive update posted live
16 August 2012 (cd) Revision: multigene panels for Brugada syndrome and sudden cardiac death available clinically
12 January 2012 (cd) Revision: clinical testing for mutations in
8 September 2011 (me) Comprehensive update posted live
11 August 2009 (cd) Revision: prenatal testing for
7 December 2007 (me) Comprehensive update posted live
31 March 2005 (me) Review posted live
11 March 2004 (rb) Original submission
• 25 August 2022 (sw) Comprehensive update posted live
• 17 November 2016 (ma) Comprehensive update posted live
• 10 April 2014 (me) Comprehensive update posted live
• 16 August 2012 (cd) Revision: multigene panels for Brugada syndrome and sudden cardiac death available clinically
• 12 January 2012 (cd) Revision: clinical testing for mutations in
• 8 September 2011 (me) Comprehensive update posted live
• 11 August 2009 (cd) Revision: prenatal testing for
• 7 December 2007 (me) Comprehensive update posted live
• 31 March 2005 (me) Review posted live
• 11 March 2004 (rb) Original submission
## Author Notes
## Acknowledgments
Research support is provided by CIBERCV and Fundació Obra Social La Caixa.
## Revision History
25 August 2022 (sw) Comprehensive update posted live
17 November 2016 (ma) Comprehensive update posted live
10 April 2014 (me) Comprehensive update posted live
16 August 2012 (cd) Revision: multigene panels for Brugada syndrome and sudden cardiac death available clinically
12 January 2012 (cd) Revision: clinical testing for mutations in
8 September 2011 (me) Comprehensive update posted live
11 August 2009 (cd) Revision: prenatal testing for
7 December 2007 (me) Comprehensive update posted live
31 March 2005 (me) Review posted live
11 March 2004 (rb) Original submission
• 25 August 2022 (sw) Comprehensive update posted live
• 17 November 2016 (ma) Comprehensive update posted live
• 10 April 2014 (me) Comprehensive update posted live
• 16 August 2012 (cd) Revision: multigene panels for Brugada syndrome and sudden cardiac death available clinically
• 12 January 2012 (cd) Revision: clinical testing for mutations in
• 8 September 2011 (me) Comprehensive update posted live
• 11 August 2009 (cd) Revision: prenatal testing for
• 7 December 2007 (me) Comprehensive update posted live
• 31 March 2005 (me) Review posted live
• 11 March 2004 (rb) Original submission
## References
## Literature Cited
Characteristic EKG in Brugada syndrome. Note presence of ST segment elevation in leads V
Diagnostic algorithm for Brugada syndrome
Reproduced from
Proposed risk stratification scheme and recommendations of ICD in individuals with Brugada syndrome
Reproduced from
|
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"S Ohno, DP Zankov, WG Ding, H Itoh, T Makiyama, T Doi, S Shizuta, T Hattori, A Miyamoto, N Naiki, JC Hancox, H Matsuura, M Horie. KCNE5 (KCNE1L) variants are novel modulators of Brugada syndrome and idiopathic ventricular fibrillation.. Circ Arrhythm Electrophysiol. 2011;4:352-61",
"TM Olson, AE Alekseev, C Moreau, XK Liu, LV Zingman, T Miki, S Seino, SJ Asirvatham, A Jahangir, A Terzic. KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation.. Nat Clin Pract Cardiovasc Med. 2007;4:110-6",
"TM Olson, VV Michels, JD Ballew, SP Reyna, ML Karst, KJ Herron, SC Horton, RJ Rodeheffer, JL Anderson. Sodium channel mutations and susceptibility to heart failure and atrial fibrillation.. JAMA 2005;293:447-54",
"P Ott, F Marcus. The Brugada syndrome: can we predict the risk?. J Cardiovasc Electrophysiol 2006;17:608-9",
"MJ Perrin, A Adler, S Green, F Al-Zoughool, P Doroshenko, N Orr, S Uppal, JS Healey, D Birnie, S Sanatani, M Gardner, J Champagne, C Simpson, K Ahmad, MP van den Berg, V Chauhan, PH Backx, JP van Tintelen, AD Krahn, MH Gollob. Evaluation of genes encoding for the transient outward current (Ito) identifies the KCND2 gene as a cause of J-wave syndrome associated with sudden cardiac death.. Circ Cardiovasc Genet. 2014;7:782-9",
"S Poelzing, C Forleo, M Samodell, L Dudash, S Sorrentino, M Anaclerio, R Troccoli, M Iacoviello, R Romito, P Guida, M Chahine, M Pitzalis, I Deschênes. SCN5A polymorphism restores trafficking of a Brugada syndrome mutation on a separate gene.. Circulation. 2006;114:368-76",
"SG Priori, C Napolitano, U Giordano, G Collisani, M Memmi. Brugada syndrome and sudden cardiac death in children.. Lancet 2000;355:808-9",
"V Probst, S Evain, V Gournay, A Marie, JJ Schott, P, LE Boisseau, H Marec. Monomorphic ventricular tachycardia due to Brugada syndrome successfully treated by hydroquinidine therapy in a 3-year-old child.. J Cardiovasc Electrophysiol. 2006;17:97-100",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"W Ramadan, N Patel, S Anazi, AY Kentab, FA Bashiri, MH Hamad, L Jad, MA Salih, H Alsaif, M Hashem, E Faqeih, HE Shamseddin, FS Alkuraya. Confirming the recessive inheritance of SCN1B mutations in developmental epileptic encephalopathy.. Clin Genet. 2017;92:327-31",
"LS Ravn, Y Aizawa, GD Pollevick, J Hofman-Bang, JM Cordeiro, U Dixen, G Jensen, Y Wu, E Burashnikov, S Haunso, A Guerchicoff, D Hu, JH Svendsen, M Christiansen, C Antzelevitch. Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation.. Heart Rhythm. 2008;5:427-35",
"M Rodríguez-Mañero, A Baluja, J Hernández, C Muñoz, D Calvo, J Fernández-Armenta, A García-Fernández, E Zorio, Á Arce-León, JM Sánchez-Gómez, I Mosquera-Pérez, MÁ Arias, E Díaz-Infante, V Expósito, V Jiménez-Ramos, E Teijeira, MV Cañadas-Godoy, JM Guerra-Ramos, T Oloriz, N Basterra, P Sousa, J Elices-Teja, I García-Bolao, JR González-Juanatey, R Brugada, JR Gimeno, J Brugada, E Arbelo. Validation of multiparametric approaches for the prediction of sudden cardiac death in patients with Brugada syndrome and electrophysiological study.. Rev Esp Cardiol (Engl Ed) 2022;75:559-67",
"IE Scheffer, LA Harkin, BE Grinton, LM Dibbens, SJ Turner, MA Zielinski, R Xu, G Jackson, J Adams, M Connellan, S Petrou, RM Wellard, RS Briellmann, RH Wallace, JC Mulley, SF Berkovic. Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations.. Brain. 2007;130:100-9",
"JJ Schott, C Alshinawi, F Kyndt, V Probst, TM Hoorntje, M Hulsbeek, AA Wilde, D Escande, MM Mannens, H Le Marec. Cardiac conduction defects associate with mutations in SCN5A.. Nat Genet 1999;23:20-1",
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"A Siekierska, M Isrie, Y Liu, C Scheldeman, N Vanthillo, L Lagae, PA de Witte, H Van Esch, M Goldfarb, GM Buyse. Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy.. Neurology. 2016;86:2162-70",
"B Singh, I Ogiwara, M Kaneda, N Tokonami, E Mazaki, K Baba, K Matsuda, Y Inoue, K. A Yamakawa. Kv4.2 truncation mutation in a patient with temporal lobe epilepsy.. Neurobiol Dis. 2006;24:245-53",
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"M Vatta, R Dumaine, G Varghese, TA Richard, W Shimizu, N Aihara, K Nademanee, R Brugada, J Brugada, G Veerakul, H Li, NE Bowles, P Brugada, C Antzelevitch, JA Towbin. Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome.. Hum Mol Genet 2002;11:337-45",
"PC Viswanathan, DW Benson, JR Balser. A common SCN5A polymorphism modulates the biophysical effects of an SCN5A mutation.. J Clin Invest. 2003;111:341-6",
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"H Wang, Z Xu, BH Lee, S Vu, L Hu, M Lee, D Bu, X Cao, S Hwang, Y Yang, J Zheng, Z Lin. Gain-of-function mutations in TRPM4 activation gate cause progressive symmetric erythrokeratodermia.. J Invest Dermatol. 2019;139:1089-97",
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"H Watanabe, A Nogami, K Ohkubo, H Kawata, Y Hayashi, T Ishikawa, T Makiyama, S Nagao, N Yagihara, N Takehara, Y Kawamura, A Sato, K Okamura, Y Hosaka, M Sato, S Fukae, M Chinushi, H Oda, M Okabe, A Kimura, K Maemura, I Watanabe, S Kamakura, M Horie, Y Aizawa, W Shimizu, N. Makita. Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrillation associated with early repolarization.. Circ Arrhythm Electrophysiol. 2011;4:874-81",
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"AA Wilde, C Antzelevitch, M Borggrefe, J Brugada, R Brugada, P Brugada, D Corrado, RN Hauer, RS Kass, K Nademanee, SG Priori, JA Towbin. Proposed diagnostic criteria for the Brugada syndrome: consensus report.. Circulation 2002;106:2514-9",
"AAM Wilde, C Semsarian, MF Márquez, A Sepehri Shamloo, MJ Ackerman, EA Ashley, EB Sternick, H Barajas-Martinez, ER Behr, CR Bezzina, J Breckpot, P Charron, P Chockalingam, L Crotti, MH Gollob, S Lubitz, N Makita, S Ohno, M Ortiz-Genga, L Sacilotto, E Schulze-Bahr, W Shimizu, N Sotoodehnia, R Tadros, JS Ware, DS Winlaw, ES Kaufman. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases.. Europace. 2022",
"Y Yang, M Xia, Q Jin, S Bendahhou, J Shi, Y Chen, B Liang, J Lin, Y Liu, B Liu, Q Zhou, D Zhang, R Wang, N Ma, X Su, K Niu, Y Pei, W Xu, Z Chen, H Wan, J Cui, J Barhanin, Y. Chen. Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation.. Am J Hum Genet. 2004;75:899-905",
"M Yokokawa, T Noda, H Okamura, K Satomi, K Suyama, T Kurita, N Aihara, S Kamakura, W Shimizu. Comparison of long-term follow-up of electrocardiographic features in Brugada syndrome between the SCN5A-positive probands and the SCN5A-negative probands.. Am J Cardiol. 2007;100:649-55"
] |
31/3/2005
|
25/8/2022
|
16/8/2012
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
brylib
|
brylib
|
[
"Histone H3.3",
"H3-3A",
"H3-3B",
"Bryant-Li-Bhoj Neurodevelopmental Syndrome"
] |
Bryant-Li-Bhoj Neurodevelopmental Syndrome
|
Laura Bryant, Elizabeth Bhoj
|
Summary Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB) is characterized by developmental delay / intellectual disability (typically in the severe range) and nonspecific craniofacial abnormalities. Many affected individuals do not achieve independent sitting, walking, or speaking, although there is a range of developmental outcomes. The presentation is highly variable and can include hypotonia, epilepsy, other neurologic findings (spasticity, loss of developmental milestones, worsening gait, and/or camptocormia – forward flexion of the spine when standing that resolves when lying down), growth abnormalities (most commonly poor growth), craniosynostosis (of any suture), and ocular involvement. Congenital anomalies are rare but can include congenital heart defects, brain malformations, and genitourinary abnormalities in males. The diagnosis of BRYLIB is established in a proband with suggestive findings and a heterozygous pathogenic variant in either BRYLIB is expressed in an autosomal dominant manner and typically caused by a
|
## Diagnosis
No consensus clinical diagnostic criteria for Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB) have been published.
Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB)
Mild-to-profound developmental delay (DD) or intellectual disability (ID), most commonly in the severe range
AND
Any of the following features:
Hypotonia
Microcephaly or macrocephaly
Craniosynostosis (of any suture) or abnormal head shape, excluding positional plagiocephaly
Poor growth with short stature
Epilepsy, including generalized myoclonic and tonic seizures, complex partial seizures, and tonic-clonic seizures
Spasticity
Progressive neurologic features, particularly loss of developmental milestones, worsening seizures, or worsening gait in adulthood
Camptocormia (forward flexion of the spine when standing that resolves when lying down; "bent spine") developing in adulthood
Ophthalmologic involvement, particularly strabismus or nystagmus
Nonspecific dysmorphic features (See
Minor congenital heart defects, most commonly atrial septal defect
Genitourinary anomalies in males, particularly cryptorchidism or retractile testes
Cortical atrophy
Small posterior fossa
The diagnosis of BRYLIB
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Bryant-Li-Bhoj Neurodevelopmental Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Mild-to-profound developmental delay (DD) or intellectual disability (ID), most commonly in the severe range
• Any of the following features:
• Hypotonia
• Microcephaly or macrocephaly
• Craniosynostosis (of any suture) or abnormal head shape, excluding positional plagiocephaly
• Poor growth with short stature
• Epilepsy, including generalized myoclonic and tonic seizures, complex partial seizures, and tonic-clonic seizures
• Spasticity
• Progressive neurologic features, particularly loss of developmental milestones, worsening seizures, or worsening gait in adulthood
• Camptocormia (forward flexion of the spine when standing that resolves when lying down; "bent spine") developing in adulthood
• Ophthalmologic involvement, particularly strabismus or nystagmus
• Nonspecific dysmorphic features (See
• Minor congenital heart defects, most commonly atrial septal defect
• Genitourinary anomalies in males, particularly cryptorchidism or retractile testes
• Hypotonia
• Microcephaly or macrocephaly
• Craniosynostosis (of any suture) or abnormal head shape, excluding positional plagiocephaly
• Poor growth with short stature
• Epilepsy, including generalized myoclonic and tonic seizures, complex partial seizures, and tonic-clonic seizures
• Spasticity
• Progressive neurologic features, particularly loss of developmental milestones, worsening seizures, or worsening gait in adulthood
• Camptocormia (forward flexion of the spine when standing that resolves when lying down; "bent spine") developing in adulthood
• Ophthalmologic involvement, particularly strabismus or nystagmus
• Nonspecific dysmorphic features (See
• Minor congenital heart defects, most commonly atrial septal defect
• Genitourinary anomalies in males, particularly cryptorchidism or retractile testes
• Hypotonia
• Microcephaly or macrocephaly
• Craniosynostosis (of any suture) or abnormal head shape, excluding positional plagiocephaly
• Poor growth with short stature
• Epilepsy, including generalized myoclonic and tonic seizures, complex partial seizures, and tonic-clonic seizures
• Spasticity
• Progressive neurologic features, particularly loss of developmental milestones, worsening seizures, or worsening gait in adulthood
• Camptocormia (forward flexion of the spine when standing that resolves when lying down; "bent spine") developing in adulthood
• Ophthalmologic involvement, particularly strabismus or nystagmus
• Nonspecific dysmorphic features (See
• Minor congenital heart defects, most commonly atrial septal defect
• Genitourinary anomalies in males, particularly cryptorchidism or retractile testes
• Cortical atrophy
• Small posterior fossa
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB)
Mild-to-profound developmental delay (DD) or intellectual disability (ID), most commonly in the severe range
AND
Any of the following features:
Hypotonia
Microcephaly or macrocephaly
Craniosynostosis (of any suture) or abnormal head shape, excluding positional plagiocephaly
Poor growth with short stature
Epilepsy, including generalized myoclonic and tonic seizures, complex partial seizures, and tonic-clonic seizures
Spasticity
Progressive neurologic features, particularly loss of developmental milestones, worsening seizures, or worsening gait in adulthood
Camptocormia (forward flexion of the spine when standing that resolves when lying down; "bent spine") developing in adulthood
Ophthalmologic involvement, particularly strabismus or nystagmus
Nonspecific dysmorphic features (See
Minor congenital heart defects, most commonly atrial septal defect
Genitourinary anomalies in males, particularly cryptorchidism or retractile testes
Cortical atrophy
Small posterior fossa
• Mild-to-profound developmental delay (DD) or intellectual disability (ID), most commonly in the severe range
• Any of the following features:
• Hypotonia
• Microcephaly or macrocephaly
• Craniosynostosis (of any suture) or abnormal head shape, excluding positional plagiocephaly
• Poor growth with short stature
• Epilepsy, including generalized myoclonic and tonic seizures, complex partial seizures, and tonic-clonic seizures
• Spasticity
• Progressive neurologic features, particularly loss of developmental milestones, worsening seizures, or worsening gait in adulthood
• Camptocormia (forward flexion of the spine when standing that resolves when lying down; "bent spine") developing in adulthood
• Ophthalmologic involvement, particularly strabismus or nystagmus
• Nonspecific dysmorphic features (See
• Minor congenital heart defects, most commonly atrial septal defect
• Genitourinary anomalies in males, particularly cryptorchidism or retractile testes
• Hypotonia
• Microcephaly or macrocephaly
• Craniosynostosis (of any suture) or abnormal head shape, excluding positional plagiocephaly
• Poor growth with short stature
• Epilepsy, including generalized myoclonic and tonic seizures, complex partial seizures, and tonic-clonic seizures
• Spasticity
• Progressive neurologic features, particularly loss of developmental milestones, worsening seizures, or worsening gait in adulthood
• Camptocormia (forward flexion of the spine when standing that resolves when lying down; "bent spine") developing in adulthood
• Ophthalmologic involvement, particularly strabismus or nystagmus
• Nonspecific dysmorphic features (See
• Minor congenital heart defects, most commonly atrial septal defect
• Genitourinary anomalies in males, particularly cryptorchidism or retractile testes
• Hypotonia
• Microcephaly or macrocephaly
• Craniosynostosis (of any suture) or abnormal head shape, excluding positional plagiocephaly
• Poor growth with short stature
• Epilepsy, including generalized myoclonic and tonic seizures, complex partial seizures, and tonic-clonic seizures
• Spasticity
• Progressive neurologic features, particularly loss of developmental milestones, worsening seizures, or worsening gait in adulthood
• Camptocormia (forward flexion of the spine when standing that resolves when lying down; "bent spine") developing in adulthood
• Ophthalmologic involvement, particularly strabismus or nystagmus
• Nonspecific dysmorphic features (See
• Minor congenital heart defects, most commonly atrial septal defect
• Genitourinary anomalies in males, particularly cryptorchidism or retractile testes
• Cortical atrophy
• Small posterior fossa
## Establishing the Diagnosis
The diagnosis of BRYLIB
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Bryant-Li-Bhoj Neurodevelopmental Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB) is characterized by developmental delay / intellectual disability and nonspecific craniofacial abnormalities. The presentation is highly variable and can include hypotonia, epilepsy, other neurologic findings (spasticity, loss of developmental milestones, worsening gait, and/or camptocormia), poor growth, and ocular involvement. Congenital anomalies are rare but can include congenital heart defects and genitourinary abnormalities in males.
To date, 57 unrelated individuals have been identified with a pathogenic variant in
Select Features of Bryant-Li-Bhoj Neurodevelopmental Syndrome
Defined as a length or height that is greater than two standard deviations below the mean for age and sex.
Defined as a head circumference that is greater than two standard deviations below the mean for age and sex.
About 78% of affected individuals have delayed independent sitting (achieved after age 8 months) or have not achieved independent sitting (older than age 8 months and still unable to sit independently). The delay can be profound. The oldest affected individual to achieve independent sitting began sitting independently at age seven years.
About 93% of affected individuals were either delayed in achieving independent walking (achieved after age 16 months) or have not achieved that milestone (older than age 16 months and not walking independently). This milestone can be achieved very late. One affected individual began independently walking at age eight years.
About 52% of affected individuals are nonverbal, with an additional 40% experiencing speech delay.
Developmental regression can occur in a minority of affected individuals. Regression is not continuous and is not always associated with seizures. Although developmental regression is typically mild, it can be severe, such that children who were previously able to walk and talk can lose those abilities.
Onset is generally in infancy or childhood.
The type of seizure disorder is variable and includes myoclonic and tonic epilepsy, partial or complex partial seizures, and tonic-clonic seizures.
Seizure frequency is highly variable, with some individuals having relatively few seizures and others experiencing progressively more frequent seizures or status epilepticus.
Some individuals with seizures are well controlled on medication while others are refractory to treatment (see
Poor weight gain was reported in eight infants.
Weight is typically less affected than length/height, with only four individuals being more than two standard deviations below the mean for their age and sex in terms of weight.
However, six individuals were at least two standard deviations above the mean for their age and sex.
Short stature was observed in 22 individuals.
Tall stature was seen in three individuals.
Congenital microcephaly was seen in 19 individuals.
Four individuals had congenital macrocephaly and two had relative macrocephaly.
Malformation of the corpus callosum, including hypoplasia and agenesis, can also be seen (28%).
About 25% of affected individuals show evidence of hypomyelination or delayed myelination.
Chiari I malformations were seen in 4/18 (22%) of individuals imaged.
There is no difference in the phenotype regardless of whether the pathogenic variant is in
No genotype-phenotype correlations have been identified for either
Germline pathogenic variants in
• About 78% of affected individuals have delayed independent sitting (achieved after age 8 months) or have not achieved independent sitting (older than age 8 months and still unable to sit independently). The delay can be profound. The oldest affected individual to achieve independent sitting began sitting independently at age seven years.
• About 93% of affected individuals were either delayed in achieving independent walking (achieved after age 16 months) or have not achieved that milestone (older than age 16 months and not walking independently). This milestone can be achieved very late. One affected individual began independently walking at age eight years.
• About 52% of affected individuals are nonverbal, with an additional 40% experiencing speech delay.
• Onset is generally in infancy or childhood.
• The type of seizure disorder is variable and includes myoclonic and tonic epilepsy, partial or complex partial seizures, and tonic-clonic seizures.
• Seizure frequency is highly variable, with some individuals having relatively few seizures and others experiencing progressively more frequent seizures or status epilepticus.
• Some individuals with seizures are well controlled on medication while others are refractory to treatment (see
•
• Poor weight gain was reported in eight infants.
• Weight is typically less affected than length/height, with only four individuals being more than two standard deviations below the mean for their age and sex in terms of weight.
• However, six individuals were at least two standard deviations above the mean for their age and sex.
• Poor weight gain was reported in eight infants.
• Weight is typically less affected than length/height, with only four individuals being more than two standard deviations below the mean for their age and sex in terms of weight.
• However, six individuals were at least two standard deviations above the mean for their age and sex.
•
• Short stature was observed in 22 individuals.
• Tall stature was seen in three individuals.
• Short stature was observed in 22 individuals.
• Tall stature was seen in three individuals.
•
• Congenital microcephaly was seen in 19 individuals.
• Four individuals had congenital macrocephaly and two had relative macrocephaly.
• Congenital microcephaly was seen in 19 individuals.
• Four individuals had congenital macrocephaly and two had relative macrocephaly.
• Poor weight gain was reported in eight infants.
• Weight is typically less affected than length/height, with only four individuals being more than two standard deviations below the mean for their age and sex in terms of weight.
• However, six individuals were at least two standard deviations above the mean for their age and sex.
• Short stature was observed in 22 individuals.
• Tall stature was seen in three individuals.
• Congenital microcephaly was seen in 19 individuals.
• Four individuals had congenital macrocephaly and two had relative macrocephaly.
• Malformation of the corpus callosum, including hypoplasia and agenesis, can also be seen (28%).
• About 25% of affected individuals show evidence of hypomyelination or delayed myelination.
• Chiari I malformations were seen in 4/18 (22%) of individuals imaged.
## Clinical Description
Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB) is characterized by developmental delay / intellectual disability and nonspecific craniofacial abnormalities. The presentation is highly variable and can include hypotonia, epilepsy, other neurologic findings (spasticity, loss of developmental milestones, worsening gait, and/or camptocormia), poor growth, and ocular involvement. Congenital anomalies are rare but can include congenital heart defects and genitourinary abnormalities in males.
To date, 57 unrelated individuals have been identified with a pathogenic variant in
Select Features of Bryant-Li-Bhoj Neurodevelopmental Syndrome
Defined as a length or height that is greater than two standard deviations below the mean for age and sex.
Defined as a head circumference that is greater than two standard deviations below the mean for age and sex.
About 78% of affected individuals have delayed independent sitting (achieved after age 8 months) or have not achieved independent sitting (older than age 8 months and still unable to sit independently). The delay can be profound. The oldest affected individual to achieve independent sitting began sitting independently at age seven years.
About 93% of affected individuals were either delayed in achieving independent walking (achieved after age 16 months) or have not achieved that milestone (older than age 16 months and not walking independently). This milestone can be achieved very late. One affected individual began independently walking at age eight years.
About 52% of affected individuals are nonverbal, with an additional 40% experiencing speech delay.
Developmental regression can occur in a minority of affected individuals. Regression is not continuous and is not always associated with seizures. Although developmental regression is typically mild, it can be severe, such that children who were previously able to walk and talk can lose those abilities.
Onset is generally in infancy or childhood.
The type of seizure disorder is variable and includes myoclonic and tonic epilepsy, partial or complex partial seizures, and tonic-clonic seizures.
Seizure frequency is highly variable, with some individuals having relatively few seizures and others experiencing progressively more frequent seizures or status epilepticus.
Some individuals with seizures are well controlled on medication while others are refractory to treatment (see
Poor weight gain was reported in eight infants.
Weight is typically less affected than length/height, with only four individuals being more than two standard deviations below the mean for their age and sex in terms of weight.
However, six individuals were at least two standard deviations above the mean for their age and sex.
Short stature was observed in 22 individuals.
Tall stature was seen in three individuals.
Congenital microcephaly was seen in 19 individuals.
Four individuals had congenital macrocephaly and two had relative macrocephaly.
Malformation of the corpus callosum, including hypoplasia and agenesis, can also be seen (28%).
About 25% of affected individuals show evidence of hypomyelination or delayed myelination.
Chiari I malformations were seen in 4/18 (22%) of individuals imaged.
• About 78% of affected individuals have delayed independent sitting (achieved after age 8 months) or have not achieved independent sitting (older than age 8 months and still unable to sit independently). The delay can be profound. The oldest affected individual to achieve independent sitting began sitting independently at age seven years.
• About 93% of affected individuals were either delayed in achieving independent walking (achieved after age 16 months) or have not achieved that milestone (older than age 16 months and not walking independently). This milestone can be achieved very late. One affected individual began independently walking at age eight years.
• About 52% of affected individuals are nonverbal, with an additional 40% experiencing speech delay.
• Onset is generally in infancy or childhood.
• The type of seizure disorder is variable and includes myoclonic and tonic epilepsy, partial or complex partial seizures, and tonic-clonic seizures.
• Seizure frequency is highly variable, with some individuals having relatively few seizures and others experiencing progressively more frequent seizures or status epilepticus.
• Some individuals with seizures are well controlled on medication while others are refractory to treatment (see
•
• Poor weight gain was reported in eight infants.
• Weight is typically less affected than length/height, with only four individuals being more than two standard deviations below the mean for their age and sex in terms of weight.
• However, six individuals were at least two standard deviations above the mean for their age and sex.
• Poor weight gain was reported in eight infants.
• Weight is typically less affected than length/height, with only four individuals being more than two standard deviations below the mean for their age and sex in terms of weight.
• However, six individuals were at least two standard deviations above the mean for their age and sex.
•
• Short stature was observed in 22 individuals.
• Tall stature was seen in three individuals.
• Short stature was observed in 22 individuals.
• Tall stature was seen in three individuals.
•
• Congenital microcephaly was seen in 19 individuals.
• Four individuals had congenital macrocephaly and two had relative macrocephaly.
• Congenital microcephaly was seen in 19 individuals.
• Four individuals had congenital macrocephaly and two had relative macrocephaly.
• Poor weight gain was reported in eight infants.
• Weight is typically less affected than length/height, with only four individuals being more than two standard deviations below the mean for their age and sex in terms of weight.
• However, six individuals were at least two standard deviations above the mean for their age and sex.
• Short stature was observed in 22 individuals.
• Tall stature was seen in three individuals.
• Congenital microcephaly was seen in 19 individuals.
• Four individuals had congenital macrocephaly and two had relative macrocephaly.
• Malformation of the corpus callosum, including hypoplasia and agenesis, can also be seen (28%).
• About 25% of affected individuals show evidence of hypomyelination or delayed myelination.
• Chiari I malformations were seen in 4/18 (22%) of individuals imaged.
## Phenotype Correlations by Gene
There is no difference in the phenotype regardless of whether the pathogenic variant is in
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified for either
## Prevalence
Germline pathogenic variants in
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The phenotypic features associated with Bryant-Li-Bhoj neurodevelopmental syndrome are not sufficient to diagnose this condition clinically; all disorders with intellectual disability without other distinctive findings should be considered in the differential diagnosis. See
## Management
No clinical practice guidelines for Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB) have been published.
To establish the extent of disease and needs in an individual diagnosed with BRYLIB, the evaluations summarized in
Bryant-Li-Bhoj Neurodevelopmental Syndrome: Recommended Evaluations Following Initial Diagnosis
To incl brain MRI
Consider EEG if seizures are a concern.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Assess for signs & symptoms of constipation.
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; BRYLIB = Bryant-Li-Bhoj neurodevelopmental syndrome; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; TSH = thyroid-stimulating hormone; T
Some affected individuals may have increased weight, tall stature, or macrocephaly.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for BRYLIB.
Bryant-Li-Bhoj Neurodevelopmental Syndrome: Treatment of Manifestations
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Some affected persons are refractory to treatment.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Children: through early intervention programs &/or school district
Adults: referral to low vision clinic &/or community vision services
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; OT = occupational therapy/therapist; PT = physical therapy/therapist
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Recommended Surveillance for Individuals with Bryant-Li-Bhoj Neurodevelopmental Syndrome
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures & changes in tone &/or gait, if ambulatory.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
Which may include thyroid-stimulating hormone, thyroxine (T
See
Search
• To incl brain MRI
• Consider EEG if seizures are a concern.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Assess for signs & symptoms of constipation.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Some affected persons are refractory to treatment.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Children: through early intervention programs &/or school district
• Adults: referral to low vision clinic &/or community vision services
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures & changes in tone &/or gait, if ambulatory.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with BRYLIB, the evaluations summarized in
Bryant-Li-Bhoj Neurodevelopmental Syndrome: Recommended Evaluations Following Initial Diagnosis
To incl brain MRI
Consider EEG if seizures are a concern.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Assess for signs & symptoms of constipation.
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; BRYLIB = Bryant-Li-Bhoj neurodevelopmental syndrome; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; TSH = thyroid-stimulating hormone; T
Some affected individuals may have increased weight, tall stature, or macrocephaly.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl brain MRI
• Consider EEG if seizures are a concern.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Assess for signs & symptoms of constipation.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
There is no cure for BRYLIB.
Bryant-Li-Bhoj Neurodevelopmental Syndrome: Treatment of Manifestations
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Some affected persons are refractory to treatment.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Children: through early intervention programs &/or school district
Adults: referral to low vision clinic &/or community vision services
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; OT = occupational therapy/therapist; PT = physical therapy/therapist
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Some affected persons are refractory to treatment.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Children: through early intervention programs &/or school district
• Adults: referral to low vision clinic &/or community vision services
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Recommended Surveillance for Individuals with Bryant-Li-Bhoj Neurodevelopmental Syndrome
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures & changes in tone &/or gait, if ambulatory.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
Which may include thyroid-stimulating hormone, thyroxine (T
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures & changes in tone &/or gait, if ambulatory.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB) is an autosomal dominant disorder typically caused by a
All probands reported to date with BRYLIB whose parents have undergone molecular genetic testing have the disorder as the result of a
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If a parent of the proband is known to have the
If the
Individuals with BRYLIB are not known to reproduce; however, many are not yet of reproductive age.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
Risk to future pregnancies is presumed to be low as the proband most likely has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• All probands reported to date with BRYLIB whose parents have undergone molecular genetic testing have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is known to have the
• If the
• Individuals with BRYLIB are not known to reproduce; however, many are not yet of reproductive age.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB) is an autosomal dominant disorder typically caused by a
## Risk to Family Members
All probands reported to date with BRYLIB whose parents have undergone molecular genetic testing have the disorder as the result of a
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If a parent of the proband is known to have the
If the
Individuals with BRYLIB are not known to reproduce; however, many are not yet of reproductive age.
• All probands reported to date with BRYLIB whose parents have undergone molecular genetic testing have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is known to have the
• If the
• Individuals with BRYLIB are not known to reproduce; however, many are not yet of reproductive age.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Risk to future pregnancies is presumed to be low as the proband most likely has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
## Molecular Genetics
Bryant-Li-Bhoj Neurodevelopmental Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Bryant-Li-Bhoj Neurodevelopmental Syndrome (
Histone H3.3 plays an important role in both development (stem cells) and in postmitotic cells, such as neurons [
## Molecular Pathogenesis
Histone H3.3 plays an important role in both development (stem cells) and in postmitotic cells, such as neurons [
## Chapter Notes
Dr Bryant's work focuses on studying the pathogenic mechanism of missense variants in
28 September 2023 (ma) Review posted live
17 January 2023 (lb) Original submission
• 28 September 2023 (ma) Review posted live
• 17 January 2023 (lb) Original submission
## Author Notes
Dr Bryant's work focuses on studying the pathogenic mechanism of missense variants in
## Revision History
28 September 2023 (ma) Review posted live
17 January 2023 (lb) Original submission
• 28 September 2023 (ma) Review posted live
• 17 January 2023 (lb) Original submission
## References
## Literature Cited
|
[] |
28/9/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
bscl
|
bscl
|
[
"Berardinelli-Seip Congenital Generalized Lipodystrophy",
"Berardinelli-Seip Congenital Generalized Lipodystrophy",
"1-acyl-sn-glycerol-3-phosphate acyltransferase beta",
"Seipin",
"AGPAT2",
"BSCL2",
"Berardinelli-Seip Congenital Lipodystrophy"
] |
Berardinelli-Seip Congenital Lipodystrophy
|
Lionel Van Maldergem
|
Summary Berardinelli-Seip congenital lipodystrophy (BSCL) is usually diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Affected individuals develop insulin resistance and approximately 25%-35% develop diabetes mellitus between ages 15 and 20 years. Hepatomegaly secondary to hepatic steatosis and skeletal muscle hypertrophy occur in all affected individuals. Hypertrophic cardiomyopathy is reported in 20%-25% of affected individuals and is a significant cause of morbidity from cardiac failure and early mortality. The diagnosis of BSCL is established in a proband with three BSCL is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family are known.
|
## Diagnosis
Berardinelli-Seip congenital lipodystrophy (BSCL)
The diagnosis of BSCL
Molecular testing approaches can include
In individuals with intellectual disability or cardiomyopathy, sequencing of
The order of molecular genetic testing may also be stratified by the ethnicity of the affected individual (see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Berardinelli-Seip Congenital Lipodystrophy
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Nearly all individuals of African origin with BSCL have the
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Pathogenic variants in
One large deletion and one large indel have been reported [
• In individuals with intellectual disability or cardiomyopathy, sequencing of
• The order of molecular genetic testing may also be stratified by the ethnicity of the affected individual (see
## Suggestive Findings
Berardinelli-Seip congenital lipodystrophy (BSCL)
## Major Criteria
## Minor Criteria
## Establishing the Diagnosis
The diagnosis of BSCL
Molecular testing approaches can include
In individuals with intellectual disability or cardiomyopathy, sequencing of
The order of molecular genetic testing may also be stratified by the ethnicity of the affected individual (see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Berardinelli-Seip Congenital Lipodystrophy
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Nearly all individuals of African origin with BSCL have the
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Pathogenic variants in
One large deletion and one large indel have been reported [
• In individuals with intellectual disability or cardiomyopathy, sequencing of
• The order of molecular genetic testing may also be stratified by the ethnicity of the affected individual (see
## Clinical Characteristics
Berardinelli-Seip congenital lipodystrophy (BSCL) is mostly diagnosed at birth or soon thereafter. Severe forms of BSCL may have prenatal onset with intrauterine growth retardation. Presentation in the first months of life includes failure to thrive (or conversely gigantism), hepatomegaly, lipoatrophy, facial dysmorphia, enlarged tongue, or developmental delay. All children with the neonatal or infantile presentation demonstrate lipoatrophy in the first year of life.
Affected adults may first be seen in the plastic surgery clinic seeking cosmetic improvement of facial lipoatrophy or in the cardiology clinic or gastroenterology clinic for manifestations such as hypertrophic cardiomyopathy or hepatomegaly.
Affected individuals develop insulin resistance and approximately 25%-35% of individuals develop diabetes mellitus, most commonly between the ages 15 and 20 years. Diabetes mellitus:
Can be difficult to control;
Manifests by weight loss, polydipsia, polyuria, or asthenia and is frequently the presenting finding in the second decade;
Presents on occasion in early adulthood.
Some women present with oligomenorrhea, amenorrhea, or features of polycystic ovary syndrome.
Three children of Pakistani, Chinese, and Turkish ancestry, respectively, came to medical attention in the first year of life with cardiac failure associated with hypertrophic cardiomyopathy [
Affected individuals have died as early as age 19 months of complications of cardiomyopathy.
A severe form of BSCL characterized by lipodystrophy followed after a couple of months by neurologic regression and death has been described in five infants in Spain [
Berardinelli-Seip syndrome is named after W Berardinelli, who reported the first affected individuals from Brazil in 1954. The syndrome was confirmed in 1959 in Norway by Martin Seip, whose affected population originated from the county of Rogaland. In the European literature, the terms "Seip syndrome," "generalized lipodystrophy," "congenital generalized lipodystrophy," or "total lipodystrophy" have been used.
Brunzell syndrome is the association of bone cysts and lipoatrophic diabetes mellitus described in five affected African Americans from the same sibship. Originally Brunzell syndrome was thought to be a separate entity, but it is now generally recognized that bone cysts represent a rare complication of Berardinelli-Seip congenital lipodystrophy. Furthermore,
After onset of diabetes mellitus, some have termed individuals with BSCL as having "lipoatrophic diabetes."
Lawrence syndrome is synonymous with acquired generalized lipodystrophy [
More than three hundred cases of BSCL have been reported in the medical literature. Prevalence estimates:
USA: 1:10,000,000 [
Norway: 1:1,000,000
Lebanon: 1:200,000
Portugal: 1:500,000
Sultanate of Oman: 1:25,000 [
• Affected individuals develop insulin resistance and approximately 25%-35% of individuals develop diabetes mellitus, most commonly between the ages 15 and 20 years. Diabetes mellitus:
• Can be difficult to control;
• Manifests by weight loss, polydipsia, polyuria, or asthenia and is frequently the presenting finding in the second decade;
• Presents on occasion in early adulthood.
• Can be difficult to control;
• Manifests by weight loss, polydipsia, polyuria, or asthenia and is frequently the presenting finding in the second decade;
• Presents on occasion in early adulthood.
• Some women present with oligomenorrhea, amenorrhea, or features of polycystic ovary syndrome.
• Can be difficult to control;
• Manifests by weight loss, polydipsia, polyuria, or asthenia and is frequently the presenting finding in the second decade;
• Presents on occasion in early adulthood.
• Three children of Pakistani, Chinese, and Turkish ancestry, respectively, came to medical attention in the first year of life with cardiac failure associated with hypertrophic cardiomyopathy [
• Affected individuals have died as early as age 19 months of complications of cardiomyopathy.
• USA: 1:10,000,000 [
• Norway: 1:1,000,000
• Lebanon: 1:200,000
• Portugal: 1:500,000
• Sultanate of Oman: 1:25,000 [
## Clinical Description
Berardinelli-Seip congenital lipodystrophy (BSCL) is mostly diagnosed at birth or soon thereafter. Severe forms of BSCL may have prenatal onset with intrauterine growth retardation. Presentation in the first months of life includes failure to thrive (or conversely gigantism), hepatomegaly, lipoatrophy, facial dysmorphia, enlarged tongue, or developmental delay. All children with the neonatal or infantile presentation demonstrate lipoatrophy in the first year of life.
Affected adults may first be seen in the plastic surgery clinic seeking cosmetic improvement of facial lipoatrophy or in the cardiology clinic or gastroenterology clinic for manifestations such as hypertrophic cardiomyopathy or hepatomegaly.
Affected individuals develop insulin resistance and approximately 25%-35% of individuals develop diabetes mellitus, most commonly between the ages 15 and 20 years. Diabetes mellitus:
Can be difficult to control;
Manifests by weight loss, polydipsia, polyuria, or asthenia and is frequently the presenting finding in the second decade;
Presents on occasion in early adulthood.
Some women present with oligomenorrhea, amenorrhea, or features of polycystic ovary syndrome.
Three children of Pakistani, Chinese, and Turkish ancestry, respectively, came to medical attention in the first year of life with cardiac failure associated with hypertrophic cardiomyopathy [
Affected individuals have died as early as age 19 months of complications of cardiomyopathy.
• Affected individuals develop insulin resistance and approximately 25%-35% of individuals develop diabetes mellitus, most commonly between the ages 15 and 20 years. Diabetes mellitus:
• Can be difficult to control;
• Manifests by weight loss, polydipsia, polyuria, or asthenia and is frequently the presenting finding in the second decade;
• Presents on occasion in early adulthood.
• Can be difficult to control;
• Manifests by weight loss, polydipsia, polyuria, or asthenia and is frequently the presenting finding in the second decade;
• Presents on occasion in early adulthood.
• Some women present with oligomenorrhea, amenorrhea, or features of polycystic ovary syndrome.
• Can be difficult to control;
• Manifests by weight loss, polydipsia, polyuria, or asthenia and is frequently the presenting finding in the second decade;
• Presents on occasion in early adulthood.
• Three children of Pakistani, Chinese, and Turkish ancestry, respectively, came to medical attention in the first year of life with cardiac failure associated with hypertrophic cardiomyopathy [
• Affected individuals have died as early as age 19 months of complications of cardiomyopathy.
## Phenotype Correlations by Gene
## Genotype-Phenotype Correlations
A severe form of BSCL characterized by lipodystrophy followed after a couple of months by neurologic regression and death has been described in five infants in Spain [
## Nomenclature
Berardinelli-Seip syndrome is named after W Berardinelli, who reported the first affected individuals from Brazil in 1954. The syndrome was confirmed in 1959 in Norway by Martin Seip, whose affected population originated from the county of Rogaland. In the European literature, the terms "Seip syndrome," "generalized lipodystrophy," "congenital generalized lipodystrophy," or "total lipodystrophy" have been used.
Brunzell syndrome is the association of bone cysts and lipoatrophic diabetes mellitus described in five affected African Americans from the same sibship. Originally Brunzell syndrome was thought to be a separate entity, but it is now generally recognized that bone cysts represent a rare complication of Berardinelli-Seip congenital lipodystrophy. Furthermore,
After onset of diabetes mellitus, some have termed individuals with BSCL as having "lipoatrophic diabetes."
Lawrence syndrome is synonymous with acquired generalized lipodystrophy [
## Prevalence
More than three hundred cases of BSCL have been reported in the medical literature. Prevalence estimates:
USA: 1:10,000,000 [
Norway: 1:1,000,000
Lebanon: 1:200,000
Portugal: 1:500,000
Sultanate of Oman: 1:25,000 [
• USA: 1:10,000,000 [
• Norway: 1:1,000,000
• Lebanon: 1:200,000
• Portugal: 1:500,000
• Sultanate of Oman: 1:25,000 [
## Genetically Related (Allelic) Disorders
Onset of symptoms ranging from the first to the seventh decade (6-66 years; mean: 19 years)
Slow disease progression
Upper-motor neuron involvement: gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responses
Lower motor neuron involvement: amyotrophy (wasting) of the peroneal muscles and the small muscles of the hand (particularly the thenar and interosseus dorsalis I muscles) that is frequently unilateral
Usually normal sensation except for pallesthesia (i.e., abnormal vibration sense)
Pes cavus and other foot deformities
Autosomal dominant inheritance
• Onset of symptoms ranging from the first to the seventh decade (6-66 years; mean: 19 years)
• Slow disease progression
• Upper-motor neuron involvement: gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responses
• Lower motor neuron involvement: amyotrophy (wasting) of the peroneal muscles and the small muscles of the hand (particularly the thenar and interosseus dorsalis I muscles) that is frequently unilateral
• Usually normal sensation except for pallesthesia (i.e., abnormal vibration sense)
• Pes cavus and other foot deformities
• Autosomal dominant inheritance
## Differential Diagnosis
Neonatal progeroid syndrome (OMIM
Neurometabolic lysosomal storage disorders:
Russell diencephalic syndrome
Leprechaunism: Donohue syndrome (See
Familial partial Dunnigan-Koëberling lipodystrophy (OMIM
Rabson-Mendenhall syndrome (See
Insulin-dependent diabetes mellitus
Acquired generalized lipodystrophy (Lawrence syndrome) [
Mandibuloacral dysplasia (MAD) caused by
Acquired partial lipodystrophy (Barraquer-Simons syndrome) (OMIM
Lipodystrophy associated with human immunodeficiency virus infection
Partial lipodystrophy with C3 nephritic factor (OMIM
Acquired generalized lipodystrophy (Lawrence syndrome)
See OMIM
•
• Neonatal progeroid syndrome (OMIM
• Neurometabolic lysosomal storage disorders:
• Russell diencephalic syndrome
• Leprechaunism: Donohue syndrome (See
• Familial partial Dunnigan-Koëberling lipodystrophy (OMIM
• Rabson-Mendenhall syndrome (See
• Insulin-dependent diabetes mellitus
• Acquired generalized lipodystrophy (Lawrence syndrome) [
• Mandibuloacral dysplasia (MAD) caused by
•
• Acquired partial lipodystrophy (Barraquer-Simons syndrome) (OMIM
• Lipodystrophy associated with human immunodeficiency virus infection
• Partial lipodystrophy with C3 nephritic factor (OMIM
• Acquired generalized lipodystrophy (Lawrence syndrome)
## Management
To establish the extent of disease and needs in an individual diagnosed with Berardinelli-Seip congenital lipodystrophy (BSCL), the following clinical evaluations are recommended:
Complete blood count
Serum concentration of electrolytes, AST, alanine transaminase, urea, creatinine, insulin, C-peptide, triglycerides, and cholesterol
Oral glucose tolerance test; when appropriate, clamp glucose homeostasis study
Ultrasound of the liver to evaluate liver size and fatty content
Echocardiogram to evaluate for cardiac hypertrophy
Renal ultrasound examination to evaluate for kidney size
Physical examination for orthopedic complications including reduced hip mobility and genu valgum
Skeletal survey, especially of the long bones, to evaluate for bone cysts
Bone age and assessment of sexual maturity rating/pubertal status
Complete ophthalmologic examination, including slit lamp examination, to evaluate for ophthalmologic complications due to hyperlipemia and/or diabetes mellitus
Assessment of cognitive ability with age-appropriate scales
Consultation with a clinical geneticist and/or genetic counselor
Restriction of total fat intake between 20% and 30% of total dietary energy is often sufficient to maintain normal triglyceride serum concentration.
Fibric acid derivatives and n-3 polyunsaturated fatty acids derived from fish oils can be tried for the treatment of extreme hypertriglyceridemia.
Leptin treatment has proven successful in controlling both hypertriglyceridemia and diabetes mellitus [
Management of diabetes mellitus does not differ from that of childhood-onset diabetes mellitus.
Special education is required for individuals with psychomotor retardation or intellectual disability.
Dietary restriction of total fat intake may prevent hypertriglyceridemia (see
The following are appropriate:
Periodic screening for glycosuria as a manifestation of diabetes mellitus
For individuals with diabetes mellitus, follow-up in a diabetes clinic every six months to monitor for possible retinal, peripheral nerve, and renal complications
Yearly cardiac ultrasound and EKG
Yearly or biennial liver ultrasound examination to detect fatty infiltration
Ultrasound surveillance is a noninvasive procedure that can, along with serum lipid concentrations and liver enzymes, provide information on the degree of lipid control and compliance with the fat-restricted diet.
Excessive dietary fat intake should be avoided.
See
Affected pregnant women should be followed in a high-risk pregnancy care unit by a multidisciplinary team including a specialist in fetal medicine and an expert in diabetic management. Pregnancy may increase the risk of diabetic decompensation. Babies born to women with diabetes are at an increased risk for fetal anomalies and postnatal complications compared to babies born to women without diabetes.
Search
Other drugs, including fenfluramine, have no proven efficacy and should be avoided.
• Complete blood count
• Serum concentration of electrolytes, AST, alanine transaminase, urea, creatinine, insulin, C-peptide, triglycerides, and cholesterol
• Oral glucose tolerance test; when appropriate, clamp glucose homeostasis study
• Ultrasound of the liver to evaluate liver size and fatty content
• Echocardiogram to evaluate for cardiac hypertrophy
• Renal ultrasound examination to evaluate for kidney size
• Physical examination for orthopedic complications including reduced hip mobility and genu valgum
• Skeletal survey, especially of the long bones, to evaluate for bone cysts
• Bone age and assessment of sexual maturity rating/pubertal status
• Complete ophthalmologic examination, including slit lamp examination, to evaluate for ophthalmologic complications due to hyperlipemia and/or diabetes mellitus
• Assessment of cognitive ability with age-appropriate scales
• Consultation with a clinical geneticist and/or genetic counselor
• Periodic screening for glycosuria as a manifestation of diabetes mellitus
• For individuals with diabetes mellitus, follow-up in a diabetes clinic every six months to monitor for possible retinal, peripheral nerve, and renal complications
• Yearly cardiac ultrasound and EKG
• Yearly or biennial liver ultrasound examination to detect fatty infiltration
• Ultrasound surveillance is a noninvasive procedure that can, along with serum lipid concentrations and liver enzymes, provide information on the degree of lipid control and compliance with the fat-restricted diet.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Berardinelli-Seip congenital lipodystrophy (BSCL), the following clinical evaluations are recommended:
Complete blood count
Serum concentration of electrolytes, AST, alanine transaminase, urea, creatinine, insulin, C-peptide, triglycerides, and cholesterol
Oral glucose tolerance test; when appropriate, clamp glucose homeostasis study
Ultrasound of the liver to evaluate liver size and fatty content
Echocardiogram to evaluate for cardiac hypertrophy
Renal ultrasound examination to evaluate for kidney size
Physical examination for orthopedic complications including reduced hip mobility and genu valgum
Skeletal survey, especially of the long bones, to evaluate for bone cysts
Bone age and assessment of sexual maturity rating/pubertal status
Complete ophthalmologic examination, including slit lamp examination, to evaluate for ophthalmologic complications due to hyperlipemia and/or diabetes mellitus
Assessment of cognitive ability with age-appropriate scales
Consultation with a clinical geneticist and/or genetic counselor
• Complete blood count
• Serum concentration of electrolytes, AST, alanine transaminase, urea, creatinine, insulin, C-peptide, triglycerides, and cholesterol
• Oral glucose tolerance test; when appropriate, clamp glucose homeostasis study
• Ultrasound of the liver to evaluate liver size and fatty content
• Echocardiogram to evaluate for cardiac hypertrophy
• Renal ultrasound examination to evaluate for kidney size
• Physical examination for orthopedic complications including reduced hip mobility and genu valgum
• Skeletal survey, especially of the long bones, to evaluate for bone cysts
• Bone age and assessment of sexual maturity rating/pubertal status
• Complete ophthalmologic examination, including slit lamp examination, to evaluate for ophthalmologic complications due to hyperlipemia and/or diabetes mellitus
• Assessment of cognitive ability with age-appropriate scales
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Restriction of total fat intake between 20% and 30% of total dietary energy is often sufficient to maintain normal triglyceride serum concentration.
Fibric acid derivatives and n-3 polyunsaturated fatty acids derived from fish oils can be tried for the treatment of extreme hypertriglyceridemia.
Leptin treatment has proven successful in controlling both hypertriglyceridemia and diabetes mellitus [
Management of diabetes mellitus does not differ from that of childhood-onset diabetes mellitus.
Special education is required for individuals with psychomotor retardation or intellectual disability.
## Prevention of Primary Manifestations
Dietary restriction of total fat intake may prevent hypertriglyceridemia (see
## Surveillance
The following are appropriate:
Periodic screening for glycosuria as a manifestation of diabetes mellitus
For individuals with diabetes mellitus, follow-up in a diabetes clinic every six months to monitor for possible retinal, peripheral nerve, and renal complications
Yearly cardiac ultrasound and EKG
Yearly or biennial liver ultrasound examination to detect fatty infiltration
Ultrasound surveillance is a noninvasive procedure that can, along with serum lipid concentrations and liver enzymes, provide information on the degree of lipid control and compliance with the fat-restricted diet.
• Periodic screening for glycosuria as a manifestation of diabetes mellitus
• For individuals with diabetes mellitus, follow-up in a diabetes clinic every six months to monitor for possible retinal, peripheral nerve, and renal complications
• Yearly cardiac ultrasound and EKG
• Yearly or biennial liver ultrasound examination to detect fatty infiltration
• Ultrasound surveillance is a noninvasive procedure that can, along with serum lipid concentrations and liver enzymes, provide information on the degree of lipid control and compliance with the fat-restricted diet.
## Agents/Circumstances to Avoid
Excessive dietary fat intake should be avoided.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Affected pregnant women should be followed in a high-risk pregnancy care unit by a multidisciplinary team including a specialist in fetal medicine and an expert in diabetic management. Pregnancy may increase the risk of diabetic decompensation. Babies born to women with diabetes are at an increased risk for fetal anomalies and postnatal complications compared to babies born to women without diabetes.
## Therapies Under Investigation
Search
## Other
Other drugs, including fenfluramine, have no proven efficacy and should be avoided.
## Genetic Counseling
Berardinelli-Seip congenital lipodystrophy (BSCL) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., carriers of one BSCL-related pathogenic variant).
Heterozygotes (carriers) are asymptomatic; increased incidence of diabetes mellitus has been suggested but never confirmed.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic, although increased incidence of diabetes mellitus is suggested.
Pregnancies in individuals with BSCL type 1 have been described [
Many individuals with BSCL type 2 (BSCL2) do not reproduce.
Carrier testing for at-risk relatives requires prior identification of the BSCL-related pathogenic variants in the family.
Differentiation between BSCL type 1 and BSCL type 2 may be useful for purposes of genetic counseling, particularly if the affected individual is too young for cognitive development to have been clearly characterized.
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the BSCL-related pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for BSCL are possible.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one BSCL-related pathogenic variant).
• Heterozygotes (carriers) are asymptomatic; increased incidence of diabetes mellitus has been suggested but never confirmed.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic, although increased incidence of diabetes mellitus is suggested.
• Pregnancies in individuals with BSCL type 1 have been described [
• Many individuals with BSCL type 2 (BSCL2) do not reproduce.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Berardinelli-Seip congenital lipodystrophy (BSCL) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one BSCL-related pathogenic variant).
Heterozygotes (carriers) are asymptomatic; increased incidence of diabetes mellitus has been suggested but never confirmed.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic, although increased incidence of diabetes mellitus is suggested.
Pregnancies in individuals with BSCL type 1 have been described [
Many individuals with BSCL type 2 (BSCL2) do not reproduce.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one BSCL-related pathogenic variant).
• Heterozygotes (carriers) are asymptomatic; increased incidence of diabetes mellitus has been suggested but never confirmed.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic, although increased incidence of diabetes mellitus is suggested.
• Pregnancies in individuals with BSCL type 1 have been described [
• Many individuals with BSCL type 2 (BSCL2) do not reproduce.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the BSCL-related pathogenic variants in the family.
## Related Genetic Counseling Issues
Differentiation between BSCL type 1 and BSCL type 2 may be useful for purposes of genetic counseling, particularly if the affected individual is too young for cognitive development to have been clearly characterized.
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the BSCL-related pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for BSCL are possible.
## Resources
United Kingdom
United Kingdom
•
•
•
•
•
• United Kingdom
•
•
• United Kingdom
•
## Molecular Genetics
Berardinelli-Seip Congenital Lipodystrophy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Berardinelli-Seip Congenital Lipodystrophy (
Pathogenic variants in
Selected
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
Recurrent variant
Selected
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
Recurrent variant
The seipin protein has a domain similar to that contained in the sterol element-binding proteins (SREBPs) which have a role in regulation of cholesterol biosynthesis and uptake. Study of yeast seipin indicates that it is located at the junction of ER and lipid droplets called adiposomes. When seipin is absent, irregularly shaped small lipid droplets replace these well-formed adiposomes, suggesting a role for seipin in the formation or maintenance of these lipid-containing vesicles.
In addition, studies in mouse models indicate that reduction of seipin strongly reduced expression and synthesis of AGPAT2 and DGAT2, suggesting that seipin is located located upstream in the metabolic pathway[
Seipin also occurs as another isoform.
## Molecular Pathogenesis
Pathogenic variants in
Selected
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
Recurrent variant
Selected
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
Recurrent variant
The seipin protein has a domain similar to that contained in the sterol element-binding proteins (SREBPs) which have a role in regulation of cholesterol biosynthesis and uptake. Study of yeast seipin indicates that it is located at the junction of ER and lipid droplets called adiposomes. When seipin is absent, irregularly shaped small lipid droplets replace these well-formed adiposomes, suggesting a role for seipin in the formation or maintenance of these lipid-containing vesicles.
In addition, studies in mouse models indicate that reduction of seipin strongly reduced expression and synthesis of AGPAT2 and DGAT2, suggesting that seipin is located located upstream in the metabolic pathway[
Seipin also occurs as another isoform.
##
Selected
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
Recurrent variant
##
Selected
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
Recurrent variant
The seipin protein has a domain similar to that contained in the sterol element-binding proteins (SREBPs) which have a role in regulation of cholesterol biosynthesis and uptake. Study of yeast seipin indicates that it is located at the junction of ER and lipid droplets called adiposomes. When seipin is absent, irregularly shaped small lipid droplets replace these well-formed adiposomes, suggesting a role for seipin in the formation or maintenance of these lipid-containing vesicles.
In addition, studies in mouse models indicate that reduction of seipin strongly reduced expression and synthesis of AGPAT2 and DGAT2, suggesting that seipin is located located upstream in the metabolic pathway[
Seipin also occurs as another isoform.
## Chapter Notes
Dr Van Maldergem is a teacher of Human Genetics with 25 years' experience in clinical genetics. He is the coordinator of the Berardinelli-Seip study group (created in 1993) and organizer of the first international conference on lipodystrophies (Brussels, 1997).
8 December 2016 (ma) Comprehensive update posted live
28 June 2012 (me) Comprehensive update posted live
23 February 2010 (me) Comprehensive update posted live
23 August 2007 (cd) Revision: sequence analysis and prenatal diagnosis for BSCL type 1 available on a clinical basis
21 December 2005 (me) Comprehensive update posted live
3 August 2004 (lvm) Revision: Genetically Related Disorders
8 September 2003 (me) Review posted live
24 April 2003 (lvm) Original submission
• 8 December 2016 (ma) Comprehensive update posted live
• 28 June 2012 (me) Comprehensive update posted live
• 23 February 2010 (me) Comprehensive update posted live
• 23 August 2007 (cd) Revision: sequence analysis and prenatal diagnosis for BSCL type 1 available on a clinical basis
• 21 December 2005 (me) Comprehensive update posted live
• 3 August 2004 (lvm) Revision: Genetically Related Disorders
• 8 September 2003 (me) Review posted live
• 24 April 2003 (lvm) Original submission
## Author Notes
Dr Van Maldergem is a teacher of Human Genetics with 25 years' experience in clinical genetics. He is the coordinator of the Berardinelli-Seip study group (created in 1993) and organizer of the first international conference on lipodystrophies (Brussels, 1997).
## Revision History
8 December 2016 (ma) Comprehensive update posted live
28 June 2012 (me) Comprehensive update posted live
23 February 2010 (me) Comprehensive update posted live
23 August 2007 (cd) Revision: sequence analysis and prenatal diagnosis for BSCL type 1 available on a clinical basis
21 December 2005 (me) Comprehensive update posted live
3 August 2004 (lvm) Revision: Genetically Related Disorders
8 September 2003 (me) Review posted live
24 April 2003 (lvm) Original submission
• 8 December 2016 (ma) Comprehensive update posted live
• 28 June 2012 (me) Comprehensive update posted live
• 23 February 2010 (me) Comprehensive update posted live
• 23 August 2007 (cd) Revision: sequence analysis and prenatal diagnosis for BSCL type 1 available on a clinical basis
• 21 December 2005 (me) Comprehensive update posted live
• 3 August 2004 (lvm) Revision: Genetically Related Disorders
• 8 September 2003 (me) Review posted live
• 24 April 2003 (lvm) Original submission
## References
## Literature Cited
|
[
"AK Agarwal, E Arioglu, S De Almeida, N Akkoc, SI Taylor, AM Bowcock, RI Barnes, A Garg. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34.. Nat Genet 2002;31:21-3",
"AK Agarwal, RI Barnes, A Garg. Genetic basis of congenital generalized lipodystrophy.. Int J Obes Relat Metab Disord 2004;28:336-9",
"AK Agarwal, A Garg. Genetic disorders of adipose tissue development, differentiation, and death.. Annu Rev Genomics Hum Genet 2006;7:175-99",
"AK Agarwal, V Simha, EA Oral, SA Moran, P Gorden, S O'Rahilly, Z Zaidi, F Gurakan, SA Arslanian, A Klar, A Ricker, NH White, L Bindl, K Herbst, K Kennel, SB Patel, L Al-Gazali, A Garg. Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy.. J Clin Endocrinol Metab 2003;88:4840-7",
"J Beltrand, M Beregszaszi, D Chevenne, G Sebag, M De Kerdanet, F Huet, M Polak, N Tubiana-Rufi, D Lacombe, M De Paoli, C Levy-Marchal. Metabolic correction induced by leptin replacement treatment in young children with Berardinelli-Seip congenital lipoatrophy.. Pediatrics 2007;120:e291-6",
"BR Cartwright, JM Goodman. Seipin: from human disease to molecular mechanism. J Lipid Res 2012;53:1042-55",
"FG Debray, C Baguette, S Colinet, L Van Maldergem, C Verellen-Dumoulin. Early infantile cardiomyopathy and liver disease: a multisystemic disorder caused by congenital lipodystrophy.. Mol Genet Metab 2013;109:227-9",
"K Ebihara, T Kusakabe, M Hirata, H Masuzaki, F Miyanaga, N Kobayashi, T Tanaka, H Chusho, T Miyazawa, T Hayashi, K Hosoda, Y Ogawa, AM DePaoli, M Fukushima, K Nakao. Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy.. J Clin Endocrinol Metab 2007;92:532-41",
"K Ebihara, T Kusakabe, H Masuzaki, N Kobayashi, T Tanaka, H Chusho, F Miyanaga, T Miyazawa, T Hayashi, K Hosoda, Y Ogawa, K Nakao. Gene and phenotype analysis of congenital generalized lipodystrophy in Japanese: a novel homozygous nonsense mutation in seipin gene.. J Clin Endocrinol Metab 2004;89:2360-4",
"B Friguls, W Coroleu, R del Alcazar, P Hilbert, L Van Maldergem, G Pintos-Morell. Severe cardiac phenotype of Berardinelli-Seip congenital lipodystrophy in an infant with homozygous E189X BSCL2 mutation.. Eur J Med Genet 2009;52:14-6",
"M Fu, R Kazlauskaite, F Baracho Mde, MG Santos, J Brandão-Neto, S Villares, FS Celi, BL Wajchenberg, AR Shuldiner. Mutations in Gng3lg and AGPAT2 in Berardinelli-Seip congenital lipodystrophy and Brunzell syndrome: phenotype variability suggests important modifier effects.. J Clin Endocrinol Metab. 2004;89:2916-22",
"A Garg, R Wilson, R Barnes, E Arioglu, Z Zaidi, F Gurakan, N Kocak, S O'Rahilly, SI Taylor, SB Patel, AM Bowcock. A gene for congenital generalized lipodystrophy maps to human chromosome 9q34.. J Clin Endocrinol Metab 1999;84:3390-4",
"A Garg. Clinical review#: Lipodystrophies: genetic and acquired body fat disorders.. J Clin Endocrinol Metab. 2011;96:3313-25",
"LM Graul-Neumann, T Kienitz, PN Robinson, S Baasanjav, B Karow, G Gillessen-Kaesbach, R Fahsold, H Schmidt, K Hoffmann, E Passarge. Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of the FBN1-gene.. Am J Med Genet A. 2010;152A:2749-55",
"E Guillén-Navarro, S Sánchez-Iglesias, R Domingo-Jiménez, B Victoria, A Ruiz-Riquelme, A Rábano, L Loidi, A Beiras, B González-Méndez, A Ramos, V López-González, MJ Ballesta-Martínez, M Garrido-Pumar, P Aguiar, A Ruibal, JR Requena, D Araújo-Vilar. A new seipin-associated neurodegenerative syndrome.. J Med Genet. 2013;50:401-9",
"YK Hayashi, C Matsuda, M Ogawa, K Goto, K Tominaga, S Mitsuhashi, Y-E Park, I Nonaka, N Hino-Fukuyo, K Haginoya, H Sugano, I Nishino. Human PTFR mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy.. J Clin Invest 2009;119:2623-33",
"D Ito, N Suzuki. Seipinopathy: a novel endoplasmic reticulum stress-associated disease.. Brain 2009;132:8-15",
"EH Jeninga, M de Vroede, N Hamers, JM Breur, NM Verhoeven-Duif, R Berger, E Kalkhoven. a patient with congenital generalized lipodystrophy due to a novel mutation in BSCL2: indications for secondary mitochondrial dysfunction.. JIMD Rep 2012;4:47-54",
"CA Kim, M Delépine, E Boutet, H El Mourabit, S Le Lay, M Meier, M Nemani, E Bridel, CC Leite, DR Bertola, RK Semple, S O'Rahilly, I Dugail, J Capeau, M Lathrop, J Magré. Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy.. J Clin Endocrinol Metab. 2008;93:1129-34",
"J Magré, M Delépine, E Khallouf, T Gedde-Dahl, L Van Maldergem, E Sobel, J Papp, M Meier, A Mégarbané, A Bachy, A Verloes, FH d'Abronzo, E Seemanova, R Assan, N Baudic, C Bourut, P Czernichow, F Huet, F Grigorescu, M de Kerdanet, D Lacombe, P Labrune, M Lanza, H Loret, F Matsuda, J Navarro, A Nivelon-Chevalier, M Polak, JJ Robert, P Tric, N Tubiana-Rufi, C Vigouroux, J Weissenbach, S Savasta, JA Maassen, O Trygstad, P Bogalho, P Freitas, JL Medina, F Bonnicci, BI Joffe, G Loyson, VR Panz, FJ Raal, S O'Rahilly, T Stephenson, CR Kahn, M Lathrop, J Capeau. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.. Nat Genet 2001;28:365-70",
"J Magré, M Delépine, L Van Maldergem, JJ Robert, JA Maassen, M Meier, VR Panz, CA Kim, N Tubiana-Rufi, P Czernichow, E Seemanova, CR Buchanan, D Lacombe, C Vigouroux, O Lascols, CR Kahn, J Capeau, M Lathrop. Prevalence of mutations in AGPAT2 among human lipodystrophies.. Diabetes 2003;52:1573-8",
"DM Miranda, BL Wajchenberg, MR Calsolari, MJ Aguiar, JM Silva, MG Ribeiro, C Fonseca, D Amaral, WL Boson, BA Resende, L De Marco. Novel mutations of the BSCL2 and AGPAT2 genes in 10 families with Berardinelli-Seip congenital generalized lipodystrophy syndrome.. Clin Endocrinol (Oxf) 2009;71:512-7",
"A Misra, A Garg. Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature.. Medicine (Baltimore) 2003;82:129-46",
"VA Payne, N Grimsey, A Tuthill, SL Gray, E Dalla Nora, RK Semple, S O’Rahilly, JJ Rochford. The human lipodystrophy gene BSCL2/seipin may be essential for adipocyte normal differentiation.. Diabetes 2008;57:2055-60",
"A Rajab, B Bappal, H Al-Shaikh, S Al-Khusaibi, AJ Mohammed. Common autosomal recessive diseases in Oman derived from a hospital-based registry.. Community Genet. 2005;8:27-30",
"A Rajab, V Straub, LJ McCann, D Seelow, R Varon, R Barresi, A Schulze, B Lucke, S Lützkendorf, M Karbasiyan, S Bachmann, S Spuler, M Schuelke. Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling (CGL4) due to PTRF-CAVIN mutations.. PLoS Genet 2010;6",
"S Shastry, MR Delgado, E Dirik, M Turkmen, AK Agarwal, A Garg. Congenital generalized lipodystrophy, type 4 (CGL4) associated with myopathy due to novel PTRF mutations.. Am J Med Genet A. 2010;152A:2245-53",
"V Simha, AK Agarwal, PA Aronin, ST Iannaccone, A Garg. Novel subtype of congenital generalized lipodystrophy associated with muscular weakness and cervical spine instability.. Am J Med Genet A. 2008;146A:2318-26",
"MA Tsoukas, MF Farr, CS Mantzoros. Leptin in congenital and HIV-associated lipodystrophy.. Metabolism. 2015;64:47-59",
"L Van Maldergem, J Magré, TE Khallouf, T Gedde-Dahl, M Delepine, O Trygstad, E Seemanova, T Stephenson, CS Albott, F Bonnici, VR Panz, JL Medina, P Bogalho, F Huet, S Savasta, A Verloes, JJ Robert, H Loret, M De Kerdanet, N Tubiana-Rufi, A Megarbane, J Maassen, M Polak, D Lacombe, CR Kahn, EL Silveira, FH D'Abronzo, F Grigorescu, M Lathrop, J Capeau, S O'Rahilly. Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy.. J Med Genet 2002;39:722-33",
"K Wee, W Yang, S Sugii, W Han. Towards a mechanistic understanding of lipodystrophy and seipin function.. Biosci Rep. 2014;34:583-91",
"S Wei, S Soh, SL Xia, WY Ong, ZP Pang, W Han. Seipin regulates excitatory synaptic transmission in cortical neurons.. J Neurochem. 2013;124:478-89",
"C Windpassinger, M Auer-Grumbach, J Irobi, H Patel, E Petek, G Horl, R Malli, JA Reed, I Dierick, N Verpoorten, TT Warner, C Proukakis, P Van den Bergh, C Verellen, L Van Maldergem, L Merlini, P De Jonghe, V Timmerman, AH Crosby, K Wagner. Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome.. Nat Genet 2004;36:271-6"
] |
8/9/2003
|
8/12/2016
|
23/8/2007
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
burn-mckeown
|
burn-mckeown
|
[
"Burn-McKeown Syndrome (BMKS)",
"TXNL4A-Related Choanal Atresia with Minor Anomalies",
"TXNL4A-Related Isolated Choanal Atresia",
"Thioredoxin-like protein 4A",
"TXNL4A",
"TXNL4A-Related Craniofacial Disorders"
] |
Hermann-Josef Lüdecke, Dagmar Wieczorek
|
Summary The diagnosis of a
|
Burn-McKeown Syndrome (BMKS)
Choanal atresia with minor anomalies
Isolated choanal atresia
For synonyms and outdated names, see
For other genetic causes of these phenotypes, see
• Burn-McKeown Syndrome (BMKS)
• Choanal atresia with minor anomalies
• Isolated choanal atresia
## Diagnosis
A
Distinctive facies (
Short palpebral fissures (i.e., distance between inner canthus and outer canthus)
Lower eyelid defects including coloboma and thick eyelashes
Prominent nasal bridge and widely spaced eyes, leading to a typical facial profile
Short philtrum, thin vermilion of the upper lip, thick vermilion of the lower lip, and reduced opening of the mouth
Normal intellect
The diagnosis of a
All probands described to date have had at least one copy of a 34-bp deletion in the promoter of
Type 1: chr18:g. 77,748,581_77,748,614del [
Type 2: chr18:g.77,748,604_77,748,637del [
The majority of reported probands have a type 1 promoter deletion on one allele and a loss-of-function pathogenic variant on the other.
Note: Identification of biallelic
Molecular genetic testing approaches can include
Note: If a deletion that includes
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
The two reported 34-bp promoter deletions can be detected and distinguished by targeted assays (e.g., PCR and subsequent sequence analysis of PCR products).
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions. To date, no partial or complete
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• Distinctive facies (
• Short palpebral fissures (i.e., distance between inner canthus and outer canthus)
• Lower eyelid defects including coloboma and thick eyelashes
• Prominent nasal bridge and widely spaced eyes, leading to a typical facial profile
• Short philtrum, thin vermilion of the upper lip, thick vermilion of the lower lip, and reduced opening of the mouth
• Short palpebral fissures (i.e., distance between inner canthus and outer canthus)
• Lower eyelid defects including coloboma and thick eyelashes
• Prominent nasal bridge and widely spaced eyes, leading to a typical facial profile
• Short philtrum, thin vermilion of the upper lip, thick vermilion of the lower lip, and reduced opening of the mouth
• Normal intellect
• Short palpebral fissures (i.e., distance between inner canthus and outer canthus)
• Lower eyelid defects including coloboma and thick eyelashes
• Prominent nasal bridge and widely spaced eyes, leading to a typical facial profile
• Short philtrum, thin vermilion of the upper lip, thick vermilion of the lower lip, and reduced opening of the mouth
• Type 1: chr18:g. 77,748,581_77,748,614del [
• Type 2: chr18:g.77,748,604_77,748,637del [
## Suggestive Findings
A
Distinctive facies (
Short palpebral fissures (i.e., distance between inner canthus and outer canthus)
Lower eyelid defects including coloboma and thick eyelashes
Prominent nasal bridge and widely spaced eyes, leading to a typical facial profile
Short philtrum, thin vermilion of the upper lip, thick vermilion of the lower lip, and reduced opening of the mouth
Normal intellect
• Distinctive facies (
• Short palpebral fissures (i.e., distance between inner canthus and outer canthus)
• Lower eyelid defects including coloboma and thick eyelashes
• Prominent nasal bridge and widely spaced eyes, leading to a typical facial profile
• Short philtrum, thin vermilion of the upper lip, thick vermilion of the lower lip, and reduced opening of the mouth
• Short palpebral fissures (i.e., distance between inner canthus and outer canthus)
• Lower eyelid defects including coloboma and thick eyelashes
• Prominent nasal bridge and widely spaced eyes, leading to a typical facial profile
• Short philtrum, thin vermilion of the upper lip, thick vermilion of the lower lip, and reduced opening of the mouth
• Normal intellect
• Short palpebral fissures (i.e., distance between inner canthus and outer canthus)
• Lower eyelid defects including coloboma and thick eyelashes
• Prominent nasal bridge and widely spaced eyes, leading to a typical facial profile
• Short philtrum, thin vermilion of the upper lip, thick vermilion of the lower lip, and reduced opening of the mouth
## Establishing the Diagnosis
The diagnosis of a
All probands described to date have had at least one copy of a 34-bp deletion in the promoter of
Type 1: chr18:g. 77,748,581_77,748,614del [
Type 2: chr18:g.77,748,604_77,748,637del [
The majority of reported probands have a type 1 promoter deletion on one allele and a loss-of-function pathogenic variant on the other.
Note: Identification of biallelic
Molecular genetic testing approaches can include
Note: If a deletion that includes
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
The two reported 34-bp promoter deletions can be detected and distinguished by targeted assays (e.g., PCR and subsequent sequence analysis of PCR products).
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions. To date, no partial or complete
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• Type 1: chr18:g. 77,748,581_77,748,614del [
• Type 2: chr18:g.77,748,604_77,748,637del [
## Recommended Testing
Note: If a deletion that includes
## Other Testing to Consider
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
The two reported 34-bp promoter deletions can be detected and distinguished by targeted assays (e.g., PCR and subsequent sequence analysis of PCR products).
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions. To date, no partial or complete
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
## Clinical Characteristics
To date, 20 individuals with biallelic pathogenic variants in
No genotype-phenotype correlations have been identified.
Initially described as a distinct entity in a highly consanguineous Alaskan family by
The prevalence of
## Clinical Description
To date, 20 individuals with biallelic pathogenic variants in
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Nomenclature
Initially described as a distinct entity in a highly consanguineous Alaskan family by
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genetic Disorders with Choanal Atresia/Stenosis in the Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance
Autosomal dominant TCS is caused by a heterozygous pathogenic variant in
## Management
To establish the extent of disease and needs in an individual diagnosed with a
Recommended Evaluations Following Initial Diagnosis in Individuals with a
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with a
The team may include a oromaxillofacial surgeon, plastic surgeon, otolaryngologist, dentist/orthodontist, and speech-language therapist.
Recommended Surveillance for Individuals with a
See
Search
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a
Recommended Evaluations Following Initial Diagnosis in Individuals with a
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with a
The team may include a oromaxillofacial surgeon, plastic surgeon, otolaryngologist, dentist/orthodontist, and speech-language therapist.
## Surveillance
Recommended Surveillance for Individuals with a
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of an affected child are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
•
• United Kingdom
•
## Molecular Genetics
TXNL4A-Related Craniofacial Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for TXNL4A-Related Craniofacial Disorders (
Two 34-bp deletions (type 1 and type 2) in the promoter region of
Probands identified to date are compound heterozygous for the type 1 promoter deletion and a loss-of-function allele, or homozygous for the type 2 promoter deletion, or more rarely, homozygous for the type 1 promoter deletion [
In yeast, homozygous null variants of the orthologous gene
## Molecular Pathogenesis
Two 34-bp deletions (type 1 and type 2) in the promoter region of
Probands identified to date are compound heterozygous for the type 1 promoter deletion and a loss-of-function allele, or homozygous for the type 2 promoter deletion, or more rarely, homozygous for the type 1 promoter deletion [
In yeast, homozygous null variants of the orthologous gene
## Chapter Notes
Dagmar Wieczorek has longstanding expertise in syndromic entities, especially those with intellectual disability (ID) and craniofacial malformations. She was principal investigator in the German Mental Retardation Network, funded by NGFNplus, and in the CRANIRARE, FACE, and Chromatin-Net consortia, all funded by the BMBF. She has published many papers on gene identification in individuals with ID and with craniofacial anomalies (e.g., Treacher Collins syndrome, Burn-McKeown syndrome, and acrofacial dysostosis, Cincinnati type), as well as papers on the clinical spectrum of new entities with special emphasis on the facial phenotype.
Dagmar WieczorekInstitut für HumangenetikUniversitätsklinikum DüsseldorfUniversitätsstr. 140225 Düsseldorf, GermanyEmail: [email protected]
The authors wish to gratefully acknowledge the contribution of the patients and their families.
12 May 2022 (ha) Comprehensive update posted live
14 July 2016 (bp) Review posted live
19 January 2016 (dw) Original submission
• 12 May 2022 (ha) Comprehensive update posted live
• 14 July 2016 (bp) Review posted live
• 19 January 2016 (dw) Original submission
## Author Notes
Dagmar Wieczorek has longstanding expertise in syndromic entities, especially those with intellectual disability (ID) and craniofacial malformations. She was principal investigator in the German Mental Retardation Network, funded by NGFNplus, and in the CRANIRARE, FACE, and Chromatin-Net consortia, all funded by the BMBF. She has published many papers on gene identification in individuals with ID and with craniofacial anomalies (e.g., Treacher Collins syndrome, Burn-McKeown syndrome, and acrofacial dysostosis, Cincinnati type), as well as papers on the clinical spectrum of new entities with special emphasis on the facial phenotype.
Dagmar WieczorekInstitut für HumangenetikUniversitätsklinikum DüsseldorfUniversitätsstr. 140225 Düsseldorf, GermanyEmail: [email protected]
## Acknowledgments
The authors wish to gratefully acknowledge the contribution of the patients and their families.
## Revision History
12 May 2022 (ha) Comprehensive update posted live
14 July 2016 (bp) Review posted live
19 January 2016 (dw) Original submission
• 12 May 2022 (ha) Comprehensive update posted live
• 14 July 2016 (bp) Review posted live
• 19 January 2016 (dw) Original submission
## References
## Literature Cited
Craniofacial phenotype in individuals with a
From
|
[
"JAC Goos, SMA Swagemakers, SRF Twigg, MF van Dooren, AJM Hoogeboom, C Beetz, S Günther, FJ Magielsen, CW Ockeloen. A Ramos-Arroyo M, Pfundt R, Yntema HG, van der Spek PJ, Stanier P, Wieczorek D, Wilkie AOM, van den Ouweland AMW, Mathijssen IMJ, Hurst JA. Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia.. Eur J Hum Genet. 2017;25:1126-33",
"AV Hing, C Leblond, RW Sze, JR Starr, S Monks, MA Parisi. A novel oculo-oto-facial dysplasia in a Native Alaskan community with autosomal recessive inheritance.. Am J Med Genet A. 2006;140:804-12",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"S Liu, R Rauhut, H-P Vornlocher, R Lührmann. The network of protein-protein interactions within the human U4/U6·U5 tri-snRNP.. RNA 2006;12:1418-30",
"DL Narayanan, G Purushothama, GS Bhavani, A Shukla. Burn-McKeown syndrome with biallelic promoter type 2 deletion in TXNL4A in two siblings.. Am J Med Genet A. 2020;182:1313-5",
"S Strang-Karlsson, J Urquhart, WG Newman, S Douzgou. Severe intellectual disability in a patient with Burn-McKeown syndrome.. Clin Dysmorphol. 2017;26:193-4",
"D Wieczorek, WG Newman, T Wieland, T Berulava, M Kaffe, D Falkenstein, C Beetz, E Graf, T Schwarzmayr, S Douzgou, J Clayton-Smith, SB Daly, SG Williams, SS Bhaskar, JE Urquhart, B Anderson, J O'Sullivan, O Boute, J Gundlach, JC Czeschik, AJ van Essen, F Hazan, S Park, A Hing, A Kuechler, DR Lohmann, KU Ludwig, E Mangold, L Steenpaß, M Zeschnigk, JR Lemke, CM Lourenco, U Hehr, EC Prott, M Waldenberger, AC Böhmer, B Horsthemke, RT O'Keefe, T Meitinger, J Burn, HJ Lüdecke, TM Strom. Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome.. Am J Hum Genet. 2014;95:698-707",
"KA Wood, JM Ellingford, HB Thomas, S Douzgou, GM Beaman, E Hobson, K Prescott, RT O'Keefe, WG Newman. Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome.. Clin Genet. 2022;101:255-9"
] |
14/7/2016
|
12/5/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
bvd
|
bvd
|
[
"Best Vitelliform Macular Dystrophy (BVMD)",
"BEST1 Adult-onset Vitelliform Macular Dystrophy (AVMD)",
"Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC)",
"Autosomal Recessive Bestrophinopathy (ARB)",
"Bestrophin-1",
"BEST1",
"Bestrophinopathies"
] |
Bestrophinopathies
|
Ian M MacDonald, Thomas Lee, Jessica Lawrence
|
Summary Bestrophinopathies, the spectrum of ophthalmic disorders caused by pathogenic variants in The diagnosis of autosomal dominant bestrophinopathy is established in a proband with suggestive findings and a heterozygous BVMD, AVMD, and ADVIRC are inherited in an autosomal dominant (AD) manner. By definition, autosomal recessive bestrophinopathy (ARB) is inherited in an autosomal recessive (AR) manner. AD bestrophinopathy. Each child of an affected individual has a 50% chance of inheriting the AR bestrophinopathy. If both parents are known to be heterozygous for a Once the
|
Best vitelliform macular dystrophy (BVMD)
Adult-onset vitelliform macular dystrophy (AVMD)
Autosomal dominant vitreoretinochoroidopathy (ADVIRC)
Autosomal recessive bestrophinopathy (ARB)
For synonyms and outdated names, see
• Best vitelliform macular dystrophy (BVMD)
• Adult-onset vitelliform macular dystrophy (AVMD)
• Autosomal dominant vitreoretinochoroidopathy (ADVIRC)
• Autosomal recessive bestrophinopathy (ARB)
## Diagnosis
No consensus diagnostic criteria for bestrophinopathies have been published.
A bestrophinopathy
Best vitelliform macular dystrophy (BVMD)
Onset age three to 15 years
Fundus examination. A typical yellow yolk-like macular lesion may be present, usually bilateral, but in some cases unilateral. Multiple lesions and lesions outside the macula occur in at least 25% of individuals. See
Onset age 30-50 years
Fundus examination. Subretinal, small, circular, yellow vitelliform lesion; vitelliform lesion can become atrophic over time.
Autosomal dominant vitreoretinochoroidopathy (ADVIRC)
Onset in the first decade of life
Fundus examination. Peripheral retinal pigmentation, white retinal opacities
Other ocular findings. Nanophthalmos, hyperopia, microcornea, narrow-angle glaucoma
Autosomal recessive bestrophinopathy (ARB)
Onset in the first decade of life
Fundus examination. White subretinal deposits with macular subretinal fluid
BVMD. Usually abnormal with a reduced light peak / dark trough ratio (Arden ratio) <1.5, most often between 1.0 and 1.3.
Note: Occasionally individuals with molecularly confirmed Best vitelliform macular dystrophy have a normal EOG [
AVMD. Normal or only slightly reduced
ADVIRC. Abnormal
ARB. Abnormal
BVMD and AVMD. Normal
ADVIRC. Normal or reduced
ARB. Reduced scotopic and photopic responses
BVMD and AVMD. Splitting and elevation of outer retina and retinal pigment epithelial layer with dome-like hyporeflective or hyperreflective material and subretinal fluid
ADVIRC. Retinal atrophy usually present; possible cystoid macular edema
ARB. Subretinal deposits with subretinal and/or intraretinal fluid
BVMD and AVMD. Hyperautofluorescence at early stages progressing to hypofluorescence in late atrophic stages
ADVIRC. Typically normal centrally with blocked fluorescence in the periphery
ARB. Diffuse, discrete small areas of hyper- and hypoautofluorescence
The diagnosis of bestrophinopathy
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Bestrophinopathies
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Best vitelliform macular dystrophy (BVMD)
• Onset age three to 15 years
• Fundus examination. A typical yellow yolk-like macular lesion may be present, usually bilateral, but in some cases unilateral. Multiple lesions and lesions outside the macula occur in at least 25% of individuals. See
• Onset age three to 15 years
• Fundus examination. A typical yellow yolk-like macular lesion may be present, usually bilateral, but in some cases unilateral. Multiple lesions and lesions outside the macula occur in at least 25% of individuals. See
• Onset age 30-50 years
• Fundus examination. Subretinal, small, circular, yellow vitelliform lesion; vitelliform lesion can become atrophic over time.
• Onset age 30-50 years
• Fundus examination. Subretinal, small, circular, yellow vitelliform lesion; vitelliform lesion can become atrophic over time.
• Autosomal dominant vitreoretinochoroidopathy (ADVIRC)
• Onset in the first decade of life
• Fundus examination. Peripheral retinal pigmentation, white retinal opacities
• Other ocular findings. Nanophthalmos, hyperopia, microcornea, narrow-angle glaucoma
• Onset in the first decade of life
• Fundus examination. Peripheral retinal pigmentation, white retinal opacities
• Other ocular findings. Nanophthalmos, hyperopia, microcornea, narrow-angle glaucoma
• Autosomal recessive bestrophinopathy (ARB)
• Onset in the first decade of life
• Fundus examination. White subretinal deposits with macular subretinal fluid
• Onset in the first decade of life
• Fundus examination. White subretinal deposits with macular subretinal fluid
• Onset age three to 15 years
• Fundus examination. A typical yellow yolk-like macular lesion may be present, usually bilateral, but in some cases unilateral. Multiple lesions and lesions outside the macula occur in at least 25% of individuals. See
• Onset age 30-50 years
• Fundus examination. Subretinal, small, circular, yellow vitelliform lesion; vitelliform lesion can become atrophic over time.
• Onset in the first decade of life
• Fundus examination. Peripheral retinal pigmentation, white retinal opacities
• Other ocular findings. Nanophthalmos, hyperopia, microcornea, narrow-angle glaucoma
• Onset in the first decade of life
• Fundus examination. White subretinal deposits with macular subretinal fluid
• BVMD. Usually abnormal with a reduced light peak / dark trough ratio (Arden ratio) <1.5, most often between 1.0 and 1.3.
• Note: Occasionally individuals with molecularly confirmed Best vitelliform macular dystrophy have a normal EOG [
• AVMD. Normal or only slightly reduced
• ADVIRC. Abnormal
• ARB. Abnormal
• BVMD. Usually abnormal with a reduced light peak / dark trough ratio (Arden ratio) <1.5, most often between 1.0 and 1.3.
• Note: Occasionally individuals with molecularly confirmed Best vitelliform macular dystrophy have a normal EOG [
• AVMD. Normal or only slightly reduced
• ADVIRC. Abnormal
• ARB. Abnormal
•
• BVMD and AVMD. Normal
• ADVIRC. Normal or reduced
• ARB. Reduced scotopic and photopic responses
• BVMD and AVMD. Normal
• ADVIRC. Normal or reduced
• ARB. Reduced scotopic and photopic responses
•
• BVMD and AVMD. Splitting and elevation of outer retina and retinal pigment epithelial layer with dome-like hyporeflective or hyperreflective material and subretinal fluid
• ADVIRC. Retinal atrophy usually present; possible cystoid macular edema
• ARB. Subretinal deposits with subretinal and/or intraretinal fluid
• BVMD and AVMD. Splitting and elevation of outer retina and retinal pigment epithelial layer with dome-like hyporeflective or hyperreflective material and subretinal fluid
• ADVIRC. Retinal atrophy usually present; possible cystoid macular edema
• ARB. Subretinal deposits with subretinal and/or intraretinal fluid
•
• BVMD and AVMD. Hyperautofluorescence at early stages progressing to hypofluorescence in late atrophic stages
• ADVIRC. Typically normal centrally with blocked fluorescence in the periphery
• ARB. Diffuse, discrete small areas of hyper- and hypoautofluorescence
• BVMD and AVMD. Hyperautofluorescence at early stages progressing to hypofluorescence in late atrophic stages
• ADVIRC. Typically normal centrally with blocked fluorescence in the periphery
• ARB. Diffuse, discrete small areas of hyper- and hypoautofluorescence
• BVMD. Usually abnormal with a reduced light peak / dark trough ratio (Arden ratio) <1.5, most often between 1.0 and 1.3.
• Note: Occasionally individuals with molecularly confirmed Best vitelliform macular dystrophy have a normal EOG [
• AVMD. Normal or only slightly reduced
• ADVIRC. Abnormal
• ARB. Abnormal
• BVMD and AVMD. Normal
• ADVIRC. Normal or reduced
• ARB. Reduced scotopic and photopic responses
• BVMD and AVMD. Splitting and elevation of outer retina and retinal pigment epithelial layer with dome-like hyporeflective or hyperreflective material and subretinal fluid
• ADVIRC. Retinal atrophy usually present; possible cystoid macular edema
• ARB. Subretinal deposits with subretinal and/or intraretinal fluid
• BVMD and AVMD. Hyperautofluorescence at early stages progressing to hypofluorescence in late atrophic stages
• ADVIRC. Typically normal centrally with blocked fluorescence in the periphery
• ARB. Diffuse, discrete small areas of hyper- and hypoautofluorescence
## Suggestive Findings
A bestrophinopathy
Best vitelliform macular dystrophy (BVMD)
Onset age three to 15 years
Fundus examination. A typical yellow yolk-like macular lesion may be present, usually bilateral, but in some cases unilateral. Multiple lesions and lesions outside the macula occur in at least 25% of individuals. See
Onset age 30-50 years
Fundus examination. Subretinal, small, circular, yellow vitelliform lesion; vitelliform lesion can become atrophic over time.
Autosomal dominant vitreoretinochoroidopathy (ADVIRC)
Onset in the first decade of life
Fundus examination. Peripheral retinal pigmentation, white retinal opacities
Other ocular findings. Nanophthalmos, hyperopia, microcornea, narrow-angle glaucoma
Autosomal recessive bestrophinopathy (ARB)
Onset in the first decade of life
Fundus examination. White subretinal deposits with macular subretinal fluid
BVMD. Usually abnormal with a reduced light peak / dark trough ratio (Arden ratio) <1.5, most often between 1.0 and 1.3.
Note: Occasionally individuals with molecularly confirmed Best vitelliform macular dystrophy have a normal EOG [
AVMD. Normal or only slightly reduced
ADVIRC. Abnormal
ARB. Abnormal
BVMD and AVMD. Normal
ADVIRC. Normal or reduced
ARB. Reduced scotopic and photopic responses
BVMD and AVMD. Splitting and elevation of outer retina and retinal pigment epithelial layer with dome-like hyporeflective or hyperreflective material and subretinal fluid
ADVIRC. Retinal atrophy usually present; possible cystoid macular edema
ARB. Subretinal deposits with subretinal and/or intraretinal fluid
BVMD and AVMD. Hyperautofluorescence at early stages progressing to hypofluorescence in late atrophic stages
ADVIRC. Typically normal centrally with blocked fluorescence in the periphery
ARB. Diffuse, discrete small areas of hyper- and hypoautofluorescence
• Best vitelliform macular dystrophy (BVMD)
• Onset age three to 15 years
• Fundus examination. A typical yellow yolk-like macular lesion may be present, usually bilateral, but in some cases unilateral. Multiple lesions and lesions outside the macula occur in at least 25% of individuals. See
• Onset age three to 15 years
• Fundus examination. A typical yellow yolk-like macular lesion may be present, usually bilateral, but in some cases unilateral. Multiple lesions and lesions outside the macula occur in at least 25% of individuals. See
• Onset age 30-50 years
• Fundus examination. Subretinal, small, circular, yellow vitelliform lesion; vitelliform lesion can become atrophic over time.
• Onset age 30-50 years
• Fundus examination. Subretinal, small, circular, yellow vitelliform lesion; vitelliform lesion can become atrophic over time.
• Autosomal dominant vitreoretinochoroidopathy (ADVIRC)
• Onset in the first decade of life
• Fundus examination. Peripheral retinal pigmentation, white retinal opacities
• Other ocular findings. Nanophthalmos, hyperopia, microcornea, narrow-angle glaucoma
• Onset in the first decade of life
• Fundus examination. Peripheral retinal pigmentation, white retinal opacities
• Other ocular findings. Nanophthalmos, hyperopia, microcornea, narrow-angle glaucoma
• Autosomal recessive bestrophinopathy (ARB)
• Onset in the first decade of life
• Fundus examination. White subretinal deposits with macular subretinal fluid
• Onset in the first decade of life
• Fundus examination. White subretinal deposits with macular subretinal fluid
• Onset age three to 15 years
• Fundus examination. A typical yellow yolk-like macular lesion may be present, usually bilateral, but in some cases unilateral. Multiple lesions and lesions outside the macula occur in at least 25% of individuals. See
• Onset age 30-50 years
• Fundus examination. Subretinal, small, circular, yellow vitelliform lesion; vitelliform lesion can become atrophic over time.
• Onset in the first decade of life
• Fundus examination. Peripheral retinal pigmentation, white retinal opacities
• Other ocular findings. Nanophthalmos, hyperopia, microcornea, narrow-angle glaucoma
• Onset in the first decade of life
• Fundus examination. White subretinal deposits with macular subretinal fluid
• BVMD. Usually abnormal with a reduced light peak / dark trough ratio (Arden ratio) <1.5, most often between 1.0 and 1.3.
• Note: Occasionally individuals with molecularly confirmed Best vitelliform macular dystrophy have a normal EOG [
• AVMD. Normal or only slightly reduced
• ADVIRC. Abnormal
• ARB. Abnormal
• BVMD. Usually abnormal with a reduced light peak / dark trough ratio (Arden ratio) <1.5, most often between 1.0 and 1.3.
• Note: Occasionally individuals with molecularly confirmed Best vitelliform macular dystrophy have a normal EOG [
• AVMD. Normal or only slightly reduced
• ADVIRC. Abnormal
• ARB. Abnormal
•
• BVMD and AVMD. Normal
• ADVIRC. Normal or reduced
• ARB. Reduced scotopic and photopic responses
• BVMD and AVMD. Normal
• ADVIRC. Normal or reduced
• ARB. Reduced scotopic and photopic responses
•
• BVMD and AVMD. Splitting and elevation of outer retina and retinal pigment epithelial layer with dome-like hyporeflective or hyperreflective material and subretinal fluid
• ADVIRC. Retinal atrophy usually present; possible cystoid macular edema
• ARB. Subretinal deposits with subretinal and/or intraretinal fluid
• BVMD and AVMD. Splitting and elevation of outer retina and retinal pigment epithelial layer with dome-like hyporeflective or hyperreflective material and subretinal fluid
• ADVIRC. Retinal atrophy usually present; possible cystoid macular edema
• ARB. Subretinal deposits with subretinal and/or intraretinal fluid
•
• BVMD and AVMD. Hyperautofluorescence at early stages progressing to hypofluorescence in late atrophic stages
• ADVIRC. Typically normal centrally with blocked fluorescence in the periphery
• ARB. Diffuse, discrete small areas of hyper- and hypoautofluorescence
• BVMD and AVMD. Hyperautofluorescence at early stages progressing to hypofluorescence in late atrophic stages
• ADVIRC. Typically normal centrally with blocked fluorescence in the periphery
• ARB. Diffuse, discrete small areas of hyper- and hypoautofluorescence
• BVMD. Usually abnormal with a reduced light peak / dark trough ratio (Arden ratio) <1.5, most often between 1.0 and 1.3.
• Note: Occasionally individuals with molecularly confirmed Best vitelliform macular dystrophy have a normal EOG [
• AVMD. Normal or only slightly reduced
• ADVIRC. Abnormal
• ARB. Abnormal
• BVMD and AVMD. Normal
• ADVIRC. Normal or reduced
• ARB. Reduced scotopic and photopic responses
• BVMD and AVMD. Splitting and elevation of outer retina and retinal pigment epithelial layer with dome-like hyporeflective or hyperreflective material and subretinal fluid
• ADVIRC. Retinal atrophy usually present; possible cystoid macular edema
• ARB. Subretinal deposits with subretinal and/or intraretinal fluid
• BVMD and AVMD. Hyperautofluorescence at early stages progressing to hypofluorescence in late atrophic stages
• ADVIRC. Typically normal centrally with blocked fluorescence in the periphery
• ARB. Diffuse, discrete small areas of hyper- and hypoautofluorescence
## Establishing the Diagnosis
The diagnosis of bestrophinopathy
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Bestrophinopathies
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Bestrophinopathies
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
Bestrophinopathies, the spectrum of ophthalmic disorders caused by pathogenic variants in
Bestrophinopathies: Frequency of Phenotypes
Multiple vitelliform lesions
Atrophic scar
Choroidal neovascularization
Unilateral vitelliform lesions
Vitelliform lesion progressing through stages of heterogeneous "scramble egg" to pseudohypopyon lesion to atrophic scar
Visual acuity can progress from 20/20 to <20/200.
Lesions ↑ & then ↓ in size, becoming an atrophic area.
Visual acuity 20/40 to 20/200
Hyperopia
Shallow anterior chamber/angle closure
Microcornea
Fibrillar vitreous condensation
White subretinal deposits
Subretinal fluid
Hyperopia
Subretinal fibrous scars
Shallow anterior chamber/angle closure
Glaucoma
Cystoid macular edema
Subretinal deposits w/subretinal fluid in early stages progressing to subretinal fibrosis
Visual acuity can progress from 20/20 to <20/200.
BVMD is a slowly progressive macular dystrophy typically with juvenile onset. The characteristic "egg yolk"-like lesion can be either unilateral or bilateral, single or multiple, and macular or eccentric. Retinal lesions progress from the "egg yolk" or vitelliform stage to a vitelliruptive form and finally to an end-stage form with macular scarring or neovascularization [
Although the following clinical stages have been described, it is important to note that the disease does not progress through each of these stages in every individual:
AVMD is part of a group of conditions called pattern dystrophy (see
Affected individuals usually become symptomatic in the fifth decade with typical onset between ages 30 and 50 years. Some individuals may be asymptomatic or have reduced visual acuity and metamorphopsia. Slow visual deterioration is the usual course. Choroidal neovascularization can occur in rare cases.
The yellow subfoveal deposits are about one third disc diameter size and will diminish over time to become atrophic. The vitelliform lesion is subretinal with heterogeneous hyperreflectivity and half of eyes can have pigment epithelial detachments.
ADVIRC is characterized by circumscribed hyperpigmentation in the peripheral retina. A sharp demarcation line exists in the midperiphery between normal and abnormal retina. White pre-retinal opacities occur with the areas of hyperpigmentation. Cystoid macular degeneration is common along with pre-retinal neovascularization. Vitreous cells and vitreous fibrillar condensation can obscure vision. Affected individuals maintain good visual acuity until later in the disease course, when the entire retina becomes involved.
There is an association with nanophthalmos, microcornea, hyperopia, and narrow anterior chamber angle with angle closure glaucoma [
Typical age of onset in ARB is in the first decade but can be as late as the fifth decade. ARB is a more severe retinopathy than BVMD. Visual acuity can range from normal to less than 20/200 depending on the macular involvement of the disease.
The multifocal subretinal yellow deposits seen in the macula and peripheral retina are associated with subretinal fibrosis and intraretinal and subretinal fluid.
Affected individuals are hyperopic with shallow anterior chambers, making them prone to angle closure glaucoma.
Six children from three different families had biallelic pathogenic variants in
For most
A family with a
A family with
Other observations:
Six children from three different families had biallelic pathogenic variants in
BVMD shows high but reduced (>70%) penetrance, especially when electrooculogram is used as evidence of clinical expression.
Individuals heterozygous for a
Nomenclature
Other terms used to refer to BVMD include Best disease, early-onset vitelliform macular dystrophy, juvenile-onset vitelliform macular dystrophy, and polymorphic vitelline macular degeneration.
BVMD is a rare disorder. The prevalence has been estimated at 1:5,500 in a North American population [
The
• Multiple vitelliform lesions
• Atrophic scar
• Choroidal neovascularization
• Unilateral vitelliform lesions
• Vitelliform lesion progressing through stages of heterogeneous "scramble egg" to pseudohypopyon lesion to atrophic scar
• Visual acuity can progress from 20/20 to <20/200.
• Lesions ↑ & then ↓ in size, becoming an atrophic area.
• Visual acuity 20/40 to 20/200
• Hyperopia
• Shallow anterior chamber/angle closure
• Microcornea
• Fibrillar vitreous condensation
• White subretinal deposits
• Subretinal fluid
• Hyperopia
• Subretinal fibrous scars
• Shallow anterior chamber/angle closure
• Glaucoma
• Cystoid macular edema
• Subretinal deposits w/subretinal fluid in early stages progressing to subretinal fibrosis
• Visual acuity can progress from 20/20 to <20/200.
• A family with a
• A family with
• Six children from three different families had biallelic pathogenic variants in
## Clinical Description
Bestrophinopathies, the spectrum of ophthalmic disorders caused by pathogenic variants in
Bestrophinopathies: Frequency of Phenotypes
Multiple vitelliform lesions
Atrophic scar
Choroidal neovascularization
Unilateral vitelliform lesions
Vitelliform lesion progressing through stages of heterogeneous "scramble egg" to pseudohypopyon lesion to atrophic scar
Visual acuity can progress from 20/20 to <20/200.
Lesions ↑ & then ↓ in size, becoming an atrophic area.
Visual acuity 20/40 to 20/200
Hyperopia
Shallow anterior chamber/angle closure
Microcornea
Fibrillar vitreous condensation
White subretinal deposits
Subretinal fluid
Hyperopia
Subretinal fibrous scars
Shallow anterior chamber/angle closure
Glaucoma
Cystoid macular edema
Subretinal deposits w/subretinal fluid in early stages progressing to subretinal fibrosis
Visual acuity can progress from 20/20 to <20/200.
BVMD is a slowly progressive macular dystrophy typically with juvenile onset. The characteristic "egg yolk"-like lesion can be either unilateral or bilateral, single or multiple, and macular or eccentric. Retinal lesions progress from the "egg yolk" or vitelliform stage to a vitelliruptive form and finally to an end-stage form with macular scarring or neovascularization [
Although the following clinical stages have been described, it is important to note that the disease does not progress through each of these stages in every individual:
AVMD is part of a group of conditions called pattern dystrophy (see
Affected individuals usually become symptomatic in the fifth decade with typical onset between ages 30 and 50 years. Some individuals may be asymptomatic or have reduced visual acuity and metamorphopsia. Slow visual deterioration is the usual course. Choroidal neovascularization can occur in rare cases.
The yellow subfoveal deposits are about one third disc diameter size and will diminish over time to become atrophic. The vitelliform lesion is subretinal with heterogeneous hyperreflectivity and half of eyes can have pigment epithelial detachments.
ADVIRC is characterized by circumscribed hyperpigmentation in the peripheral retina. A sharp demarcation line exists in the midperiphery between normal and abnormal retina. White pre-retinal opacities occur with the areas of hyperpigmentation. Cystoid macular degeneration is common along with pre-retinal neovascularization. Vitreous cells and vitreous fibrillar condensation can obscure vision. Affected individuals maintain good visual acuity until later in the disease course, when the entire retina becomes involved.
There is an association with nanophthalmos, microcornea, hyperopia, and narrow anterior chamber angle with angle closure glaucoma [
Typical age of onset in ARB is in the first decade but can be as late as the fifth decade. ARB is a more severe retinopathy than BVMD. Visual acuity can range from normal to less than 20/200 depending on the macular involvement of the disease.
The multifocal subretinal yellow deposits seen in the macula and peripheral retina are associated with subretinal fibrosis and intraretinal and subretinal fluid.
Affected individuals are hyperopic with shallow anterior chambers, making them prone to angle closure glaucoma.
Six children from three different families had biallelic pathogenic variants in
• Multiple vitelliform lesions
• Atrophic scar
• Choroidal neovascularization
• Unilateral vitelliform lesions
• Vitelliform lesion progressing through stages of heterogeneous "scramble egg" to pseudohypopyon lesion to atrophic scar
• Visual acuity can progress from 20/20 to <20/200.
• Lesions ↑ & then ↓ in size, becoming an atrophic area.
• Visual acuity 20/40 to 20/200
• Hyperopia
• Shallow anterior chamber/angle closure
• Microcornea
• Fibrillar vitreous condensation
• White subretinal deposits
• Subretinal fluid
• Hyperopia
• Subretinal fibrous scars
• Shallow anterior chamber/angle closure
• Glaucoma
• Cystoid macular edema
• Subretinal deposits w/subretinal fluid in early stages progressing to subretinal fibrosis
• Visual acuity can progress from 20/20 to <20/200.
## Best Vitelliform Macular Dystrophy (BVMD)
BVMD is a slowly progressive macular dystrophy typically with juvenile onset. The characteristic "egg yolk"-like lesion can be either unilateral or bilateral, single or multiple, and macular or eccentric. Retinal lesions progress from the "egg yolk" or vitelliform stage to a vitelliruptive form and finally to an end-stage form with macular scarring or neovascularization [
Although the following clinical stages have been described, it is important to note that the disease does not progress through each of these stages in every individual:
AVMD is part of a group of conditions called pattern dystrophy (see
Affected individuals usually become symptomatic in the fifth decade with typical onset between ages 30 and 50 years. Some individuals may be asymptomatic or have reduced visual acuity and metamorphopsia. Slow visual deterioration is the usual course. Choroidal neovascularization can occur in rare cases.
The yellow subfoveal deposits are about one third disc diameter size and will diminish over time to become atrophic. The vitelliform lesion is subretinal with heterogeneous hyperreflectivity and half of eyes can have pigment epithelial detachments.
## Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC)
ADVIRC is characterized by circumscribed hyperpigmentation in the peripheral retina. A sharp demarcation line exists in the midperiphery between normal and abnormal retina. White pre-retinal opacities occur with the areas of hyperpigmentation. Cystoid macular degeneration is common along with pre-retinal neovascularization. Vitreous cells and vitreous fibrillar condensation can obscure vision. Affected individuals maintain good visual acuity until later in the disease course, when the entire retina becomes involved.
There is an association with nanophthalmos, microcornea, hyperopia, and narrow anterior chamber angle with angle closure glaucoma [
## Autosomal Recessive Bestrophinopathy (ARB)
Typical age of onset in ARB is in the first decade but can be as late as the fifth decade. ARB is a more severe retinopathy than BVMD. Visual acuity can range from normal to less than 20/200 depending on the macular involvement of the disease.
The multifocal subretinal yellow deposits seen in the macula and peripheral retina are associated with subretinal fibrosis and intraretinal and subretinal fluid.
Affected individuals are hyperopic with shallow anterior chambers, making them prone to angle closure glaucoma.
Six children from three different families had biallelic pathogenic variants in
## Genotype-Phenotype Correlations
For most
A family with a
A family with
Other observations:
Six children from three different families had biallelic pathogenic variants in
• A family with a
• A family with
• Six children from three different families had biallelic pathogenic variants in
## Penetrance
BVMD shows high but reduced (>70%) penetrance, especially when electrooculogram is used as evidence of clinical expression.
Individuals heterozygous for a
Nomenclature
Other terms used to refer to BVMD include Best disease, early-onset vitelliform macular dystrophy, juvenile-onset vitelliform macular dystrophy, and polymorphic vitelline macular degeneration.
## Prevalence
BVMD is a rare disorder. The prevalence has been estimated at 1:5,500 in a North American population [
The
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Note: Although
## Differential Diagnosis
Best vitelliform macular dystrophy (BVMD) is the second most common hereditary macular dystrophy. The most common heritable juvenile-onset macular dystrophy is Stargardt disease.
Although the cause of adult-onset vitelliform macular dystrophy (AVMD) in most individuals is unknown, this phenotype is observed in the spectrum of bestrophinopathies and with heterozygous pathogenic variants in
## Management
No clinical practice guidelines for bestrophinopathies have been published.
To establish the extent of disease and needs in an individual diagnosed with a bestrophinopathy, the evaluations summarized below (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Ophthalmologic examination, including best-corrected visual acuity, fundus examination, fundus photographs, and spectral-domain optical coherence tomography (SD-OCT) to determine the stage of disease
Consultation with a low vision specialist/clinic as needed
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of bestrophinopathies in order to facilitate medical and personal decision making
Low vision aids benefit those individuals with significantly reduced visual acuity.
In the United States (US), educational issues for children with visual impairment can be addressed in the following:
Individualized education plan (IEP) services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Occupational counseling, often available through state agencies, patient advocacy groups, and health plans, should be offered.
Best vitelliform macular dystrophy (BVMD) stage 4c fundus lesions (see
Anti-VEGF (vascular endothelial growth factor) agents are the standard treatment for individuals with subfoveal choroidal neovascularization (CNV).
Ophthalmologic examination (including best-corrected visual acuity, visual fields, and SD-OCT) should be performed annually to monitor the progression of the fundus lesions and to evaluate for coincident development of choroidal neovascularization (CNV).
In children, annual examinations are important in preventing the development of amblyopia, especially if there is a significant difference in the best-corrected visual acuity of one eye. A trial of conventional patching therapy of the better-seeing eye may be able to determine if amblyopia is present.
Affected individuals should be advised to see their ophthalmologist in the event of decreased vision or metamorphopsia (straight lines appearing wavy), which could be signs of CNV. In some cases, affected individuals can be advised to use an Amsler grid for self-evaluation.
Cessation of smoking helps prevent neovascularization of the retina [
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt ophthalmologic evaluation and routine follow up.
See
Search
• Ophthalmologic examination, including best-corrected visual acuity, fundus examination, fundus photographs, and spectral-domain optical coherence tomography (SD-OCT) to determine the stage of disease
• Consultation with a low vision specialist/clinic as needed
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of bestrophinopathies in order to facilitate medical and personal decision making
• Individualized education plan (IEP) services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a bestrophinopathy, the evaluations summarized below (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Ophthalmologic examination, including best-corrected visual acuity, fundus examination, fundus photographs, and spectral-domain optical coherence tomography (SD-OCT) to determine the stage of disease
Consultation with a low vision specialist/clinic as needed
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of bestrophinopathies in order to facilitate medical and personal decision making
• Ophthalmologic examination, including best-corrected visual acuity, fundus examination, fundus photographs, and spectral-domain optical coherence tomography (SD-OCT) to determine the stage of disease
• Consultation with a low vision specialist/clinic as needed
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of bestrophinopathies in order to facilitate medical and personal decision making
## Treatment of Manifestations
Low vision aids benefit those individuals with significantly reduced visual acuity.
In the United States (US), educational issues for children with visual impairment can be addressed in the following:
Individualized education plan (IEP) services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Occupational counseling, often available through state agencies, patient advocacy groups, and health plans, should be offered.
Best vitelliform macular dystrophy (BVMD) stage 4c fundus lesions (see
Anti-VEGF (vascular endothelial growth factor) agents are the standard treatment for individuals with subfoveal choroidal neovascularization (CNV).
• Individualized education plan (IEP) services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
## Surveillance
Ophthalmologic examination (including best-corrected visual acuity, visual fields, and SD-OCT) should be performed annually to monitor the progression of the fundus lesions and to evaluate for coincident development of choroidal neovascularization (CNV).
In children, annual examinations are important in preventing the development of amblyopia, especially if there is a significant difference in the best-corrected visual acuity of one eye. A trial of conventional patching therapy of the better-seeing eye may be able to determine if amblyopia is present.
Affected individuals should be advised to see their ophthalmologist in the event of decreased vision or metamorphopsia (straight lines appearing wavy), which could be signs of CNV. In some cases, affected individuals can be advised to use an Amsler grid for self-evaluation.
## Agents/Circumstances to Avoid
Cessation of smoking helps prevent neovascularization of the retina [
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt ophthalmologic evaluation and routine follow up.
See
## Therapies Under Investigation
Search
## Genetic Counseling
Best vitelliform macular dystrophy (BVMD),
By definition, autosomal recessive bestrophinopathy (ARB) is inherited in an autosomal recessive manner.
Most individuals diagnosed with BVMD, AVMD, or ADVIRC have an affected parent.
A proband with BVMD, AVMD, or ADVIRC may have the disorder as the result of a
Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk counseling. Note: Fundoscopic examination may be unreliable for the evaluation of the parents because the fundus may appear normal in affected individuals.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Though theoretically possible, no instances of a proband inheriting a pathogenic variant from a parent with germline mosaicism have been reported. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
The family history of some individuals diagnosed with BVMD, AVMD, or ADVIRC may appear to be negative because of failure to recognize the disorder in family members and/or reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Note: The age of onset, clinical manifestations, and degree of functional impairment is highly variable among heterozygous family members.
If the
If the parents have not been tested for the
The parents of an affected child are typically heterozygotes (i.e., carriers of one
Accurate recurrence risk counseling relies on carrier testing of both parents to determine if each is heterozygous for a
And the child appears to have homozygous
And the child has compound heterozygous
Individuals who are heterozygous for a
If both parents are known to be heterozygous for a
Individuals who are heterozygous for a
Heterozygote testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals diagnosed with BVMD, AVMD, or ADVIRC have an affected parent.
• A proband with BVMD, AVMD, or ADVIRC may have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk counseling. Note: Fundoscopic examination may be unreliable for the evaluation of the parents because the fundus may appear normal in affected individuals.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Though theoretically possible, no instances of a proband inheriting a pathogenic variant from a parent with germline mosaicism have been reported. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Though theoretically possible, no instances of a proband inheriting a pathogenic variant from a parent with germline mosaicism have been reported. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The family history of some individuals diagnosed with BVMD, AVMD, or ADVIRC may appear to be negative because of failure to recognize the disorder in family members and/or reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Though theoretically possible, no instances of a proband inheriting a pathogenic variant from a parent with germline mosaicism have been reported. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Note: The age of onset, clinical manifestations, and degree of functional impairment is highly variable among heterozygous family members.
• If the
• If the parents have not been tested for the
• The parents of an affected child are typically heterozygotes (i.e., carriers of one
• Accurate recurrence risk counseling relies on carrier testing of both parents to determine if each is heterozygous for a
• And the child appears to have homozygous
• And the child has compound heterozygous
• And the child appears to have homozygous
• And the child has compound heterozygous
• Individuals who are heterozygous for a
• And the child appears to have homozygous
• And the child has compound heterozygous
• If both parents are known to be heterozygous for a
• Individuals who are heterozygous for a
• The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk.
## Mode of Inheritance
Best vitelliform macular dystrophy (BVMD),
By definition, autosomal recessive bestrophinopathy (ARB) is inherited in an autosomal recessive manner.
## Autosomal Dominant Inheritance – Risk to Family Members
Most individuals diagnosed with BVMD, AVMD, or ADVIRC have an affected parent.
A proband with BVMD, AVMD, or ADVIRC may have the disorder as the result of a
Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk counseling. Note: Fundoscopic examination may be unreliable for the evaluation of the parents because the fundus may appear normal in affected individuals.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Though theoretically possible, no instances of a proband inheriting a pathogenic variant from a parent with germline mosaicism have been reported. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
The family history of some individuals diagnosed with BVMD, AVMD, or ADVIRC may appear to be negative because of failure to recognize the disorder in family members and/or reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Note: The age of onset, clinical manifestations, and degree of functional impairment is highly variable among heterozygous family members.
If the
If the parents have not been tested for the
• Most individuals diagnosed with BVMD, AVMD, or ADVIRC have an affected parent.
• A proband with BVMD, AVMD, or ADVIRC may have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk counseling. Note: Fundoscopic examination may be unreliable for the evaluation of the parents because the fundus may appear normal in affected individuals.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Though theoretically possible, no instances of a proband inheriting a pathogenic variant from a parent with germline mosaicism have been reported. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Though theoretically possible, no instances of a proband inheriting a pathogenic variant from a parent with germline mosaicism have been reported. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The family history of some individuals diagnosed with BVMD, AVMD, or ADVIRC may appear to be negative because of failure to recognize the disorder in family members and/or reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Though theoretically possible, no instances of a proband inheriting a pathogenic variant from a parent with germline mosaicism have been reported. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Note: The age of onset, clinical manifestations, and degree of functional impairment is highly variable among heterozygous family members.
• If the
• If the parents have not been tested for the
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected child are typically heterozygotes (i.e., carriers of one
Accurate recurrence risk counseling relies on carrier testing of both parents to determine if each is heterozygous for a
And the child appears to have homozygous
And the child has compound heterozygous
Individuals who are heterozygous for a
If both parents are known to be heterozygous for a
Individuals who are heterozygous for a
Heterozygote testing for at-risk relatives requires prior identification of the
• The parents of an affected child are typically heterozygotes (i.e., carriers of one
• Accurate recurrence risk counseling relies on carrier testing of both parents to determine if each is heterozygous for a
• And the child appears to have homozygous
• And the child has compound heterozygous
• And the child appears to have homozygous
• And the child has compound heterozygous
• Individuals who are heterozygous for a
• And the child appears to have homozygous
• And the child has compound heterozygous
• If both parents are known to be heterozygous for a
• Individuals who are heterozygous for a
## Heterozygote Detection
Heterozygote testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk.
• The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
PO Box 531313
Henderson NV 89053
210 East 64th Street
8th Floor
New York NY 10065
•
• PO Box 531313
• Henderson NV 89053
•
•
•
•
•
•
• 210 East 64th Street
• 8th Floor
• New York NY 10065
•
•
•
## Molecular Genetics
Bestrophinopathies: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Bestrophinopathies (
Expression of disease-associated missense variants causes reduced or abolished membrane current. Bestrophin undergoes dephosphorylation by a protein phosphatase, suggesting that bestrophin participates in a signal transduction pathway that may be related to the modulation of the light peak on electrooculogram [
Notable
Variants listed in the table have been provided by the authors.
Described as "pedigree S1" [
## Molecular Pathogenesis
Expression of disease-associated missense variants causes reduced or abolished membrane current. Bestrophin undergoes dephosphorylation by a protein phosphatase, suggesting that bestrophin participates in a signal transduction pathway that may be related to the modulation of the light peak on electrooculogram [
Notable
Variants listed in the table have been provided by the authors.
Described as "pedigree S1" [
## Chapter Notes
Jessica Lawrence, MSc (2020-present)Thomas Lee, MD (2003-present)Ian M MacDonald, MD, CM (2003-present)Dean Y Mah, MSc, MD; University of Alberta (2003-2009)
16 July 2020 (bp) Comprehensive update posted live
12 December 2013 (me) Comprehensive update posted live
7 April 2009 (me) Comprehensive update posted live
8 December 2005 (me) Comprehensive update posted live
27 October 2003 (imd) Revision: sequence analysis clinically available
30 September 2003 (me) Review posted live
14 July 2003 (imd) Original submission
• 16 July 2020 (bp) Comprehensive update posted live
• 12 December 2013 (me) Comprehensive update posted live
• 7 April 2009 (me) Comprehensive update posted live
• 8 December 2005 (me) Comprehensive update posted live
• 27 October 2003 (imd) Revision: sequence analysis clinically available
• 30 September 2003 (me) Review posted live
• 14 July 2003 (imd) Original submission
## Author History
Jessica Lawrence, MSc (2020-present)Thomas Lee, MD (2003-present)Ian M MacDonald, MD, CM (2003-present)Dean Y Mah, MSc, MD; University of Alberta (2003-2009)
## Revision History
16 July 2020 (bp) Comprehensive update posted live
12 December 2013 (me) Comprehensive update posted live
7 April 2009 (me) Comprehensive update posted live
8 December 2005 (me) Comprehensive update posted live
27 October 2003 (imd) Revision: sequence analysis clinically available
30 September 2003 (me) Review posted live
14 July 2003 (imd) Original submission
• 16 July 2020 (bp) Comprehensive update posted live
• 12 December 2013 (me) Comprehensive update posted live
• 7 April 2009 (me) Comprehensive update posted live
• 8 December 2005 (me) Comprehensive update posted live
• 27 October 2003 (imd) Revision: sequence analysis clinically available
• 30 September 2003 (me) Review posted live
• 14 July 2003 (imd) Original submission
## References
## Literature Cited
Best vitelliform macular dystrophy: Vitelliform stage (Stage 2)
Best vitelliform macular dystrophy: Pseudohypopyon (Stage 3)
Best vitelliform macular dystrophy: Central scarring (Stage 4b)
Right eye of a male age 72 years with molecularly confirmed Best disease
A. Macula shows loss of photoreceptor cells and an attenuated outer plexiform layer (OPL).
B & C. Fovea shows deposits of PAS-positive material and pigment granules (arrows) without underlying RPE cells.
D. Hyperpigmentation of the RPE (red arrows) is seen in the perifovea.
Image courtesy of C-C Chan, National Eye Institute, NIH, retired
Left eye of the same individual
A. Macula shows loss of photoreceptor cells and attenuated OPL.
B & C. Fovea shows a small disciform scar of thin fibrous tissue containing PAS-positive material (arrows) without underlying RPE cells.
D. Hyperpigmentation of RPE (red arrows) is noted in the perifovea.
Image courtesy of C-C Chan, National Eye Institute, NIH, retired
|
[
"RE Andrade, ME Farah, RA Costa. Photodynamic therapy with verteporfin for subfoveal choroidal neovascularization in best disease.. Am J Ophthalmol 2003;136:1179-81",
"MA Apushkin, GA Fishman, CM Taylor, EM Stone. Novel de novo mutation in a patient with Best macular dystrophy.. Arch Ophthalmol 2006;124:887-9",
"LO Atchaneeyasakul, W Jinda, N Sakolsatayadorn, A Trinavarat, N Ruangvoravate, N Thanasombatskul, W Thongnoppakhun, C Limwongse. Mutation analysis of the VMD2 gene in Thai families with Best macular dystrophy.. Ophthalmic Genet 2008;29:139-44",
"H Bitner, L Mizrahi-Meissonnier, G Griefner, I Erdinest, D Sharon, E Banin. A homozygous frameshift mutation in BEST1 causes the classical form of Best disease in an autosomal recessive mode.. Invest Ophthalmol Vis Sci 2011;52:5332-8",
"CJ Boon, BJ Klevering, BP Leroy, CB Hoyng, JE Keunen, AI den Hollander. The spectrum of ocular phenotypes caused by mutations in the BEST1 gene.. Prog Retin Eye Res. 2009;28:187-205",
"CJ Boon, LI van den Born, L Visser, JE Keunen, AA Bergen, JC Booij, FC Riemslag, RJ Florijn, MJ van Schooneveld. Autosomal recessive bestrophinopathy: differential diagnosis and treatment options.. Ophthalmology. 2013;120:809-20",
"TE Clemons, RC Milton, R Klein, JM Seddon, FL Ferris. Risk factors for the incidence of advanced age-related macular degeneration in the Age-Related Eye Disease Study (AREDS) AREDS report no. 19.. Ophthalmology 2005;112:533-9",
"LA Dalvin, JS Pulido, AD Marmorstein. Vitelliform dystrophies: prevalence in Olmsted County, Minnesota, United States.. Ophthalmic Genet. 2017;38:143-7",
"AE Davidson, ID Millar, JE Urquhart, R Burgess-Mullan, Y Shweikh, N Parry, J O'Sullivan, GJ Maher, M McKibbin, SM Downes, AJ Lotery, SG Jacobson, PD Brown, GC Black, FD Manson. Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa.. Am J Hum Genet. 2009;85:581-92",
"JM Ellingford, C Campbell, S Barton, S Bhaskar, S Gupta, RL Taylor, PI Sergouniotis, B Horn, JA Lamb, M Michaelides, AR Webster, WG Newman, B Panda, SC Ramsden, GC Black. Validation of copy number variation analysis for next-generation sequencing diagnostics. Version 2.. Eur J Hum Genet. 2017;25:719-24",
"L Eksandh, B Bakall, B Bauer, C Wadelius, S Andréasson. Best's vitelliform macular dystrophy caused by a new mutation (Val89Ala) in the VMD2 gene.. Ophthalmic Genet 2001;22:107-15",
"IV Glybina, RN Frank. Localization of multifocal electroretinogram abnormalities to the lesion site: findings in a family with Best disease.. Arch Ophthalmol 2006;124:1593-600",
"HC Hartzell, Z Qu, K Yu, Q Xiao, LT Chien. Molecular physiology of bestrophins: multifunctional membrane proteins linked to best disease and other retinopathies.. Physiol Rev 2008;88:639-72",
"A Iannaccone, NC Kerr, TR Kinnick, JI Calzada, EM Stone. Autosomal recessive best vitelliform macular dystrophy: report of a family and management of early-onset neovascular complications.. Arch Ophthalmol. 2011;129:211-7",
"AA Johnson, KE Guziewicz, CJ Lee, RC Kalathur, JS Pulido, LY Marmorstein, AD Marmorstein. Bestrophin 1 and retinal disease.. Prog Retin Eye Res. 2017;58:45-69",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"KN Khan, F Islam, AT Moore, M Michaelides. The fundus phenotype associated with the p.ala243val best1 mutation.. Retina. 2018;38:606-13",
"TR Kinnick, RF Mullins, S Dev, M Leys, DA Mackey, CN Kay, BL Lam, GA Fishman, E Traboulsi, R Iezzi, EM Stone. Autosomal recessive vitelliform macular dystrophy in a large cohort of vitelliform macular dystrophy patients.. Retina. 2011;31:581-95",
"J Leu, NF Schrage, RF Degenring. Choroidal neovascularisation secondary to Best's disease in a 13-year-old boy treated by intravitreal bevacizumab.. Graefes Arch Clin Exp Ophthalmol 2007;245:1723-5",
"Y Li, G Wang, B Dong, X Sun, MJ Turner, S Kamaya, K Zhang. A novel mutation of the VMD2 gene in a Chinese family with best vitelliform macular dystrophy.. Ann Acad Med Singapore 2006;35:408-10",
"IM MacDonald, HV Gudiseva, A Villanueva, M Greve, R Caruso, R Ayyagari. Phenotype and genotype of patients with autosomal recessive bestrophinopathy.. Ophthalmic Genet 2012;33:123-9",
"F Marano, AF Deutman, A Leys, AL Aandekerk. Hereditary retinal dystrophies and choroidal neovascularization.. Graefes Arch Clin Exp Ophthalmol 2000;238:760-4",
"D Marchant, K Yu, K Bigot, O Roche, A Germain, D Bonneau, V Drouin-Garraud, DF Schorderet, F Munier, D Schmidt, P Le Neindre, C Marsac, M Menasche, JL Dufier, R Fischmeister, C Hartzell, M Abitbol. New VMD2 gene mutations identified in patients affected by Best vitelliform macular dystrophy.. J Med Genet 2007;44",
"AD Marmorstein, LY Marmorstein, M Rayborn, X Wang, JG Hollyfield, K Petrukhin. Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium.. Proc Natl Acad Sci U S A 2000;97:12758-63",
"LY Marmorstein, PJ McLaughlin, JB Stanton, L Yan, JW Crabb, AD Marmorstein. Bestrophin interacts physically and functionally with protein phosphatase 2A.. J Biol Chem 2002;277:30591-7",
"RF Mullins, KT Oh, E Heffron, GS Hageman, EM Stone. Late development of vitelliform lesions and flecks in a patient with best disease: clinicopathologic correlation.. Arch Ophthalmol 2005;123:1588-94",
"AM Palmowski, R Allgayer, B Heinemann-Vernaleken, V Scherer, KW Ruprecht. Detection of retinal dysfunction in vitelliform macular dystrophy using the multifocal ERG (MF-ERG).. Doc Ophthalmol 2003;106:145-52",
"K Petrukhin, MJ Koisti, B Bakall, W Li, G Xie, T Marknell, O Sandgren, K Forsman, G Holmgren, S Andreasson, M Vujic, AA Bergen, V McGarty-Dugan, D Figueroa, CP Austin, ML Metzker, CT Caskey, C Wadelius. Identification of the gene responsible for Best macular dystrophy.. Nat Genet 1998;19:241-7",
"MJ Pianta, TS Aleman, AV Cideciyan, JS Sunness, Y Li, BA Campochiaro, PA Campochiaro, DJ Zack, EM Stone, SG Jacobson. In vivo micropathology of Best macular dystrophy with optical coherence tomography.. Exp Eye Res 2003;76:203-11",
"Z Qu, LT Chien, Y Cui, HC Hartzell. The anion-selective pore of the bestrophins, a family of chloride channels associated with retinal degeneration.. J Neurosci 2006;26:5411-9",
"G Querques, M Regenbogen, C Quijano, N Delphin, G Soubrane, EH Souied. High-definition optical coherence tomography features in vitelliform macular dystrophy.. Am J Ophthalmol 2008;146:501-7",
"G Querques, J Zerbib, R Santacroce, M Margaglione, N Delphin, L Querques, JM Rozet, J Kaplan, EH Souied. The spectrum of subclinical Best vitelliform macular dystrophy in subjects with mutations in BEST1 gene.. Invest Ophthalmol Vis Sci. 2011;52:4678-84",
"G Querques, J Zerbib, R Santacroce, M Margaglione, N Delphin, JM Rozet, J Kaplan, D Martinelli, N Delle Noci, G Soubrane, EH Souied. Functional and clinical data of Best vitelliform macular dystrophy patients with mutations in the BEST1 gene.. Mol Vis. 2009;15:2960-72",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"G Rudolph, P Kalpadakis. Topographic mapping of retinal function with the SLO-mfERG under simultaneous control of fixation in Best's disease.. Ophthalmologica 2003;217:154-9",
"HP Scholl, AM Schuster, R Vonthein, E Zrenner. Mapping of retinal function in Best macular dystrophy using multifocal electroretinography.. Vision Res 2002;42:1053-61",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"H Sun, T Tsunenari, KW Yau, J Nathans. The vitelliform macular dystrophy protein defines a new family of chloride channels.. Proc Natl Acad Sci U S A 2002;99:4008-13",
"F Testa, S Rossi, I Passerini, A Sodi, V Di Iorio, E Interlandi, M Della Corte, U Menchini, E Rinaldi, F Torricelli, F Simonelli. A normal electro-oculography in a family affected by Best disease with a novel spontaneous mutation of the BEST1 gene.. Br J Ophthalmol 2008;92:1467-70",
"K Van Schil, S Naessens, S Van de Sompele, M Carron, A Aslanidis, C Van Cauwenbergh, A Kathrin Mayer, M Van Heetvelde, M Bauwens, H Verdin, F Coppieters, ME Greenberg, MG Yang, M Karlstetter, T Langmann, K De Preter, S Kohl, TJ Cherry, BP Leroy, E De Baere. Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations.. Genet Med. 2018;20:202-13",
"R Wivestad Jansson, S Berland, C Bredrup, D Austeng, S Andréasson, E. Wittström. Biallelic mutations in the BEST1 gene: additional families with autosomal recessive bestrophinopathy.. Ophthalmic Genet. 2016;37:183-93",
"J Yardley, BP Leroy, N Hart-Holden, BA Lafaut, B Loeys, LM Messiaen, R Perveen, MA Reddy, SS Bhattacharya, E Traboulsi, D Baralle, JJ De Laey, B Puech, P Kestelyn, AT Moore, FD Manson, GC Black. Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC).. Invest Ophthalmol Vis Sci 2004;45:3683-9",
"K Yu, Z Qu, Y Cui, HC Hartzell. Chloride channel activity of bestrophin mutants associated with mild or late-onset macular degeneration.. Invest Ophthalmol Vis Sci 2007;48:4694-705",
"K Yu, Q Xiao, G Cui, A Lee, HC Hartzell. The Best disease-linked Cl- channel hBest1 regulates Ca V 1 (L-type) Ca2+ channels via src-homology-binding domains.. J Neurosci 2008;28:5660-70",
"L Zhao, S Grob, R Corey, M Krupa, J Luo, H Du, C Lee, G Hughes, J Lee, J Quach, J Zhu, PX Shaw, I Kozak, K Zhang. A novel compound heterozygous mutation in the BEST1 gene causes autosomal recessive Best vitelliform macular dystrophy.. Eye (Lond) 2012;26:866-71"
] |
30/9/2003
|
16/7/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
bws
|
bws
|
[
"Wiedemann-Beckwith Syndrome",
"Beckwith-Wiedemann Spectrum (BWSp)",
"Wiedemann-Beckwith Syndrome",
"Beckwith-Wiedemann Spectrum (BWSp)",
"Cyclin-dependent kinase inhibitor 1C",
"Insulin-like growth factor 2",
"Potassium voltage-gated channel subfamily KQT member 1",
"CDKN1C",
"H19",
"IGF2",
"KCNQ1",
"KCNQ1OT1",
"Beckwith-Wiedemann Syndrome"
] |
Beckwith-Wiedemann Syndrome
|
Cheryl Shuman, Jennifer M Kalish, Rosanna Weksberg
|
Summary Beckwith-Wiedemann syndrome (BWS) is a growth disorder variably characterized by macroglossia, hemihyperplasia, omphalocele, neonatal hypoglycemia, macrosomia, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma), visceromegaly, adrenocortical cytomegaly, kidney abnormalities (e.g., medullary dysplasia, nephrocalcinosis, and medullary sponge kidney), and ear creases / posterior helical ear pits. BWS is considered a clinical spectrum, in which affected individuals may have many or only one or two of the characteristic clinical features. Although most individuals with BWS show rapid growth in late fetal development and early childhood, growth rate usually slows by age seven to eight years. Adult heights are typically within the normal range. Hemihyperplasia (also known as lateralized overgrowth) is often appreciated at birth and may become more or less evident over time. Hemihyperplasia may affect segmental regions of the body or selected organs and tissues. Hemihyperplasia may be limited to one side of the body (ipsilateral) or involve opposite sides of the body (contralateral). Macroglossia is generally present at birth and can obstruct breathing or interfere with feeding in infants. Neonatal hypoglycemia occurs in approximately 50% of infants with BWS; most episodes are mild and transient. However, in some cases, persistent hypoglycemia due to hyperinsulinism may require consultation with an endocrinologist for therapeutic intervention. With respect to the increased risk for embryonal tumor development, the risk for Wilms tumor appears to be concentrated in the first seven years of life, whereas the risk for developing hepatoblastoma is concentrated in the first three to four years of life. Cognitive and neurobehavioral development is usually normal. After childhood, prognosis is generally favorable, although some adults experience issues requiring medical management (e.g., for renal or skeletal concerns). The clinical diagnosis of BWS can be established in a proband who has two tier 1 characteristic clinical findings OR one tier 1 and one tier 2 clinical finding. A diagnosis can also be established in a proband with at least one tier 1 or tier 2 clinical finding AND either: A constitutional epigenetic or genomic alteration leading to an abnormal methylation pattern at 11p15.5 known to be associated with BWS; OR A copy number variant of chromosome 11p15.5 known to be associated with BWS; OR A heterozygous BWS-causing pathogenic variant in BWS is associated with abnormal expression of imprinted genes in the BWS critical region. Reliable recurrence risk assessment requires identification of the genetic mechanism in the proband that underlies the abnormal expression of imprinted genes in the BWS critical region. While the majority of families have a recurrence risk of less than 1%, certain underlying genetic mechanisms (e.g.,
|
## Diagnosis
The phenotypic presentation of Beckwith-Wiedemann syndrome (BWS) is highly variable, and no consensus clinical diagnostic criteria are universally accepted at this time. Clinical diagnostic scoring systems have been proposed and can assist with guiding diagnostic considerations, genetic testing, and management [
Beckwith-Wiedemann syndrome (BWS)
Macroglossia
Omphalocele (also sometimes referred to as exomphalos)
Embryonal tumor, such as Wilms tumor (unilateral or bilateral), hepatoblastoma, or nephroblastomatosis
Hemihyperplasia (lateralized overgrowth) of one or more body segments
Macrosomia, defined as pre- and/or postnatal overgrowth, often using a cutoff of >90th or >97th centile, depending on the study
Hyperinsulinemic hypoglycemia
Cytomegaly of the adrenal cortex, which is considered pathognomonic for BWS
Other pathologic findings, including placental mesenchymal dysplasia and pancreatic adenomatosis
Family history of ≥1 family members with clinical features suggestive of BWS
Visceromegaly, typically from an imaging study such as ultrasound, involving ≥1 intra-abdominal organs, such as the liver, kidneys, and/or adrenal glands
Unilateral or bilateral earlobe creases and/or posterior helical ear pits
Characteristic facies (See
Kidney anomalies, such as structural malformations, nephrocalcinosis, or medullary sponge kidney
Large umbilical hernia that requires surgical correction
Other embryonal tumors, including rhabdomyoscarcoma, neuroblastoma, or adrenal tumors (pheochromocytoma, adrenocortical carcinoma)
Transient hypoglycemia requiring medical intervention
Small umbilical hernia or diastasis recti
Polyhydramnios and/or placentomegaly during pregnancy
Premature birth
Nevus simplex, typically on the forehead, glabella, and/or back of the neck AND/OR hemangioma (cutaneous or within organs such as the liver)
Isolated transient hypoglycemia that does not require medical intervention
Structural cardiac anomalies or cardiomegaly
History of assisted reproductive technology (ART) to achieve the proband's pregnancy OR history of subfertility in a parent
Monozygotic twinning that includes the proband
A constitutional epigenetic or genomic alteration leading to an abnormal methylation pattern at 11p15.5 known to be associated with BWS; OR
A copy number variant of chromosome 11p15.5 known to be associated with BWS; OR
A heterozygous BWS-causing pathogenic (or likely pathogenic) variant in
Note: (1) A molecular diagnosis of a constitutional BWS-associated 11p15.5 (epi)genomic alteration in the absence of clinical features associated with BWS does not automatically merit a BWS clinical diagnosis. However, this molecular finding confers an increased risk for tumor development [
BWS is associated with abnormal regulation of gene transcription in two imprinted domains on chromosome 11p15.5 (also known as the BWS critical region). Regulation may be disrupted by any one of numerous mechanisms; a simplified description of known etiologic mechanisms is given here to clarify the testing pipelines described in
The BWS critical region includes two domains: imprinting center 1 (IC1) regulates the expression of
In more than 80% of individuals with BWS, genetic testing can detect one of five alterations [
A schematic of the following four molecular alterations is shown in
Loss of methylation of IC2 (at the transcriptional start site [TSS] of the
Gain of methylation of IC1 (
Paternal uniparental disomy (UPD) of 11p15.5 (See
A heterozygous pathogenic variant on the maternal
Genomic variants involving chromosome 11p15.5 including cytogenetically visible duplications, inversions or translocations, or copy number variants including small duplications or deletions of 11p15.5 are not represented in
Note: Methylation changes may be associated with any of the primary genomic variants above except for pathogenic variants on the maternal
Children who have milder or atypical phenotypes (e.g., ear pits and umbilical hernia) may have mosaic pathogenic BWS-causing alterations but may still be at increased risk (compared to the general population) of developing tumors associated with BWS. This is in part because cells with BWS-associated molecular changes may be present in organs "at risk" for tumor development (e.g., liver or kidneys) but not in tissues that influence external clinical presentation. Therefore, the index of suspicion should be high when evaluating children with minimal clinical features in the BWS phenotypic spectrum, with strong consideration of the use of genetic testing to confirm the diagnosis. Individuals with minimal features of BWS and normal genetic testing may still be at increased risk of developing childhood tumors.
Genetic testing approaches can include
Methylation alterations at both IC1 and IC2 suggest uniparental disomy (UPD).
For recurrence risk purposes, further genetic studies can be undertaken to define the mechanism that leads to the methylation abnormality (see
For an introduction to multigene panels click
Genetic Testing Used in Beckwith-Wiedemann Syndrome
SNP = single nucleotide polymorphism; UPD = uniparental disomy
Proportion of affected individuals as classified by gene/locus, phenotype, population group, and/or test method, in individuals fulfilling clinical diagnostic criteria for BWS. Note: Frequencies may vary in different populations [
Assays developed to be methylation sensitive (e.g., methylation-specific multiplex ligation-dependent probe amplification [MS-MLPA], quantitative PCR [MS-qPCR], Southern blotting) allow detection of epigenetic and genomic alterations of 11p15.5. Methylation-sensitive assays can discern microdeletions and microduplications, DNA methylation alterations, and uniparental disomy (UPD). Interpretation of methylation data should take into account results of karyotype analysis because karyotypic abnormalities that alter the relative dosage of parental contributions (e.g., paternal duplication) are associated with abnormal methylation status. Other methods to confirm UPD at 11p15.5 include short tandem repeat (STR) analysis or SNP analysis [
Altered methylation at imprinted loci outside of 11p15.5 can be detected in approximately 30%-50% of individuals with BWS and loss of methylation at IC2. This condition is termed multilocus imprinting disturbance (MLID) and is more common in females (4:1 female-to-male ratio) [
If the affected individual is found to have altered methylation at imprinted loci outside of 11p15.5, they may have MLID, for which further genetic testing may be entertained (see
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Some pathogenic variants may be missed on targeted sequencing and/or deletion/duplication testing and newer sequencing technologies (e.g., whole-genome sequencing) may be able to detect these.
The detection rate for
Paternal UPD occurs by postzygotic somatic recombination and can, therefore, be identified by proband-only SNP array analysis.
Many small chromosomal deletions, small chromosomal duplications, and UPDs are not detected by current microarray testing on the proband. These require high-density SNP arrays for detection.
• Macroglossia
• Omphalocele (also sometimes referred to as exomphalos)
• Embryonal tumor, such as Wilms tumor (unilateral or bilateral), hepatoblastoma, or nephroblastomatosis
• Hemihyperplasia (lateralized overgrowth) of one or more body segments
• Macrosomia, defined as pre- and/or postnatal overgrowth, often using a cutoff of >90th or >97th centile, depending on the study
• Hyperinsulinemic hypoglycemia
• Cytomegaly of the adrenal cortex, which is considered pathognomonic for BWS
• Other pathologic findings, including placental mesenchymal dysplasia and pancreatic adenomatosis
• Family history of ≥1 family members with clinical features suggestive of BWS
• Visceromegaly, typically from an imaging study such as ultrasound, involving ≥1 intra-abdominal organs, such as the liver, kidneys, and/or adrenal glands
• Unilateral or bilateral earlobe creases and/or posterior helical ear pits
• Characteristic facies (See
• Kidney anomalies, such as structural malformations, nephrocalcinosis, or medullary sponge kidney
• Large umbilical hernia that requires surgical correction
• Other embryonal tumors, including rhabdomyoscarcoma, neuroblastoma, or adrenal tumors (pheochromocytoma, adrenocortical carcinoma)
• Transient hypoglycemia requiring medical intervention
• Small umbilical hernia or diastasis recti
• Polyhydramnios and/or placentomegaly during pregnancy
• Premature birth
• Nevus simplex, typically on the forehead, glabella, and/or back of the neck AND/OR hemangioma (cutaneous or within organs such as the liver)
• Isolated transient hypoglycemia that does not require medical intervention
• Structural cardiac anomalies or cardiomegaly
• History of assisted reproductive technology (ART) to achieve the proband's pregnancy OR history of subfertility in a parent
• Monozygotic twinning that includes the proband
• A constitutional epigenetic or genomic alteration leading to an abnormal methylation pattern at 11p15.5 known to be associated with BWS; OR
• A copy number variant of chromosome 11p15.5 known to be associated with BWS; OR
• A heterozygous BWS-causing pathogenic (or likely pathogenic) variant in
• A schematic of the following four molecular alterations is shown in
• Loss of methylation of IC2 (at the transcriptional start site [TSS] of the
• Gain of methylation of IC1 (
• Paternal uniparental disomy (UPD) of 11p15.5 (See
• A heterozygous pathogenic variant on the maternal
• Loss of methylation of IC2 (at the transcriptional start site [TSS] of the
• Gain of methylation of IC1 (
• Paternal uniparental disomy (UPD) of 11p15.5 (See
• A heterozygous pathogenic variant on the maternal
• Genomic variants involving chromosome 11p15.5 including cytogenetically visible duplications, inversions or translocations, or copy number variants including small duplications or deletions of 11p15.5 are not represented in
• Loss of methylation of IC2 (at the transcriptional start site [TSS] of the
• Gain of methylation of IC1 (
• Paternal uniparental disomy (UPD) of 11p15.5 (See
• A heterozygous pathogenic variant on the maternal
• Methylation alterations at both IC1 and IC2 suggest uniparental disomy (UPD).
• For recurrence risk purposes, further genetic studies can be undertaken to define the mechanism that leads to the methylation abnormality (see
• Methylation alterations at both IC1 and IC2 suggest uniparental disomy (UPD).
• For recurrence risk purposes, further genetic studies can be undertaken to define the mechanism that leads to the methylation abnormality (see
• For an introduction to multigene panels click
• Methylation alterations at both IC1 and IC2 suggest uniparental disomy (UPD).
• For recurrence risk purposes, further genetic studies can be undertaken to define the mechanism that leads to the methylation abnormality (see
## Suggestive Findings
Beckwith-Wiedemann syndrome (BWS)
Macroglossia
Omphalocele (also sometimes referred to as exomphalos)
Embryonal tumor, such as Wilms tumor (unilateral or bilateral), hepatoblastoma, or nephroblastomatosis
Hemihyperplasia (lateralized overgrowth) of one or more body segments
Macrosomia, defined as pre- and/or postnatal overgrowth, often using a cutoff of >90th or >97th centile, depending on the study
Hyperinsulinemic hypoglycemia
Cytomegaly of the adrenal cortex, which is considered pathognomonic for BWS
Other pathologic findings, including placental mesenchymal dysplasia and pancreatic adenomatosis
Family history of ≥1 family members with clinical features suggestive of BWS
Visceromegaly, typically from an imaging study such as ultrasound, involving ≥1 intra-abdominal organs, such as the liver, kidneys, and/or adrenal glands
Unilateral or bilateral earlobe creases and/or posterior helical ear pits
Characteristic facies (See
Kidney anomalies, such as structural malformations, nephrocalcinosis, or medullary sponge kidney
Large umbilical hernia that requires surgical correction
Other embryonal tumors, including rhabdomyoscarcoma, neuroblastoma, or adrenal tumors (pheochromocytoma, adrenocortical carcinoma)
Transient hypoglycemia requiring medical intervention
Small umbilical hernia or diastasis recti
Polyhydramnios and/or placentomegaly during pregnancy
Premature birth
Nevus simplex, typically on the forehead, glabella, and/or back of the neck AND/OR hemangioma (cutaneous or within organs such as the liver)
Isolated transient hypoglycemia that does not require medical intervention
Structural cardiac anomalies or cardiomegaly
History of assisted reproductive technology (ART) to achieve the proband's pregnancy OR history of subfertility in a parent
Monozygotic twinning that includes the proband
• Macroglossia
• Omphalocele (also sometimes referred to as exomphalos)
• Embryonal tumor, such as Wilms tumor (unilateral or bilateral), hepatoblastoma, or nephroblastomatosis
• Hemihyperplasia (lateralized overgrowth) of one or more body segments
• Macrosomia, defined as pre- and/or postnatal overgrowth, often using a cutoff of >90th or >97th centile, depending on the study
• Hyperinsulinemic hypoglycemia
• Cytomegaly of the adrenal cortex, which is considered pathognomonic for BWS
• Other pathologic findings, including placental mesenchymal dysplasia and pancreatic adenomatosis
• Family history of ≥1 family members with clinical features suggestive of BWS
• Visceromegaly, typically from an imaging study such as ultrasound, involving ≥1 intra-abdominal organs, such as the liver, kidneys, and/or adrenal glands
• Unilateral or bilateral earlobe creases and/or posterior helical ear pits
• Characteristic facies (See
• Kidney anomalies, such as structural malformations, nephrocalcinosis, or medullary sponge kidney
• Large umbilical hernia that requires surgical correction
• Other embryonal tumors, including rhabdomyoscarcoma, neuroblastoma, or adrenal tumors (pheochromocytoma, adrenocortical carcinoma)
• Transient hypoglycemia requiring medical intervention
• Small umbilical hernia or diastasis recti
• Polyhydramnios and/or placentomegaly during pregnancy
• Premature birth
• Nevus simplex, typically on the forehead, glabella, and/or back of the neck AND/OR hemangioma (cutaneous or within organs such as the liver)
• Isolated transient hypoglycemia that does not require medical intervention
• Structural cardiac anomalies or cardiomegaly
• History of assisted reproductive technology (ART) to achieve the proband's pregnancy OR history of subfertility in a parent
• Monozygotic twinning that includes the proband
## Establishing the Diagnosis
A constitutional epigenetic or genomic alteration leading to an abnormal methylation pattern at 11p15.5 known to be associated with BWS; OR
A copy number variant of chromosome 11p15.5 known to be associated with BWS; OR
A heterozygous BWS-causing pathogenic (or likely pathogenic) variant in
Note: (1) A molecular diagnosis of a constitutional BWS-associated 11p15.5 (epi)genomic alteration in the absence of clinical features associated with BWS does not automatically merit a BWS clinical diagnosis. However, this molecular finding confers an increased risk for tumor development [
BWS is associated with abnormal regulation of gene transcription in two imprinted domains on chromosome 11p15.5 (also known as the BWS critical region). Regulation may be disrupted by any one of numerous mechanisms; a simplified description of known etiologic mechanisms is given here to clarify the testing pipelines described in
The BWS critical region includes two domains: imprinting center 1 (IC1) regulates the expression of
In more than 80% of individuals with BWS, genetic testing can detect one of five alterations [
A schematic of the following four molecular alterations is shown in
Loss of methylation of IC2 (at the transcriptional start site [TSS] of the
Gain of methylation of IC1 (
Paternal uniparental disomy (UPD) of 11p15.5 (See
A heterozygous pathogenic variant on the maternal
Genomic variants involving chromosome 11p15.5 including cytogenetically visible duplications, inversions or translocations, or copy number variants including small duplications or deletions of 11p15.5 are not represented in
Note: Methylation changes may be associated with any of the primary genomic variants above except for pathogenic variants on the maternal
Children who have milder or atypical phenotypes (e.g., ear pits and umbilical hernia) may have mosaic pathogenic BWS-causing alterations but may still be at increased risk (compared to the general population) of developing tumors associated with BWS. This is in part because cells with BWS-associated molecular changes may be present in organs "at risk" for tumor development (e.g., liver or kidneys) but not in tissues that influence external clinical presentation. Therefore, the index of suspicion should be high when evaluating children with minimal clinical features in the BWS phenotypic spectrum, with strong consideration of the use of genetic testing to confirm the diagnosis. Individuals with minimal features of BWS and normal genetic testing may still be at increased risk of developing childhood tumors.
Genetic testing approaches can include
Methylation alterations at both IC1 and IC2 suggest uniparental disomy (UPD).
For recurrence risk purposes, further genetic studies can be undertaken to define the mechanism that leads to the methylation abnormality (see
For an introduction to multigene panels click
Genetic Testing Used in Beckwith-Wiedemann Syndrome
SNP = single nucleotide polymorphism; UPD = uniparental disomy
Proportion of affected individuals as classified by gene/locus, phenotype, population group, and/or test method, in individuals fulfilling clinical diagnostic criteria for BWS. Note: Frequencies may vary in different populations [
Assays developed to be methylation sensitive (e.g., methylation-specific multiplex ligation-dependent probe amplification [MS-MLPA], quantitative PCR [MS-qPCR], Southern blotting) allow detection of epigenetic and genomic alterations of 11p15.5. Methylation-sensitive assays can discern microdeletions and microduplications, DNA methylation alterations, and uniparental disomy (UPD). Interpretation of methylation data should take into account results of karyotype analysis because karyotypic abnormalities that alter the relative dosage of parental contributions (e.g., paternal duplication) are associated with abnormal methylation status. Other methods to confirm UPD at 11p15.5 include short tandem repeat (STR) analysis or SNP analysis [
Altered methylation at imprinted loci outside of 11p15.5 can be detected in approximately 30%-50% of individuals with BWS and loss of methylation at IC2. This condition is termed multilocus imprinting disturbance (MLID) and is more common in females (4:1 female-to-male ratio) [
If the affected individual is found to have altered methylation at imprinted loci outside of 11p15.5, they may have MLID, for which further genetic testing may be entertained (see
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Some pathogenic variants may be missed on targeted sequencing and/or deletion/duplication testing and newer sequencing technologies (e.g., whole-genome sequencing) may be able to detect these.
The detection rate for
Paternal UPD occurs by postzygotic somatic recombination and can, therefore, be identified by proband-only SNP array analysis.
Many small chromosomal deletions, small chromosomal duplications, and UPDs are not detected by current microarray testing on the proband. These require high-density SNP arrays for detection.
• A constitutional epigenetic or genomic alteration leading to an abnormal methylation pattern at 11p15.5 known to be associated with BWS; OR
• A copy number variant of chromosome 11p15.5 known to be associated with BWS; OR
• A heterozygous BWS-causing pathogenic (or likely pathogenic) variant in
• A schematic of the following four molecular alterations is shown in
• Loss of methylation of IC2 (at the transcriptional start site [TSS] of the
• Gain of methylation of IC1 (
• Paternal uniparental disomy (UPD) of 11p15.5 (See
• A heterozygous pathogenic variant on the maternal
• Loss of methylation of IC2 (at the transcriptional start site [TSS] of the
• Gain of methylation of IC1 (
• Paternal uniparental disomy (UPD) of 11p15.5 (See
• A heterozygous pathogenic variant on the maternal
• Genomic variants involving chromosome 11p15.5 including cytogenetically visible duplications, inversions or translocations, or copy number variants including small duplications or deletions of 11p15.5 are not represented in
• Loss of methylation of IC2 (at the transcriptional start site [TSS] of the
• Gain of methylation of IC1 (
• Paternal uniparental disomy (UPD) of 11p15.5 (See
• A heterozygous pathogenic variant on the maternal
• Methylation alterations at both IC1 and IC2 suggest uniparental disomy (UPD).
• For recurrence risk purposes, further genetic studies can be undertaken to define the mechanism that leads to the methylation abnormality (see
• Methylation alterations at both IC1 and IC2 suggest uniparental disomy (UPD).
• For recurrence risk purposes, further genetic studies can be undertaken to define the mechanism that leads to the methylation abnormality (see
• For an introduction to multigene panels click
• Methylation alterations at both IC1 and IC2 suggest uniparental disomy (UPD).
• For recurrence risk purposes, further genetic studies can be undertaken to define the mechanism that leads to the methylation abnormality (see
## Genetic Testing
Children who have milder or atypical phenotypes (e.g., ear pits and umbilical hernia) may have mosaic pathogenic BWS-causing alterations but may still be at increased risk (compared to the general population) of developing tumors associated with BWS. This is in part because cells with BWS-associated molecular changes may be present in organs "at risk" for tumor development (e.g., liver or kidneys) but not in tissues that influence external clinical presentation. Therefore, the index of suspicion should be high when evaluating children with minimal clinical features in the BWS phenotypic spectrum, with strong consideration of the use of genetic testing to confirm the diagnosis. Individuals with minimal features of BWS and normal genetic testing may still be at increased risk of developing childhood tumors.
Genetic testing approaches can include
Methylation alterations at both IC1 and IC2 suggest uniparental disomy (UPD).
For recurrence risk purposes, further genetic studies can be undertaken to define the mechanism that leads to the methylation abnormality (see
For an introduction to multigene panels click
Genetic Testing Used in Beckwith-Wiedemann Syndrome
SNP = single nucleotide polymorphism; UPD = uniparental disomy
Proportion of affected individuals as classified by gene/locus, phenotype, population group, and/or test method, in individuals fulfilling clinical diagnostic criteria for BWS. Note: Frequencies may vary in different populations [
Assays developed to be methylation sensitive (e.g., methylation-specific multiplex ligation-dependent probe amplification [MS-MLPA], quantitative PCR [MS-qPCR], Southern blotting) allow detection of epigenetic and genomic alterations of 11p15.5. Methylation-sensitive assays can discern microdeletions and microduplications, DNA methylation alterations, and uniparental disomy (UPD). Interpretation of methylation data should take into account results of karyotype analysis because karyotypic abnormalities that alter the relative dosage of parental contributions (e.g., paternal duplication) are associated with abnormal methylation status. Other methods to confirm UPD at 11p15.5 include short tandem repeat (STR) analysis or SNP analysis [
Altered methylation at imprinted loci outside of 11p15.5 can be detected in approximately 30%-50% of individuals with BWS and loss of methylation at IC2. This condition is termed multilocus imprinting disturbance (MLID) and is more common in females (4:1 female-to-male ratio) [
If the affected individual is found to have altered methylation at imprinted loci outside of 11p15.5, they may have MLID, for which further genetic testing may be entertained (see
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Some pathogenic variants may be missed on targeted sequencing and/or deletion/duplication testing and newer sequencing technologies (e.g., whole-genome sequencing) may be able to detect these.
The detection rate for
Paternal UPD occurs by postzygotic somatic recombination and can, therefore, be identified by proband-only SNP array analysis.
Many small chromosomal deletions, small chromosomal duplications, and UPDs are not detected by current microarray testing on the proband. These require high-density SNP arrays for detection.
• Methylation alterations at both IC1 and IC2 suggest uniparental disomy (UPD).
• For recurrence risk purposes, further genetic studies can be undertaken to define the mechanism that leads to the methylation abnormality (see
• Methylation alterations at both IC1 and IC2 suggest uniparental disomy (UPD).
• For recurrence risk purposes, further genetic studies can be undertaken to define the mechanism that leads to the methylation abnormality (see
• For an introduction to multigene panels click
• Methylation alterations at both IC1 and IC2 suggest uniparental disomy (UPD).
• For recurrence risk purposes, further genetic studies can be undertaken to define the mechanism that leads to the methylation abnormality (see
## Clinical Characteristics
Beckwith-Wiedemann syndrome (BWS) is a growth disorder variably characterized by neonatal hypoglycemia (persistent hypoglycemia or transient hypoglycemia due to hyperinsulinemia), macrosomia, macroglossia, hemihyperplasia, omphalocele, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma), visceromegaly, adrenocortical cytomegaly, kidney abnormalities (e.g., medullary dysplasia, nephrocalcinosis, and medullary sponge kidney), and ear creases / posterior helical ear pits. BWS is considered a clinical spectrum, in which affected individuals may have many or only one or two of the characteristic clinical features.
General incidence figures for the clinical findings in Beckwith-Wiedemann syndrome (BWS) are summarized in
Beckwith-Wiedemann Syndrome: Frequency of Select Features
Adapted from
Data were collected retrospectively and potentially with significant ascertainment bias. Updated prospective and filtered data (e.g., macrosomia in the context of parental growth parameters, molecular subgroups) will need to be collected.
Infants with BWS are at increased risk for mortality mainly as a result of complications of prematurity, macroglossia, hypoglycemia, and, rarely, cardiomyopathy. However, the previously reported mortality rate of 20% is likely an overestimate given the recent improvements in syndrome recognition and treatment.
Growth parameters should be assessed in the context of parental/familial growth parameters (e.g., a child's height at the 85th centile may reflect overgrowth when parental heights plot at ~10th centile).
Growth parameters obtained in the neonatal period following a premature delivery may not be indicative of subsequent growth patterns.
Macrocephaly is not a typical feature of BWS.
Hemihyperplasia may affect segmental regions of the body or selected organs and tissues.
Hemihyperplasia is typically characterized by overgrowth of muscle tissue leading to differences in bulk but can be associated with bone overgrowth as well.
When several body segments are involved, hemihyperplasia may be limited to one side of the body (ipsilateral) or involve opposite sides of the body (contralateral).
Asymmetric growth can remain relatively stable throughout childhood. However, progressive asymmetric growth has also been observed, and this is likely related to mosaicism in the specific tissue (i.e., the percent of cells with the 11p15.5 alteration).
Referral to an orthopedist for periodic monitoring of leg length discrepancy may include imaging to assess rate of growth and the potential development of scoliosis (see
*Note: Hemihyperplasia refers to an abnormality of cell proliferation leading to asymmetric overgrowth; in BWS, hemihyperplasia, referring to increased cell number, has replaced the term hemihypertrophy, which refers to increased cell size.
Macroglossia can occasionally obstruct breathing in neonates, who may require respiratory support, tongue reduction, or in some cases tracheostomy.
Macroglossia may also interfere with feeding in neonates and infants.
Many affected individuals do not require surgical intervention for macroglossia (see Management,
Indications and timing for surgical correction of macroglossia (reduction glossectomy) vary across different centers. Indications for reduction glossectomy can include airway obstruction leading to sleep apnea, feeding issues, anterior open bite malocclusion, prognathism, and aesthetic concerns [
Ear lobe creases are typically on the anterior aspect of the lobe; ear lobe creases that develop in adulthood are not considered to be a feature of BWS.
Ear pits associated with BWS are located on the posterior aspect of the helix.
Most episodes of hypoglycemia are mild and transient and resolve in 72 hours or less.
In more severe situations, hypoglycemia can persist beyond 72 hours because of hyperinsulinism (defined as increased insulin secretion and/or action at the time of hypoglycemia). Monitoring for hypoglycemia with pre-feed glucose / insulin checks and referral to an endocrinologist for possible fasting studies is recommended if hypoglycemia is persistent (see
Delayed onset of hypoglycemia (i.e., in the first month of life) is occasionally observed.
The increased risk for Wilms tumor appears to be concentrated in the first seven years of life [
The risk for developing hepatoblastoma is concentrated in the first three to four years of life [
The risk of developing a specific tumor in children with BWS is associated with the underlying molecular mechanism and certain phenotypic features (e.g., hemihyperplasia, nephromegaly) [
Beckwith-Wiedemann Syndrome: Frequency of Select Tumors by Molecular Mechanism
Adapted from
BWS = Beckwith-Wiedemann syndrome; IC1 = imprinting center 2; IC2 = imprinting center 2; UPD = uniparental disomy
Molecular test results undertaken on blood sampling should be used cautiously when applied to tumor risk determination given that tissue-specific mosaicism is known to impact test results and molecular changes may vary by the tissue tested [
The risks for Wilms tumor and for hepatoblastoma are not increased compared to the general population.
Perspectives on screening for malignant tumors in childhood differ based on local, national, and international practices. In North America, proactive tumor screening is commonly recommended when the risk of tumor development exceeds 1%; however, in many European countries, proactive tumor screening protocols are typically undertaken when the risk of tumor development exceeds 5% [
Cardiomyopathy has been reported but is rare.
Long QT syndrome has been reported in a child with BWS who had a balanced translocation between chromosomes 11 and 17 that interrupted
Note: Although parents of children with BWS occasionally raise concerns regarding hearing loss and hypotonia, it is difficult to ascertain whether these and other issues occur with a greater frequency in individuals with BWS compared to the general population.
While general phenotypic correlations by molecular mechanism are provided below, specific clinical outcomes in any individual with BWS cannot be precisely predicted based on the molecular alteration. The remaining variability in individuals with BWS may be due to somatic mosaicism, genetic background, and/or other unidentified factors. For information on tumor risk based on molecular mechanism, see
Associated Findings in Individuals with BWS by Molecular Mechanism
ART = assisted reproductive technology; BWS = Beckwith-Wiedemann syndrome; IC1 = imprinting center 2; IC2 = imprinting center 2; UPD = uniparental disomy; WT = Wilms tumor
Typically with unbalanced rearrangements
BWS was originally called EMG, based on the three clinical findings of
In terms of syndromic nomenclature, it is well accepted that clinical diagnoses of many genetic disorders caused by germline pathogenic variants can be challenging when there is a wide range of clinical expressivity. This is particularly true for disorders associated with somatic mosaicism of pathogenic variants. Utilization of a dyadic approach to nomenclature as proposed by
The reported prevalence of ~1:10,000 [
• Growth parameters should be assessed in the context of parental/familial growth parameters (e.g., a child's height at the 85th centile may reflect overgrowth when parental heights plot at ~10th centile).
• Growth parameters obtained in the neonatal period following a premature delivery may not be indicative of subsequent growth patterns.
• Macrocephaly is not a typical feature of BWS.
• Hemihyperplasia may affect segmental regions of the body or selected organs and tissues.
• Hemihyperplasia is typically characterized by overgrowth of muscle tissue leading to differences in bulk but can be associated with bone overgrowth as well.
• When several body segments are involved, hemihyperplasia may be limited to one side of the body (ipsilateral) or involve opposite sides of the body (contralateral).
• Asymmetric growth can remain relatively stable throughout childhood. However, progressive asymmetric growth has also been observed, and this is likely related to mosaicism in the specific tissue (i.e., the percent of cells with the 11p15.5 alteration).
• Referral to an orthopedist for periodic monitoring of leg length discrepancy may include imaging to assess rate of growth and the potential development of scoliosis (see
• Macroglossia can occasionally obstruct breathing in neonates, who may require respiratory support, tongue reduction, or in some cases tracheostomy.
• Macroglossia may also interfere with feeding in neonates and infants.
• Many affected individuals do not require surgical intervention for macroglossia (see Management,
• Indications and timing for surgical correction of macroglossia (reduction glossectomy) vary across different centers. Indications for reduction glossectomy can include airway obstruction leading to sleep apnea, feeding issues, anterior open bite malocclusion, prognathism, and aesthetic concerns [
• Macroglossia can occasionally obstruct breathing in neonates, who may require respiratory support, tongue reduction, or in some cases tracheostomy.
• Macroglossia may also interfere with feeding in neonates and infants.
• Many affected individuals do not require surgical intervention for macroglossia (see Management,
• Indications and timing for surgical correction of macroglossia (reduction glossectomy) vary across different centers. Indications for reduction glossectomy can include airway obstruction leading to sleep apnea, feeding issues, anterior open bite malocclusion, prognathism, and aesthetic concerns [
• Ear lobe creases are typically on the anterior aspect of the lobe; ear lobe creases that develop in adulthood are not considered to be a feature of BWS.
• Ear pits associated with BWS are located on the posterior aspect of the helix.
• Ear lobe creases are typically on the anterior aspect of the lobe; ear lobe creases that develop in adulthood are not considered to be a feature of BWS.
• Ear pits associated with BWS are located on the posterior aspect of the helix.
• Macroglossia can occasionally obstruct breathing in neonates, who may require respiratory support, tongue reduction, or in some cases tracheostomy.
• Macroglossia may also interfere with feeding in neonates and infants.
• Many affected individuals do not require surgical intervention for macroglossia (see Management,
• Indications and timing for surgical correction of macroglossia (reduction glossectomy) vary across different centers. Indications for reduction glossectomy can include airway obstruction leading to sleep apnea, feeding issues, anterior open bite malocclusion, prognathism, and aesthetic concerns [
• Ear lobe creases are typically on the anterior aspect of the lobe; ear lobe creases that develop in adulthood are not considered to be a feature of BWS.
• Ear pits associated with BWS are located on the posterior aspect of the helix.
• Most episodes of hypoglycemia are mild and transient and resolve in 72 hours or less.
• In more severe situations, hypoglycemia can persist beyond 72 hours because of hyperinsulinism (defined as increased insulin secretion and/or action at the time of hypoglycemia). Monitoring for hypoglycemia with pre-feed glucose / insulin checks and referral to an endocrinologist for possible fasting studies is recommended if hypoglycemia is persistent (see
• Delayed onset of hypoglycemia (i.e., in the first month of life) is occasionally observed.
• Most episodes of hypoglycemia are mild and transient and resolve in 72 hours or less.
• In more severe situations, hypoglycemia can persist beyond 72 hours because of hyperinsulinism (defined as increased insulin secretion and/or action at the time of hypoglycemia). Monitoring for hypoglycemia with pre-feed glucose / insulin checks and referral to an endocrinologist for possible fasting studies is recommended if hypoglycemia is persistent (see
• Delayed onset of hypoglycemia (i.e., in the first month of life) is occasionally observed.
• Most episodes of hypoglycemia are mild and transient and resolve in 72 hours or less.
• In more severe situations, hypoglycemia can persist beyond 72 hours because of hyperinsulinism (defined as increased insulin secretion and/or action at the time of hypoglycemia). Monitoring for hypoglycemia with pre-feed glucose / insulin checks and referral to an endocrinologist for possible fasting studies is recommended if hypoglycemia is persistent (see
• Delayed onset of hypoglycemia (i.e., in the first month of life) is occasionally observed.
• The increased risk for Wilms tumor appears to be concentrated in the first seven years of life [
• The risk for developing hepatoblastoma is concentrated in the first three to four years of life [
• The risk of developing a specific tumor in children with BWS is associated with the underlying molecular mechanism and certain phenotypic features (e.g., hemihyperplasia, nephromegaly) [
• Cardiomyopathy has been reported but is rare.
• Long QT syndrome has been reported in a child with BWS who had a balanced translocation between chromosomes 11 and 17 that interrupted
## Clinical Description
Beckwith-Wiedemann syndrome (BWS) is a growth disorder variably characterized by neonatal hypoglycemia (persistent hypoglycemia or transient hypoglycemia due to hyperinsulinemia), macrosomia, macroglossia, hemihyperplasia, omphalocele, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma), visceromegaly, adrenocortical cytomegaly, kidney abnormalities (e.g., medullary dysplasia, nephrocalcinosis, and medullary sponge kidney), and ear creases / posterior helical ear pits. BWS is considered a clinical spectrum, in which affected individuals may have many or only one or two of the characteristic clinical features.
General incidence figures for the clinical findings in Beckwith-Wiedemann syndrome (BWS) are summarized in
Beckwith-Wiedemann Syndrome: Frequency of Select Features
Adapted from
Data were collected retrospectively and potentially with significant ascertainment bias. Updated prospective and filtered data (e.g., macrosomia in the context of parental growth parameters, molecular subgroups) will need to be collected.
Infants with BWS are at increased risk for mortality mainly as a result of complications of prematurity, macroglossia, hypoglycemia, and, rarely, cardiomyopathy. However, the previously reported mortality rate of 20% is likely an overestimate given the recent improvements in syndrome recognition and treatment.
Growth parameters should be assessed in the context of parental/familial growth parameters (e.g., a child's height at the 85th centile may reflect overgrowth when parental heights plot at ~10th centile).
Growth parameters obtained in the neonatal period following a premature delivery may not be indicative of subsequent growth patterns.
Macrocephaly is not a typical feature of BWS.
Hemihyperplasia may affect segmental regions of the body or selected organs and tissues.
Hemihyperplasia is typically characterized by overgrowth of muscle tissue leading to differences in bulk but can be associated with bone overgrowth as well.
When several body segments are involved, hemihyperplasia may be limited to one side of the body (ipsilateral) or involve opposite sides of the body (contralateral).
Asymmetric growth can remain relatively stable throughout childhood. However, progressive asymmetric growth has also been observed, and this is likely related to mosaicism in the specific tissue (i.e., the percent of cells with the 11p15.5 alteration).
Referral to an orthopedist for periodic monitoring of leg length discrepancy may include imaging to assess rate of growth and the potential development of scoliosis (see
*Note: Hemihyperplasia refers to an abnormality of cell proliferation leading to asymmetric overgrowth; in BWS, hemihyperplasia, referring to increased cell number, has replaced the term hemihypertrophy, which refers to increased cell size.
Macroglossia can occasionally obstruct breathing in neonates, who may require respiratory support, tongue reduction, or in some cases tracheostomy.
Macroglossia may also interfere with feeding in neonates and infants.
Many affected individuals do not require surgical intervention for macroglossia (see Management,
Indications and timing for surgical correction of macroglossia (reduction glossectomy) vary across different centers. Indications for reduction glossectomy can include airway obstruction leading to sleep apnea, feeding issues, anterior open bite malocclusion, prognathism, and aesthetic concerns [
Ear lobe creases are typically on the anterior aspect of the lobe; ear lobe creases that develop in adulthood are not considered to be a feature of BWS.
Ear pits associated with BWS are located on the posterior aspect of the helix.
Most episodes of hypoglycemia are mild and transient and resolve in 72 hours or less.
In more severe situations, hypoglycemia can persist beyond 72 hours because of hyperinsulinism (defined as increased insulin secretion and/or action at the time of hypoglycemia). Monitoring for hypoglycemia with pre-feed glucose / insulin checks and referral to an endocrinologist for possible fasting studies is recommended if hypoglycemia is persistent (see
Delayed onset of hypoglycemia (i.e., in the first month of life) is occasionally observed.
The increased risk for Wilms tumor appears to be concentrated in the first seven years of life [
The risk for developing hepatoblastoma is concentrated in the first three to four years of life [
The risk of developing a specific tumor in children with BWS is associated with the underlying molecular mechanism and certain phenotypic features (e.g., hemihyperplasia, nephromegaly) [
Beckwith-Wiedemann Syndrome: Frequency of Select Tumors by Molecular Mechanism
Adapted from
BWS = Beckwith-Wiedemann syndrome; IC1 = imprinting center 2; IC2 = imprinting center 2; UPD = uniparental disomy
Molecular test results undertaken on blood sampling should be used cautiously when applied to tumor risk determination given that tissue-specific mosaicism is known to impact test results and molecular changes may vary by the tissue tested [
The risks for Wilms tumor and for hepatoblastoma are not increased compared to the general population.
Perspectives on screening for malignant tumors in childhood differ based on local, national, and international practices. In North America, proactive tumor screening is commonly recommended when the risk of tumor development exceeds 1%; however, in many European countries, proactive tumor screening protocols are typically undertaken when the risk of tumor development exceeds 5% [
Cardiomyopathy has been reported but is rare.
Long QT syndrome has been reported in a child with BWS who had a balanced translocation between chromosomes 11 and 17 that interrupted
Note: Although parents of children with BWS occasionally raise concerns regarding hearing loss and hypotonia, it is difficult to ascertain whether these and other issues occur with a greater frequency in individuals with BWS compared to the general population.
• Growth parameters should be assessed in the context of parental/familial growth parameters (e.g., a child's height at the 85th centile may reflect overgrowth when parental heights plot at ~10th centile).
• Growth parameters obtained in the neonatal period following a premature delivery may not be indicative of subsequent growth patterns.
• Macrocephaly is not a typical feature of BWS.
• Hemihyperplasia may affect segmental regions of the body or selected organs and tissues.
• Hemihyperplasia is typically characterized by overgrowth of muscle tissue leading to differences in bulk but can be associated with bone overgrowth as well.
• When several body segments are involved, hemihyperplasia may be limited to one side of the body (ipsilateral) or involve opposite sides of the body (contralateral).
• Asymmetric growth can remain relatively stable throughout childhood. However, progressive asymmetric growth has also been observed, and this is likely related to mosaicism in the specific tissue (i.e., the percent of cells with the 11p15.5 alteration).
• Referral to an orthopedist for periodic monitoring of leg length discrepancy may include imaging to assess rate of growth and the potential development of scoliosis (see
• Macroglossia can occasionally obstruct breathing in neonates, who may require respiratory support, tongue reduction, or in some cases tracheostomy.
• Macroglossia may also interfere with feeding in neonates and infants.
• Many affected individuals do not require surgical intervention for macroglossia (see Management,
• Indications and timing for surgical correction of macroglossia (reduction glossectomy) vary across different centers. Indications for reduction glossectomy can include airway obstruction leading to sleep apnea, feeding issues, anterior open bite malocclusion, prognathism, and aesthetic concerns [
• Macroglossia can occasionally obstruct breathing in neonates, who may require respiratory support, tongue reduction, or in some cases tracheostomy.
• Macroglossia may also interfere with feeding in neonates and infants.
• Many affected individuals do not require surgical intervention for macroglossia (see Management,
• Indications and timing for surgical correction of macroglossia (reduction glossectomy) vary across different centers. Indications for reduction glossectomy can include airway obstruction leading to sleep apnea, feeding issues, anterior open bite malocclusion, prognathism, and aesthetic concerns [
• Ear lobe creases are typically on the anterior aspect of the lobe; ear lobe creases that develop in adulthood are not considered to be a feature of BWS.
• Ear pits associated with BWS are located on the posterior aspect of the helix.
• Ear lobe creases are typically on the anterior aspect of the lobe; ear lobe creases that develop in adulthood are not considered to be a feature of BWS.
• Ear pits associated with BWS are located on the posterior aspect of the helix.
• Macroglossia can occasionally obstruct breathing in neonates, who may require respiratory support, tongue reduction, or in some cases tracheostomy.
• Macroglossia may also interfere with feeding in neonates and infants.
• Many affected individuals do not require surgical intervention for macroglossia (see Management,
• Indications and timing for surgical correction of macroglossia (reduction glossectomy) vary across different centers. Indications for reduction glossectomy can include airway obstruction leading to sleep apnea, feeding issues, anterior open bite malocclusion, prognathism, and aesthetic concerns [
• Ear lobe creases are typically on the anterior aspect of the lobe; ear lobe creases that develop in adulthood are not considered to be a feature of BWS.
• Ear pits associated with BWS are located on the posterior aspect of the helix.
• Most episodes of hypoglycemia are mild and transient and resolve in 72 hours or less.
• In more severe situations, hypoglycemia can persist beyond 72 hours because of hyperinsulinism (defined as increased insulin secretion and/or action at the time of hypoglycemia). Monitoring for hypoglycemia with pre-feed glucose / insulin checks and referral to an endocrinologist for possible fasting studies is recommended if hypoglycemia is persistent (see
• Delayed onset of hypoglycemia (i.e., in the first month of life) is occasionally observed.
• Most episodes of hypoglycemia are mild and transient and resolve in 72 hours or less.
• In more severe situations, hypoglycemia can persist beyond 72 hours because of hyperinsulinism (defined as increased insulin secretion and/or action at the time of hypoglycemia). Monitoring for hypoglycemia with pre-feed glucose / insulin checks and referral to an endocrinologist for possible fasting studies is recommended if hypoglycemia is persistent (see
• Delayed onset of hypoglycemia (i.e., in the first month of life) is occasionally observed.
• Most episodes of hypoglycemia are mild and transient and resolve in 72 hours or less.
• In more severe situations, hypoglycemia can persist beyond 72 hours because of hyperinsulinism (defined as increased insulin secretion and/or action at the time of hypoglycemia). Monitoring for hypoglycemia with pre-feed glucose / insulin checks and referral to an endocrinologist for possible fasting studies is recommended if hypoglycemia is persistent (see
• Delayed onset of hypoglycemia (i.e., in the first month of life) is occasionally observed.
• The increased risk for Wilms tumor appears to be concentrated in the first seven years of life [
• The risk for developing hepatoblastoma is concentrated in the first three to four years of life [
• The risk of developing a specific tumor in children with BWS is associated with the underlying molecular mechanism and certain phenotypic features (e.g., hemihyperplasia, nephromegaly) [
• Cardiomyopathy has been reported but is rare.
• Long QT syndrome has been reported in a child with BWS who had a balanced translocation between chromosomes 11 and 17 that interrupted
## Phenotype Correlations by Molecular Mechanism
While general phenotypic correlations by molecular mechanism are provided below, specific clinical outcomes in any individual with BWS cannot be precisely predicted based on the molecular alteration. The remaining variability in individuals with BWS may be due to somatic mosaicism, genetic background, and/or other unidentified factors. For information on tumor risk based on molecular mechanism, see
Associated Findings in Individuals with BWS by Molecular Mechanism
ART = assisted reproductive technology; BWS = Beckwith-Wiedemann syndrome; IC1 = imprinting center 2; IC2 = imprinting center 2; UPD = uniparental disomy; WT = Wilms tumor
Typically with unbalanced rearrangements
## Nomenclature
BWS was originally called EMG, based on the three clinical findings of
In terms of syndromic nomenclature, it is well accepted that clinical diagnoses of many genetic disorders caused by germline pathogenic variants can be challenging when there is a wide range of clinical expressivity. This is particularly true for disorders associated with somatic mosaicism of pathogenic variants. Utilization of a dyadic approach to nomenclature as proposed by
## Prevalence
The reported prevalence of ~1:10,000 [
## Genetically Related (Allelic) Disorders
Molecular alterations at 11p15 including loss of methylation at imprinting center 2 (IC2), gain of methylation at imprinting center 1 (IC1) [
Somatic mosaicism for loss of methylation at the paternal IC1 is associated with
## Differential Diagnosis
Of note: In children considered to have BWS and developmental delay who have a normal chromosome study, no history of hypoxia or hypoglycemia, and normal brain imaging, other causes of developmental delay need to be considered.
Overgrowth Disorders to Consider in the Differential Diagnosis of Beckwith-Wiedemann Syndrome
AD = autosomal dominant; AR = autosomal recessive; ASD = autism spectrum disorder; BWS = Beckwith-Wiedemann syndrome; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance; SRS = Silver-Russell syndrome; TNDM = transient neonatal diabetes mellitus; XL = X-linked
Multilocus imprinting disorder can be associated with pathogenic variants in maternal effect genes (e.g.,
Most probands have the disorder as the result of a
Disorders with Hemihyperplasia or Lateralized Overgrowth to Consider in the Differential Diagnosis of Beckwith-Wiedemann Syndrome
AD = autosomal dominant; AR = autosomal recessive; CLOVES syndrome = congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal syndrome; CNS = central nervous system; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MCAP syndrome = megalencephaly-capillary malformation syndrome; MOI = mode of inheritance; XL = X-linked
Hypomethylation of the imprinted control region 1 (ICR1) at 11p15.5 causes SRS in 35%-50% of individuals, and maternal uniparental disomy (mUPD7) causes SRS in 7%-10% of individuals. A small number of affected individuals have duplications, deletions, or translocations involving the imprinting centers at 11p15.5 or duplications, deletions, or translocations involving chromosome 7. Rarely, affected individuals with pathogenic variants in
SRS typically has a low recurrence risk; however, accurate assessment of recurrence risk requires identification of the causative genetic mechanism in the affected family member.
Not known to be inherited; most identified pathogenic variants are somatic (mosaic).
For individuals with methylation alterations in the 11p15 imprinted domain as well as in other imprinted loci, review of the maternal history should be undertaken for findings such as recurrent pregnancy loss or molar pregnancy. In these situations, consideration should be given to testing for pathogenic variants in maternal effect genes that lead to BWS. If a pathogenic variant in a maternal effect gene is detected in the proband and mother, information regarding the increased risk for reproductive complications such as preeclampsia, recurrent pregnancy loss, and molar pregnancy as well as the significant risk for having children with imprinting disorders should be addressed through genetic counseling [
Note: It is not yet clear if oligogenic or multifactorial causes are relevant in MLID. While it appears that some heterozygous variants in SCMC genes may be disease causing, such cases may also be associated with unidentified pathogenic variants in the second allele or other SCMC genes. In addition, the potential interaction of pathogenic variants with interventions such as assisted reproductive technology will be an important area of future work
## Management
Clinical practice guidelines for Beckwith-Wiedemann syndrome have been published and most frequently focus on the issue of tumor screening protocols (see
To establish the extent of disease and needs in an individual diagnosed with Beckwith-Wiedemann syndrome, the evaluations summarized in
Beckwith-Wiedemann Syndrome: Recommended Evaluations Following Initial Diagnosis
Gross motor skills
PT (if delay in gross motor skills) &/or orthopedic referral if leg length discrepancy >1 cm
Community or
Social work involvement for parental support, if needed.
AFP = alpha-fetoprotein; MOI = mode of inheritance; PT = physical therapy
Transient hypoglycemia typically resolves in the first few days of life; evaluation for hyperinsulinism is recommended for those who have hypoglycemia that persists for longer than 72 hours.
Renal ultrasound alone is insufficient, as it will not evaluate for liver or other abdominal tumors.
Perspectives on obtaining and monitoring serum AFP levels to screen for hepatoblastoma differ based on local, national, and international practices [
Current data suggest that those who undergo serial serum AFP screening for hepatoblastoma have an earlier stage at diagnosis and a better overall prognosis compared to those who do not undergo serum AFP screening [
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Beckwith-Wiedemann Syndrome: Treatment of Manifestations
Oral feeding if hypoglycemia is mild
Prompt treatment w/glucose supplementation, most typically IV D10 or D25 solutions if hypoglycemia is more severe, w/goal of keeping glucose levels in 3.9-5.5 mmol/L (70-100 mg/dL) range
Consult endocrinologist for escalated treatment & eval if hypoglycemia is severe.
This may incl using medications such as diazoxide or somatostatin analogs.
Newer medications may incl mTOR inhibitors or glucagon-like peptide receptor antagonists.
Long nipples may be considered, like those used for infants w/cleft palate.
Supplemental feeding tube may be considered in those w/severe feeding difficulties.
Ensure appropriate genetic counseling / social work involvement to connect families w/resources & support.
Coordinate care to manage multiple subspecialty appointments if indicated.
IEP = individualized education program; OT = occupational therapy; PT = physical therapy
Because onset of hypoglycemia is occasionally delayed for several days, or even months, parents should be informed of the symptoms of hypoglycemia so that they can seek appropriate medical attention.
Tongue growth does slow over time and jaw growth can accelerate to accommodate the enlarged tongue.
Surgical reduction approaches may vary depending on the nature of macroglossia (e.g., if asymmetry is present, etc.), tongue function concerns, and/or the preferential approach of the surgical team. Indications for tongue reduction surgery vary but may include airway obstruction, orthodontic issues, and/or social/aesthetic issues. Residual aesthetic and speech issues may require further assessment and alternate treatment approaches [
In those who do not have a known molecular genetic cause for BWS, genetic testing can be undertaken on tissue available from surgical reduction during tongue reduction surgery.
Perspectives on screening for malignant tumors in childhood differ based on local, national, and international practices. In North America proactive tumor screening is often recommended when the risk of tumor development exceeds 1% [
For general screening guidelines outside of tumor surveillance, see
Beckwith-Wiedemann Syndrome: Tumor Surveillance Protocols
For alternate tumor surveillance recommendations utilized in many European countries, see
The tumor screening protocol does NOT take into account the underlying molecular mechanism for BWS (see
This avoids confusion about whether to perform renal ultrasound only or abdominal ultrasound based on age.
AFP serum concentration may be elevated in children with BWS in the first year of life.
Most cases of hepatoblastoma will occur in the first year of life, with the oldest known case of hepatoblastoma in BWS detected at age 30 months [
Increased frequency of serum AFP testing will depend on significant increases in the AFP level as defined by the AACR guidelines [
Beckwith-Wiedemann Syndrome: Recommended General (Non-Tumor) Surveillance
Consider a sleep study to assess for obstructive sleep apnea in symptomatic individuals.
It is appropriate to evaluate the newborn sib of an individual with BWS in order to identify as early as possible those who would benefit from initiation of preventive measures. Evaluations can include:
Genetic testing if a maternal
Monitoring of an at-risk newborn sib for hypoglycemia, even in the absence of obvious clinical findings on prenatal investigation;
Careful evaluation of the apparently unaffected twin of discordant monozygotic twins (MZ), including clinical examination and molecular testing, preferably of multiple tissues, if available. There should be strong consideration of tumor surveillance for the apparently unaffected MZ twin given the possibility of shared fetal circulation and the potential for resulting somatic mosaicism [
See
Search
• Gross motor skills
• PT (if delay in gross motor skills) &/or orthopedic referral if leg length discrepancy >1 cm
• Community or
• Social work involvement for parental support, if needed.
• Oral feeding if hypoglycemia is mild
• Prompt treatment w/glucose supplementation, most typically IV D10 or D25 solutions if hypoglycemia is more severe, w/goal of keeping glucose levels in 3.9-5.5 mmol/L (70-100 mg/dL) range
• Consult endocrinologist for escalated treatment & eval if hypoglycemia is severe.
• This may incl using medications such as diazoxide or somatostatin analogs.
• Newer medications may incl mTOR inhibitors or glucagon-like peptide receptor antagonists.
• Long nipples may be considered, like those used for infants w/cleft palate.
• Supplemental feeding tube may be considered in those w/severe feeding difficulties.
• Ensure appropriate genetic counseling / social work involvement to connect families w/resources & support.
• Coordinate care to manage multiple subspecialty appointments if indicated.
• Genetic testing if a maternal
• Monitoring of an at-risk newborn sib for hypoglycemia, even in the absence of obvious clinical findings on prenatal investigation;
• Careful evaluation of the apparently unaffected twin of discordant monozygotic twins (MZ), including clinical examination and molecular testing, preferably of multiple tissues, if available. There should be strong consideration of tumor surveillance for the apparently unaffected MZ twin given the possibility of shared fetal circulation and the potential for resulting somatic mosaicism [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Beckwith-Wiedemann syndrome, the evaluations summarized in
Beckwith-Wiedemann Syndrome: Recommended Evaluations Following Initial Diagnosis
Gross motor skills
PT (if delay in gross motor skills) &/or orthopedic referral if leg length discrepancy >1 cm
Community or
Social work involvement for parental support, if needed.
AFP = alpha-fetoprotein; MOI = mode of inheritance; PT = physical therapy
Transient hypoglycemia typically resolves in the first few days of life; evaluation for hyperinsulinism is recommended for those who have hypoglycemia that persists for longer than 72 hours.
Renal ultrasound alone is insufficient, as it will not evaluate for liver or other abdominal tumors.
Perspectives on obtaining and monitoring serum AFP levels to screen for hepatoblastoma differ based on local, national, and international practices [
Current data suggest that those who undergo serial serum AFP screening for hepatoblastoma have an earlier stage at diagnosis and a better overall prognosis compared to those who do not undergo serum AFP screening [
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Gross motor skills
• PT (if delay in gross motor skills) &/or orthopedic referral if leg length discrepancy >1 cm
• Community or
• Social work involvement for parental support, if needed.
## Treatment of Manifestations
Beckwith-Wiedemann Syndrome: Treatment of Manifestations
Oral feeding if hypoglycemia is mild
Prompt treatment w/glucose supplementation, most typically IV D10 or D25 solutions if hypoglycemia is more severe, w/goal of keeping glucose levels in 3.9-5.5 mmol/L (70-100 mg/dL) range
Consult endocrinologist for escalated treatment & eval if hypoglycemia is severe.
This may incl using medications such as diazoxide or somatostatin analogs.
Newer medications may incl mTOR inhibitors or glucagon-like peptide receptor antagonists.
Long nipples may be considered, like those used for infants w/cleft palate.
Supplemental feeding tube may be considered in those w/severe feeding difficulties.
Ensure appropriate genetic counseling / social work involvement to connect families w/resources & support.
Coordinate care to manage multiple subspecialty appointments if indicated.
IEP = individualized education program; OT = occupational therapy; PT = physical therapy
Because onset of hypoglycemia is occasionally delayed for several days, or even months, parents should be informed of the symptoms of hypoglycemia so that they can seek appropriate medical attention.
Tongue growth does slow over time and jaw growth can accelerate to accommodate the enlarged tongue.
Surgical reduction approaches may vary depending on the nature of macroglossia (e.g., if asymmetry is present, etc.), tongue function concerns, and/or the preferential approach of the surgical team. Indications for tongue reduction surgery vary but may include airway obstruction, orthodontic issues, and/or social/aesthetic issues. Residual aesthetic and speech issues may require further assessment and alternate treatment approaches [
In those who do not have a known molecular genetic cause for BWS, genetic testing can be undertaken on tissue available from surgical reduction during tongue reduction surgery.
• Oral feeding if hypoglycemia is mild
• Prompt treatment w/glucose supplementation, most typically IV D10 or D25 solutions if hypoglycemia is more severe, w/goal of keeping glucose levels in 3.9-5.5 mmol/L (70-100 mg/dL) range
• Consult endocrinologist for escalated treatment & eval if hypoglycemia is severe.
• This may incl using medications such as diazoxide or somatostatin analogs.
• Newer medications may incl mTOR inhibitors or glucagon-like peptide receptor antagonists.
• Long nipples may be considered, like those used for infants w/cleft palate.
• Supplemental feeding tube may be considered in those w/severe feeding difficulties.
• Ensure appropriate genetic counseling / social work involvement to connect families w/resources & support.
• Coordinate care to manage multiple subspecialty appointments if indicated.
## Surveillance
Perspectives on screening for malignant tumors in childhood differ based on local, national, and international practices. In North America proactive tumor screening is often recommended when the risk of tumor development exceeds 1% [
For general screening guidelines outside of tumor surveillance, see
Beckwith-Wiedemann Syndrome: Tumor Surveillance Protocols
For alternate tumor surveillance recommendations utilized in many European countries, see
The tumor screening protocol does NOT take into account the underlying molecular mechanism for BWS (see
This avoids confusion about whether to perform renal ultrasound only or abdominal ultrasound based on age.
AFP serum concentration may be elevated in children with BWS in the first year of life.
Most cases of hepatoblastoma will occur in the first year of life, with the oldest known case of hepatoblastoma in BWS detected at age 30 months [
Increased frequency of serum AFP testing will depend on significant increases in the AFP level as defined by the AACR guidelines [
Beckwith-Wiedemann Syndrome: Recommended General (Non-Tumor) Surveillance
Consider a sleep study to assess for obstructive sleep apnea in symptomatic individuals.
## Evaluation of Relatives at Risk
It is appropriate to evaluate the newborn sib of an individual with BWS in order to identify as early as possible those who would benefit from initiation of preventive measures. Evaluations can include:
Genetic testing if a maternal
Monitoring of an at-risk newborn sib for hypoglycemia, even in the absence of obvious clinical findings on prenatal investigation;
Careful evaluation of the apparently unaffected twin of discordant monozygotic twins (MZ), including clinical examination and molecular testing, preferably of multiple tissues, if available. There should be strong consideration of tumor surveillance for the apparently unaffected MZ twin given the possibility of shared fetal circulation and the potential for resulting somatic mosaicism [
See
• Genetic testing if a maternal
• Monitoring of an at-risk newborn sib for hypoglycemia, even in the absence of obvious clinical findings on prenatal investigation;
• Careful evaluation of the apparently unaffected twin of discordant monozygotic twins (MZ), including clinical examination and molecular testing, preferably of multiple tissues, if available. There should be strong consideration of tumor surveillance for the apparently unaffected MZ twin given the possibility of shared fetal circulation and the potential for resulting somatic mosaicism [
## Therapies Under Investigation
Search
## Genetic Counseling
The following recurrence risk information pertains to individuals who have Beckwith-Wiedemann syndrome (BWS) without other imprinting disorders, such as multilocus imprinting disturbances (MLID). See
BWS without MLID is associated with abnormal expression of imprinted genes in the BWS critical region. Abnormal expression of imprinted genes can be caused by an epigenetic or genomic alteration leading to an abnormal methylation pattern at 11p15.5, a copy number variant of chromosome 11p15.5, or a heterozygous maternally inherited
Most individuals with BWS do not have an affected parent.
Recommendations for the clinical evaluation of the parents of a child with BWS and no known family history of BWS include a medical and family history focused on BWS-associated medical issues in early childhood. Infant and childhood photographs of the parents may be useful. Although physical examination may be of limited value in adulthood, ear pits/creases may still be present. Anterior ear lobe creases are not uncommon in the general population; however, posterior ear pits are rarely reported outside of the association with BWS.
If the proband has BWS associated with MLID, the maternal history should also be reviewed with respect to potential recurrent pregnancy loss or other adverse outcomes that could indicate a maternal effect gene abnormality. Pathogenic variants in maternal effect genes are associated with an increased risk for reproductive complications such as preeclampsia, recurrent pregnancy loss, and molar pregnancy as well as the risk for having children with imprinting disorders [
Clarification of the genetic status of the parents of the proband is recommended to allow reliable recurrence risk assessment. Testing recommendations for the parents are based on the genetic alteration identified in the proband. If the genetic alteration identified in the proband is a:
Cytogenetically visible duplication, inversion, or translocation involving chromosome 11p15.5, then chromosome analysis (karyotyping) should be offered to both parents;
Copy number variant (e.g., a small 11p15.5 duplication or deletion), then microarray (SNP based) should be offered to both parents;
Heterozygous
Paternal uniparental disomy (UPD) of 11p15.5, then parental testing is not indicated/recommended/required, as paternal UPD of 11p15.5 is typically due to postzygotic somatic recombination;
Loss of methylation of imprinting center 2 (IC2) or gain of methylation of imprinting center 1 (IC1), then maternal history should be reviewed for findings suggestive of a variant in a maternal effect gene.
If the proband has neither a genomic variant (i.e., a copy number variant at 11p15.5 or a cytogenetically visible chromosome alternation) nor a
Note: If the family history suggests possible MLID, further consideration for genetic testing for pathogenic variants in maternal effect genes should be entertained (see
Risk to Sibs of a Proband with Beckwith-Wiedemann Syndrome
Cytogenetically visible duplication, inversion, or translocation
CNV (e.g., small 11p15.5 duplication or deletion)
BWS = Beckwith-Wiedemann syndrome; CNV = copy number variant; GOM = gain of methylation; IC1 = imprinting center 1; IC2 = imprinting center 2; LOM = loss of methylation; MLID = multilocus imprinting disturbances; SRS = Silver-Russell syndrome; UPD = uniparental disomy
If the father is heterozygous for the
Risk to Offspring of a Proband with Beckwith-Wiedemann Syndrome
Cytogenetically visible duplication, inversion, or translocations
CNV (e.g., small 11p15.5 duplication or deletion)
The recurrence risk may be as high as 50% depending on the sex of the proband and the specific alteration. Small deletions at IC1 & rarely small duplications at IC2 have been reported in familial cases.
Rare familial cases of
BWS = Beckwith-Wiedemann syndrome; CNV = copy number variant; LOM = loss of methylation; MLID = multilocus imprinting disturbances; SCMC = subcortical maternal complex; SRS = Silver-Russell syndrome; UPD = uniparental disomy
See Management,
The optimal time for determination of genetic risk and genetic counseling regarding prenatal testing is before pregnancy. Decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or who carry genomic alterations that increase the risk of BWS in offspring (e.g., an unaffected female who has inherited a balanced 11p15 translocation from her father).
If pathogenic variants in maternal effect genes are detected in the proband and mother, information regarding the increased risk for reproductive complications such as preeclampsia, recurrent pregnancy loss, and molar pregnancy as well as the risk for having children with imprinting disorders should be included in genetic counseling [
Maternal serum alpha-fetoprotein (AFP) concentration may be elevated at 16 weeks' gestation in the presence of omphalocele.
Ultrasound examination can be performed at 19-20 weeks' gestation and again at 25-32 weeks' gestation to assess growth parameters that may become advanced for gestational age late in the second trimester and to detect abdominal wall defects, organomegaly, kidney anomalies, cleft palate, cardiac abnormalities, and macroglossia.
Note: (1) If ultrasound examination does not show malformations or abnormalities of fetal growth, a residual risk for recurrence of BWS remains, given the variability in clinical presentation. (2) Even in the absence of obvious clinical findings on prenatal investigation, the newborn should be monitored for hypoglycemia.
Molecular genetic testing for methylation alterations in amniocytes, and if no methylation alteration is identified, testing for a
Chromosomal microarray for copy number variants involving chromosome 11p15 and/or cytogenetic testing to evaluate for duplications, inversions, or translocations involving 11p15;
Serial ultrasound examinations to assess fetal growth and to detect other abnormalities characteristic of BWS.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Molecular genetic testing can be offered if there is a high index of suspicion for BWS.
• Most individuals with BWS do not have an affected parent.
• Recommendations for the clinical evaluation of the parents of a child with BWS and no known family history of BWS include a medical and family history focused on BWS-associated medical issues in early childhood. Infant and childhood photographs of the parents may be useful. Although physical examination may be of limited value in adulthood, ear pits/creases may still be present. Anterior ear lobe creases are not uncommon in the general population; however, posterior ear pits are rarely reported outside of the association with BWS.
• If the proband has BWS associated with MLID, the maternal history should also be reviewed with respect to potential recurrent pregnancy loss or other adverse outcomes that could indicate a maternal effect gene abnormality. Pathogenic variants in maternal effect genes are associated with an increased risk for reproductive complications such as preeclampsia, recurrent pregnancy loss, and molar pregnancy as well as the risk for having children with imprinting disorders [
• Clarification of the genetic status of the parents of the proband is recommended to allow reliable recurrence risk assessment. Testing recommendations for the parents are based on the genetic alteration identified in the proband. If the genetic alteration identified in the proband is a:
• Cytogenetically visible duplication, inversion, or translocation involving chromosome 11p15.5, then chromosome analysis (karyotyping) should be offered to both parents;
• Copy number variant (e.g., a small 11p15.5 duplication or deletion), then microarray (SNP based) should be offered to both parents;
• Heterozygous
• Paternal uniparental disomy (UPD) of 11p15.5, then parental testing is not indicated/recommended/required, as paternal UPD of 11p15.5 is typically due to postzygotic somatic recombination;
• Loss of methylation of imprinting center 2 (IC2) or gain of methylation of imprinting center 1 (IC1), then maternal history should be reviewed for findings suggestive of a variant in a maternal effect gene.
• Cytogenetically visible duplication, inversion, or translocation involving chromosome 11p15.5, then chromosome analysis (karyotyping) should be offered to both parents;
• Copy number variant (e.g., a small 11p15.5 duplication or deletion), then microarray (SNP based) should be offered to both parents;
• Heterozygous
• Paternal uniparental disomy (UPD) of 11p15.5, then parental testing is not indicated/recommended/required, as paternal UPD of 11p15.5 is typically due to postzygotic somatic recombination;
• Loss of methylation of imprinting center 2 (IC2) or gain of methylation of imprinting center 1 (IC1), then maternal history should be reviewed for findings suggestive of a variant in a maternal effect gene.
• If the proband has neither a genomic variant (i.e., a copy number variant at 11p15.5 or a cytogenetically visible chromosome alternation) nor a
• Note: If the family history suggests possible MLID, further consideration for genetic testing for pathogenic variants in maternal effect genes should be entertained (see
• Cytogenetically visible duplication, inversion, or translocation involving chromosome 11p15.5, then chromosome analysis (karyotyping) should be offered to both parents;
• Copy number variant (e.g., a small 11p15.5 duplication or deletion), then microarray (SNP based) should be offered to both parents;
• Heterozygous
• Paternal uniparental disomy (UPD) of 11p15.5, then parental testing is not indicated/recommended/required, as paternal UPD of 11p15.5 is typically due to postzygotic somatic recombination;
• Loss of methylation of imprinting center 2 (IC2) or gain of methylation of imprinting center 1 (IC1), then maternal history should be reviewed for findings suggestive of a variant in a maternal effect gene.
• Cytogenetically visible duplication, inversion, or translocation
• CNV (e.g., small 11p15.5 duplication or deletion)
• Cytogenetically visible duplication, inversion, or translocations
• CNV (e.g., small 11p15.5 duplication or deletion)
• The recurrence risk may be as high as 50% depending on the sex of the proband and the specific alteration. Small deletions at IC1 & rarely small duplications at IC2 have been reported in familial cases.
• Rare familial cases of
• The optimal time for determination of genetic risk and genetic counseling regarding prenatal testing is before pregnancy. Decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or who carry genomic alterations that increase the risk of BWS in offspring (e.g., an unaffected female who has inherited a balanced 11p15 translocation from her father).
• If pathogenic variants in maternal effect genes are detected in the proband and mother, information regarding the increased risk for reproductive complications such as preeclampsia, recurrent pregnancy loss, and molar pregnancy as well as the risk for having children with imprinting disorders should be included in genetic counseling [
• Maternal serum alpha-fetoprotein (AFP) concentration may be elevated at 16 weeks' gestation in the presence of omphalocele.
• Ultrasound examination can be performed at 19-20 weeks' gestation and again at 25-32 weeks' gestation to assess growth parameters that may become advanced for gestational age late in the second trimester and to detect abdominal wall defects, organomegaly, kidney anomalies, cleft palate, cardiac abnormalities, and macroglossia.
• Molecular genetic testing for methylation alterations in amniocytes, and if no methylation alteration is identified, testing for a
• Chromosomal microarray for copy number variants involving chromosome 11p15 and/or cytogenetic testing to evaluate for duplications, inversions, or translocations involving 11p15;
• Serial ultrasound examinations to assess fetal growth and to detect other abnormalities characteristic of BWS.
## Mode of Inheritance
The following recurrence risk information pertains to individuals who have Beckwith-Wiedemann syndrome (BWS) without other imprinting disorders, such as multilocus imprinting disturbances (MLID). See
BWS without MLID is associated with abnormal expression of imprinted genes in the BWS critical region. Abnormal expression of imprinted genes can be caused by an epigenetic or genomic alteration leading to an abnormal methylation pattern at 11p15.5, a copy number variant of chromosome 11p15.5, or a heterozygous maternally inherited
## Risk to Family Members
Most individuals with BWS do not have an affected parent.
Recommendations for the clinical evaluation of the parents of a child with BWS and no known family history of BWS include a medical and family history focused on BWS-associated medical issues in early childhood. Infant and childhood photographs of the parents may be useful. Although physical examination may be of limited value in adulthood, ear pits/creases may still be present. Anterior ear lobe creases are not uncommon in the general population; however, posterior ear pits are rarely reported outside of the association with BWS.
If the proband has BWS associated with MLID, the maternal history should also be reviewed with respect to potential recurrent pregnancy loss or other adverse outcomes that could indicate a maternal effect gene abnormality. Pathogenic variants in maternal effect genes are associated with an increased risk for reproductive complications such as preeclampsia, recurrent pregnancy loss, and molar pregnancy as well as the risk for having children with imprinting disorders [
Clarification of the genetic status of the parents of the proband is recommended to allow reliable recurrence risk assessment. Testing recommendations for the parents are based on the genetic alteration identified in the proband. If the genetic alteration identified in the proband is a:
Cytogenetically visible duplication, inversion, or translocation involving chromosome 11p15.5, then chromosome analysis (karyotyping) should be offered to both parents;
Copy number variant (e.g., a small 11p15.5 duplication or deletion), then microarray (SNP based) should be offered to both parents;
Heterozygous
Paternal uniparental disomy (UPD) of 11p15.5, then parental testing is not indicated/recommended/required, as paternal UPD of 11p15.5 is typically due to postzygotic somatic recombination;
Loss of methylation of imprinting center 2 (IC2) or gain of methylation of imprinting center 1 (IC1), then maternal history should be reviewed for findings suggestive of a variant in a maternal effect gene.
If the proband has neither a genomic variant (i.e., a copy number variant at 11p15.5 or a cytogenetically visible chromosome alternation) nor a
Note: If the family history suggests possible MLID, further consideration for genetic testing for pathogenic variants in maternal effect genes should be entertained (see
Risk to Sibs of a Proband with Beckwith-Wiedemann Syndrome
Cytogenetically visible duplication, inversion, or translocation
CNV (e.g., small 11p15.5 duplication or deletion)
BWS = Beckwith-Wiedemann syndrome; CNV = copy number variant; GOM = gain of methylation; IC1 = imprinting center 1; IC2 = imprinting center 2; LOM = loss of methylation; MLID = multilocus imprinting disturbances; SRS = Silver-Russell syndrome; UPD = uniparental disomy
If the father is heterozygous for the
Risk to Offspring of a Proband with Beckwith-Wiedemann Syndrome
Cytogenetically visible duplication, inversion, or translocations
CNV (e.g., small 11p15.5 duplication or deletion)
The recurrence risk may be as high as 50% depending on the sex of the proband and the specific alteration. Small deletions at IC1 & rarely small duplications at IC2 have been reported in familial cases.
Rare familial cases of
BWS = Beckwith-Wiedemann syndrome; CNV = copy number variant; LOM = loss of methylation; MLID = multilocus imprinting disturbances; SCMC = subcortical maternal complex; SRS = Silver-Russell syndrome; UPD = uniparental disomy
• Most individuals with BWS do not have an affected parent.
• Recommendations for the clinical evaluation of the parents of a child with BWS and no known family history of BWS include a medical and family history focused on BWS-associated medical issues in early childhood. Infant and childhood photographs of the parents may be useful. Although physical examination may be of limited value in adulthood, ear pits/creases may still be present. Anterior ear lobe creases are not uncommon in the general population; however, posterior ear pits are rarely reported outside of the association with BWS.
• If the proband has BWS associated with MLID, the maternal history should also be reviewed with respect to potential recurrent pregnancy loss or other adverse outcomes that could indicate a maternal effect gene abnormality. Pathogenic variants in maternal effect genes are associated with an increased risk for reproductive complications such as preeclampsia, recurrent pregnancy loss, and molar pregnancy as well as the risk for having children with imprinting disorders [
• Clarification of the genetic status of the parents of the proband is recommended to allow reliable recurrence risk assessment. Testing recommendations for the parents are based on the genetic alteration identified in the proband. If the genetic alteration identified in the proband is a:
• Cytogenetically visible duplication, inversion, or translocation involving chromosome 11p15.5, then chromosome analysis (karyotyping) should be offered to both parents;
• Copy number variant (e.g., a small 11p15.5 duplication or deletion), then microarray (SNP based) should be offered to both parents;
• Heterozygous
• Paternal uniparental disomy (UPD) of 11p15.5, then parental testing is not indicated/recommended/required, as paternal UPD of 11p15.5 is typically due to postzygotic somatic recombination;
• Loss of methylation of imprinting center 2 (IC2) or gain of methylation of imprinting center 1 (IC1), then maternal history should be reviewed for findings suggestive of a variant in a maternal effect gene.
• Cytogenetically visible duplication, inversion, or translocation involving chromosome 11p15.5, then chromosome analysis (karyotyping) should be offered to both parents;
• Copy number variant (e.g., a small 11p15.5 duplication or deletion), then microarray (SNP based) should be offered to both parents;
• Heterozygous
• Paternal uniparental disomy (UPD) of 11p15.5, then parental testing is not indicated/recommended/required, as paternal UPD of 11p15.5 is typically due to postzygotic somatic recombination;
• Loss of methylation of imprinting center 2 (IC2) or gain of methylation of imprinting center 1 (IC1), then maternal history should be reviewed for findings suggestive of a variant in a maternal effect gene.
• If the proband has neither a genomic variant (i.e., a copy number variant at 11p15.5 or a cytogenetically visible chromosome alternation) nor a
• Note: If the family history suggests possible MLID, further consideration for genetic testing for pathogenic variants in maternal effect genes should be entertained (see
• Cytogenetically visible duplication, inversion, or translocation involving chromosome 11p15.5, then chromosome analysis (karyotyping) should be offered to both parents;
• Copy number variant (e.g., a small 11p15.5 duplication or deletion), then microarray (SNP based) should be offered to both parents;
• Heterozygous
• Paternal uniparental disomy (UPD) of 11p15.5, then parental testing is not indicated/recommended/required, as paternal UPD of 11p15.5 is typically due to postzygotic somatic recombination;
• Loss of methylation of imprinting center 2 (IC2) or gain of methylation of imprinting center 1 (IC1), then maternal history should be reviewed for findings suggestive of a variant in a maternal effect gene.
• Cytogenetically visible duplication, inversion, or translocation
• CNV (e.g., small 11p15.5 duplication or deletion)
• Cytogenetically visible duplication, inversion, or translocations
• CNV (e.g., small 11p15.5 duplication or deletion)
• The recurrence risk may be as high as 50% depending on the sex of the proband and the specific alteration. Small deletions at IC1 & rarely small duplications at IC2 have been reported in familial cases.
• Rare familial cases of
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and genetic counseling regarding prenatal testing is before pregnancy. Decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or who carry genomic alterations that increase the risk of BWS in offspring (e.g., an unaffected female who has inherited a balanced 11p15 translocation from her father).
If pathogenic variants in maternal effect genes are detected in the proband and mother, information regarding the increased risk for reproductive complications such as preeclampsia, recurrent pregnancy loss, and molar pregnancy as well as the risk for having children with imprinting disorders should be included in genetic counseling [
• The optimal time for determination of genetic risk and genetic counseling regarding prenatal testing is before pregnancy. Decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or who carry genomic alterations that increase the risk of BWS in offspring (e.g., an unaffected female who has inherited a balanced 11p15 translocation from her father).
• If pathogenic variants in maternal effect genes are detected in the proband and mother, information regarding the increased risk for reproductive complications such as preeclampsia, recurrent pregnancy loss, and molar pregnancy as well as the risk for having children with imprinting disorders should be included in genetic counseling [
## Prenatal Testing and Preimplantation Genetic Testing
Maternal serum alpha-fetoprotein (AFP) concentration may be elevated at 16 weeks' gestation in the presence of omphalocele.
Ultrasound examination can be performed at 19-20 weeks' gestation and again at 25-32 weeks' gestation to assess growth parameters that may become advanced for gestational age late in the second trimester and to detect abdominal wall defects, organomegaly, kidney anomalies, cleft palate, cardiac abnormalities, and macroglossia.
Note: (1) If ultrasound examination does not show malformations or abnormalities of fetal growth, a residual risk for recurrence of BWS remains, given the variability in clinical presentation. (2) Even in the absence of obvious clinical findings on prenatal investigation, the newborn should be monitored for hypoglycemia.
Molecular genetic testing for methylation alterations in amniocytes, and if no methylation alteration is identified, testing for a
Chromosomal microarray for copy number variants involving chromosome 11p15 and/or cytogenetic testing to evaluate for duplications, inversions, or translocations involving 11p15;
Serial ultrasound examinations to assess fetal growth and to detect other abnormalities characteristic of BWS.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Molecular genetic testing can be offered if there is a high index of suspicion for BWS.
• Maternal serum alpha-fetoprotein (AFP) concentration may be elevated at 16 weeks' gestation in the presence of omphalocele.
• Ultrasound examination can be performed at 19-20 weeks' gestation and again at 25-32 weeks' gestation to assess growth parameters that may become advanced for gestational age late in the second trimester and to detect abdominal wall defects, organomegaly, kidney anomalies, cleft palate, cardiac abnormalities, and macroglossia.
• Molecular genetic testing for methylation alterations in amniocytes, and if no methylation alteration is identified, testing for a
• Chromosomal microarray for copy number variants involving chromosome 11p15 and/or cytogenetic testing to evaluate for duplications, inversions, or translocations involving 11p15;
• Serial ultrasound examinations to assess fetal growth and to detect other abnormalities characteristic of BWS.
## Resources
Italy
•
• Italy
•
•
•
•
•
## Molecular Genetics
Beckwith-Wiedemann Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Beckwith-Wiedemann Syndrome (
Gain of methylation or hypermethylation: increased level of DNA methylation compared to control samples. For imprinted regions this may be associated with methylation of a normally unmethylated allele.
Loss of methylation or hypomethylation: decreased level of DNA methylation compared to control samples. For imprinted regions, this may be associated with loss of methylation of a normally methylated allele.
An
Many different molecular alterations in the 11p15 region occur in association with Beckwith-Wiedemann syndrome (BWS). Several imprinted genes, including growth factors and tumor suppressor genes, that are located in the 11p15 region have been implicated in the pathogenesis of this condition:
Imprinting centers 1 and 2 (IC1 and IC2) within the 11p15.5 region control gene expression across large chromosomal domains:
Overall, there are two imprinted domains in the BWS critical region (see
• Gain of methylation or hypermethylation: increased level of DNA methylation compared to control samples. For imprinted regions this may be associated with methylation of a normally unmethylated allele.
• Loss of methylation or hypomethylation: decreased level of DNA methylation compared to control samples. For imprinted regions, this may be associated with loss of methylation of a normally methylated allele.
## Molecular Pathogenesis
Gain of methylation or hypermethylation: increased level of DNA methylation compared to control samples. For imprinted regions this may be associated with methylation of a normally unmethylated allele.
Loss of methylation or hypomethylation: decreased level of DNA methylation compared to control samples. For imprinted regions, this may be associated with loss of methylation of a normally methylated allele.
An
Many different molecular alterations in the 11p15 region occur in association with Beckwith-Wiedemann syndrome (BWS). Several imprinted genes, including growth factors and tumor suppressor genes, that are located in the 11p15 region have been implicated in the pathogenesis of this condition:
Imprinting centers 1 and 2 (IC1 and IC2) within the 11p15.5 region control gene expression across large chromosomal domains:
Overall, there are two imprinted domains in the BWS critical region (see
• Gain of methylation or hypermethylation: increased level of DNA methylation compared to control samples. For imprinted regions this may be associated with methylation of a normally unmethylated allele.
• Loss of methylation or hypomethylation: decreased level of DNA methylation compared to control samples. For imprinted regions, this may be associated with loss of methylation of a normally methylated allele.
## Chapter Notes
Sanaa Choufani, Khadine Wiltshire, Evan Hathaway
J Bruce Beckwith, MD; Loma Linda University (2010-2023)Jennifer M Kalish, MD, PhD (2023-present)Cheryl Shuman, MS, CGC (2000-present)Adam C Smith, PhD; The Hospital for Sick Children (2000-2016)Rosanna Weksberg, MD, PhD, FRCPC, FCCMG, FACMG (2000-present)
21 September 2023 (ma/cs) Revision: updated information regarding tumor risk associated with heterozygous
8 June 2023 (ma) Comprehensive update posted live
11 August 2016 (ma) Comprehensive update posted live
14 December 2010 (me) Comprehensive update posted live
8 September 2005 (me) Comprehensive update posted live
10 April 2003 (tk) Comprehensive update posted live
3 March 2000 (me) Review posted live
28 July 1999 (cs) Original submission
• 21 September 2023 (ma/cs) Revision: updated information regarding tumor risk associated with heterozygous
• 8 June 2023 (ma) Comprehensive update posted live
• 11 August 2016 (ma) Comprehensive update posted live
• 14 December 2010 (me) Comprehensive update posted live
• 8 September 2005 (me) Comprehensive update posted live
• 10 April 2003 (tk) Comprehensive update posted live
• 3 March 2000 (me) Review posted live
• 28 July 1999 (cs) Original submission
## Acknowledgments
Sanaa Choufani, Khadine Wiltshire, Evan Hathaway
## Author History
J Bruce Beckwith, MD; Loma Linda University (2010-2023)Jennifer M Kalish, MD, PhD (2023-present)Cheryl Shuman, MS, CGC (2000-present)Adam C Smith, PhD; The Hospital for Sick Children (2000-2016)Rosanna Weksberg, MD, PhD, FRCPC, FCCMG, FACMG (2000-present)
## Revision History
21 September 2023 (ma/cs) Revision: updated information regarding tumor risk associated with heterozygous
8 June 2023 (ma) Comprehensive update posted live
11 August 2016 (ma) Comprehensive update posted live
14 December 2010 (me) Comprehensive update posted live
8 September 2005 (me) Comprehensive update posted live
10 April 2003 (tk) Comprehensive update posted live
3 March 2000 (me) Review posted live
28 July 1999 (cs) Original submission
• 21 September 2023 (ma/cs) Revision: updated information regarding tumor risk associated with heterozygous
• 8 June 2023 (ma) Comprehensive update posted live
• 11 August 2016 (ma) Comprehensive update posted live
• 14 December 2010 (me) Comprehensive update posted live
• 8 September 2005 (me) Comprehensive update posted live
• 10 April 2003 (tk) Comprehensive update posted live
• 3 March 2000 (me) Review posted live
• 28 July 1999 (cs) Original submission
## References
Brioude F, Kalish JM, Mussa A, Foster AC, Bliek J, Ferrero GB, Boonen SE, Cole T, Baker R, Bertoletti M, Cocchi G, Coze C, De Pellegrin M, Hussain K, Ibrahim A, Kilby MD, Krajewska-Walasek M, Kratz CP, Ladusans EJ, Lapunzina P, Le Bouc Y, Maas SM, Macdonald F, Õunap K, Peruzzi L, Rossignol S, Russo S, Shipster C, Skórka A, Tatton-Brown K, Tenorio J, Tortora C, Grønskov K, Netchine I, Hennekam RC, Prawitt D, Tümer Z, Eggermann T, Mackay DJG, Riccio A, Maher ER. Expert consensus document: clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 2018;14:229-49. [
Eggermann T, Brioude F, Russo S, Lombardi MP, Bliek J, Maher ER, Larizza L, Prawitt D, Netchine I, Gonzales M, Grønskov K, Tümer Z, Monk D, Mannens M, Chrzanowska K, Walasek MK, Begemann M, Soellner L, Eggermann K, Tenorio J, Nevado J, Moore GE, Mackay DJ, Temple K, Gillessen-Kaesbach G, Ogata T, Weksberg R, Algar E, Lapunzina P. Prenatal molecular testing for Beckwith-Wiedemann and Silver-Russell syndromes: a challenge for molecular analysis and genetic counseling. Eur J Hum Genet. 2016;24:784-93. [
Kalish JM, Doros L, Helman LJ, Hennekam RC, Kuiper RP, Maas SM, Maher ER, Nichols KE, Plon SE, Porter CC, Rednam S, Schultz KAP, States LJ, Tomlinson GE, Zelley K, Druley TE. Surveillance recommendations for children with overgrowth syndromes and predisposition to Wilms tumors and hepatoblastoma. Clin Cancer Res. 2017;23:e115-e122. [
Mussa A, Di Candia S, Russo S, Catania S, De Pellegrin M, Di Luzio L, Ferrari M, Tortora C, Meazzini MC, Brusati R, Milani D, Zampino G, Montirosso R, Riccio A, Selicorni A, Cocchi G, Ferrero GB. Recommendations of the Scientific Committee of the Italian Beckwith-Wiedemann Syndrome Association on the diagnosis, management and follow-up of the syndrome. Eur J Med Genet. 2016;59:52-64. [
• Brioude F, Kalish JM, Mussa A, Foster AC, Bliek J, Ferrero GB, Boonen SE, Cole T, Baker R, Bertoletti M, Cocchi G, Coze C, De Pellegrin M, Hussain K, Ibrahim A, Kilby MD, Krajewska-Walasek M, Kratz CP, Ladusans EJ, Lapunzina P, Le Bouc Y, Maas SM, Macdonald F, Õunap K, Peruzzi L, Rossignol S, Russo S, Shipster C, Skórka A, Tatton-Brown K, Tenorio J, Tortora C, Grønskov K, Netchine I, Hennekam RC, Prawitt D, Tümer Z, Eggermann T, Mackay DJG, Riccio A, Maher ER. Expert consensus document: clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 2018;14:229-49. [
• Eggermann T, Brioude F, Russo S, Lombardi MP, Bliek J, Maher ER, Larizza L, Prawitt D, Netchine I, Gonzales M, Grønskov K, Tümer Z, Monk D, Mannens M, Chrzanowska K, Walasek MK, Begemann M, Soellner L, Eggermann K, Tenorio J, Nevado J, Moore GE, Mackay DJ, Temple K, Gillessen-Kaesbach G, Ogata T, Weksberg R, Algar E, Lapunzina P. Prenatal molecular testing for Beckwith-Wiedemann and Silver-Russell syndromes: a challenge for molecular analysis and genetic counseling. Eur J Hum Genet. 2016;24:784-93. [
• Kalish JM, Doros L, Helman LJ, Hennekam RC, Kuiper RP, Maas SM, Maher ER, Nichols KE, Plon SE, Porter CC, Rednam S, Schultz KAP, States LJ, Tomlinson GE, Zelley K, Druley TE. Surveillance recommendations for children with overgrowth syndromes and predisposition to Wilms tumors and hepatoblastoma. Clin Cancer Res. 2017;23:e115-e122. [
• Mussa A, Di Candia S, Russo S, Catania S, De Pellegrin M, Di Luzio L, Ferrari M, Tortora C, Meazzini MC, Brusati R, Milani D, Zampino G, Montirosso R, Riccio A, Selicorni A, Cocchi G, Ferrero GB. Recommendations of the Scientific Committee of the Italian Beckwith-Wiedemann Syndrome Association on the diagnosis, management and follow-up of the syndrome. Eur J Med Genet. 2016;59:52-64. [
## Published Guidelines / Consensus Statements
Brioude F, Kalish JM, Mussa A, Foster AC, Bliek J, Ferrero GB, Boonen SE, Cole T, Baker R, Bertoletti M, Cocchi G, Coze C, De Pellegrin M, Hussain K, Ibrahim A, Kilby MD, Krajewska-Walasek M, Kratz CP, Ladusans EJ, Lapunzina P, Le Bouc Y, Maas SM, Macdonald F, Õunap K, Peruzzi L, Rossignol S, Russo S, Shipster C, Skórka A, Tatton-Brown K, Tenorio J, Tortora C, Grønskov K, Netchine I, Hennekam RC, Prawitt D, Tümer Z, Eggermann T, Mackay DJG, Riccio A, Maher ER. Expert consensus document: clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 2018;14:229-49. [
Eggermann T, Brioude F, Russo S, Lombardi MP, Bliek J, Maher ER, Larizza L, Prawitt D, Netchine I, Gonzales M, Grønskov K, Tümer Z, Monk D, Mannens M, Chrzanowska K, Walasek MK, Begemann M, Soellner L, Eggermann K, Tenorio J, Nevado J, Moore GE, Mackay DJ, Temple K, Gillessen-Kaesbach G, Ogata T, Weksberg R, Algar E, Lapunzina P. Prenatal molecular testing for Beckwith-Wiedemann and Silver-Russell syndromes: a challenge for molecular analysis and genetic counseling. Eur J Hum Genet. 2016;24:784-93. [
Kalish JM, Doros L, Helman LJ, Hennekam RC, Kuiper RP, Maas SM, Maher ER, Nichols KE, Plon SE, Porter CC, Rednam S, Schultz KAP, States LJ, Tomlinson GE, Zelley K, Druley TE. Surveillance recommendations for children with overgrowth syndromes and predisposition to Wilms tumors and hepatoblastoma. Clin Cancer Res. 2017;23:e115-e122. [
Mussa A, Di Candia S, Russo S, Catania S, De Pellegrin M, Di Luzio L, Ferrari M, Tortora C, Meazzini MC, Brusati R, Milani D, Zampino G, Montirosso R, Riccio A, Selicorni A, Cocchi G, Ferrero GB. Recommendations of the Scientific Committee of the Italian Beckwith-Wiedemann Syndrome Association on the diagnosis, management and follow-up of the syndrome. Eur J Med Genet. 2016;59:52-64. [
• Brioude F, Kalish JM, Mussa A, Foster AC, Bliek J, Ferrero GB, Boonen SE, Cole T, Baker R, Bertoletti M, Cocchi G, Coze C, De Pellegrin M, Hussain K, Ibrahim A, Kilby MD, Krajewska-Walasek M, Kratz CP, Ladusans EJ, Lapunzina P, Le Bouc Y, Maas SM, Macdonald F, Õunap K, Peruzzi L, Rossignol S, Russo S, Shipster C, Skórka A, Tatton-Brown K, Tenorio J, Tortora C, Grønskov K, Netchine I, Hennekam RC, Prawitt D, Tümer Z, Eggermann T, Mackay DJG, Riccio A, Maher ER. Expert consensus document: clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 2018;14:229-49. [
• Eggermann T, Brioude F, Russo S, Lombardi MP, Bliek J, Maher ER, Larizza L, Prawitt D, Netchine I, Gonzales M, Grønskov K, Tümer Z, Monk D, Mannens M, Chrzanowska K, Walasek MK, Begemann M, Soellner L, Eggermann K, Tenorio J, Nevado J, Moore GE, Mackay DJ, Temple K, Gillessen-Kaesbach G, Ogata T, Weksberg R, Algar E, Lapunzina P. Prenatal molecular testing for Beckwith-Wiedemann and Silver-Russell syndromes: a challenge for molecular analysis and genetic counseling. Eur J Hum Genet. 2016;24:784-93. [
• Kalish JM, Doros L, Helman LJ, Hennekam RC, Kuiper RP, Maas SM, Maher ER, Nichols KE, Plon SE, Porter CC, Rednam S, Schultz KAP, States LJ, Tomlinson GE, Zelley K, Druley TE. Surveillance recommendations for children with overgrowth syndromes and predisposition to Wilms tumors and hepatoblastoma. Clin Cancer Res. 2017;23:e115-e122. [
• Mussa A, Di Candia S, Russo S, Catania S, De Pellegrin M, Di Luzio L, Ferrari M, Tortora C, Meazzini MC, Brusati R, Milani D, Zampino G, Montirosso R, Riccio A, Selicorni A, Cocchi G, Ferrero GB. Recommendations of the Scientific Committee of the Italian Beckwith-Wiedemann Syndrome Association on the diagnosis, management and follow-up of the syndrome. Eur J Med Genet. 2016;59:52-64. [
## Literature Cited
Map of the BWS locus on 11p15.5
a) A schematic representation of the normal parent of origin-specific imprinted allelic expression. Note: b) and c) show the altered region only. The image is not drawn to scale.
Cen = centromere; DMR = differentially methylated region; IC = imprinting center; M = maternal; OT1 = KCNQ1 antisense transcript, KCNQ1OT1; P = paternal; Tel = telomere
Republished with permission from
Causes of Beckwith-Wiedemann syndrome by genetic mechanism
* These molecular subgroups, defined by DNA methylation abnormalities, may also be the result of an underlying genomic alteration. Such genomic aberrations are most common for hypermethylation of IC1 and least common for hypomethylation at IC2. Genomic aberrations, limited to the BWS critical region on chromosome 11p15.5, can be detected by MS-MLPA or various sequencing technologies. Some deletions/duplications may be detected by CMA.
BWS = Beckwith-Wiedemann syndrome; CMA = chromosomal microarray; IC1 = imprinting center 1; IC2 = imprinting center 2; MS-MLPA = methylation-specific multiplex ligation-dependent probe amplification
Flowchart for molecular diagnosis of Beckwith-Wiedemann syndrome
Recommended first-line testing (highlighted in orange) analyzes methylation at H19/IGF2:IG DMR (IC1) and KCNQ1OT1:TSS DMR (IC2) and copy number variation (CNV). These tests can yield positive molecular diagnoses of chromosome 11 abnormalities, paternal uniparental disomy of chromosome 11 (pUPD), IC1 gain of methylation (IC1 GOM), and IC2 loss of methylation (IC2 LOM) (highlighted in dark green). Further testing (highlighted in blue) can determine chromosomal abnormalities more precisely. If DNA methylation testing is normal,
Adapted from
|
[] |
3/3/2000
|
8/6/2023
|
21/9/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
ca5a-def
|
ca5a-def
|
[
"CA-VA Deficiency",
"CA-VA Deficiency",
"Carbonic anhydrase 5A, mitochondrial",
"CA5A",
"Carbonic Anhydrase VA Deficiency"
] |
Carbonic Anhydrase VA Deficiency
|
Clara van Karnebeek, Johannes Häberle
|
Summary Most children with carbonic anhydrase VA (CA-VA) deficiency reported to date have presented between day 2 of life and early childhood (up to age 20 months) with hyperammonemic encephalopathy (i.e., lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma). Given that fewer than 20 affected individuals have been reported to date, the ranges of initial presentations and long-term prognoses are not completely understood. As of 2021 the oldest known affected individual is an adolescent. Almost all affected individuals reported to date have shown normal psychomotor development and no further episodes of metabolic crisis; however, a few have shown mild learning difficulties or delayed motor skills. The diagnosis of CA-VA deficiency is established in children with suggestive clinical findings (metabolic hyperammonemic encephalopathy), laboratory findings (complex acid-base status including respiratory alkalosis and metabolic acidosis; elevated plasma glutamine and alanine and low-to-normal citrulline; and urine organic acid analysis showing elevations of carboxylase substrates and related metabolites suggestive of multiple carboxylase deficiency), and biallelic pathogenic variants in To prevent metabolic decompensation during any catabolic state (viral illness or fasting conditions): Use a sick day formula (i.e., with extra calories and lipids, with but limited proteins) and monitor parameters per acute care protocols. An affected infant diagnosed prenatally: Delivery in hospital with monitoring for ~3 days (including physical examination and monitoring especially of plasma ammonia, serum lactate, serum glucose, and blood gases) An infant at risk because of a previous affected sib: Close clinical monitoring for the first week of life by a healthcare professional and immediate action if symptoms (of hyperammonemia or hypoglycemia) occur CA-VA deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
No consensus clinical diagnostic criteria for carbonic anhydrase VA (CA-VA) deficiency have been published.
Significant elevation of plasma ammonia, lactate, and ketones (with concomitant increased urinary ketones). Hypoglycemia can also be seen.
Complex acid-base status that includes respiratory alkalosis and metabolic acidosis (with decreased bicarbonate and base excess), reflecting the respiratory consequence of hyperammonemia and accumulation of titratable organic acids, respectively
Plasma amino acid analysis showing elevation of glutamine and alanine and low-to-normal citrulline
Urine organic acid analysis showing elevations of carboxylase substrates and related metabolites suggestive of multiple carboxylase deficiency: 3-OH propionate, propionylglycine, methylcitrate and lactate, beta-hydroxybutyrate, and acetoacetate
While newborn screening using tandem mass spectrometry can theoretically detect carboxylase substrates (specifically C3 and C5OH levels as seen in multiple carboxylase deficiency), they were unremarkable in some of the affected individuals reported to date [
Liver transaminases, albumin, and clotting factors have been normal in the affected individuals reported to date.
The diagnosis of carbonic anhydrase VA (CA-VA) deficiency
Note: Identification of biallelic
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Carbonic Anhydrase VA Deficiency
See
See
Data derived from
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
• Significant elevation of plasma ammonia, lactate, and ketones (with concomitant increased urinary ketones). Hypoglycemia can also be seen.
• Complex acid-base status that includes respiratory alkalosis and metabolic acidosis (with decreased bicarbonate and base excess), reflecting the respiratory consequence of hyperammonemia and accumulation of titratable organic acids, respectively
• Plasma amino acid analysis showing elevation of glutamine and alanine and low-to-normal citrulline
• Urine organic acid analysis showing elevations of carboxylase substrates and related metabolites suggestive of multiple carboxylase deficiency: 3-OH propionate, propionylglycine, methylcitrate and lactate, beta-hydroxybutyrate, and acetoacetate
• Significant elevation of plasma ammonia, lactate, and ketones (with concomitant increased urinary ketones). Hypoglycemia can also be seen.
• Complex acid-base status that includes respiratory alkalosis and metabolic acidosis (with decreased bicarbonate and base excess), reflecting the respiratory consequence of hyperammonemia and accumulation of titratable organic acids, respectively
• Plasma amino acid analysis showing elevation of glutamine and alanine and low-to-normal citrulline
• Urine organic acid analysis showing elevations of carboxylase substrates and related metabolites suggestive of multiple carboxylase deficiency: 3-OH propionate, propionylglycine, methylcitrate and lactate, beta-hydroxybutyrate, and acetoacetate
•
• While newborn screening using tandem mass spectrometry can theoretically detect carboxylase substrates (specifically C3 and C5OH levels as seen in multiple carboxylase deficiency), they were unremarkable in some of the affected individuals reported to date [
• Liver transaminases, albumin, and clotting factors have been normal in the affected individuals reported to date.
• While newborn screening using tandem mass spectrometry can theoretically detect carboxylase substrates (specifically C3 and C5OH levels as seen in multiple carboxylase deficiency), they were unremarkable in some of the affected individuals reported to date [
• Liver transaminases, albumin, and clotting factors have been normal in the affected individuals reported to date.
• Significant elevation of plasma ammonia, lactate, and ketones (with concomitant increased urinary ketones). Hypoglycemia can also be seen.
• Complex acid-base status that includes respiratory alkalosis and metabolic acidosis (with decreased bicarbonate and base excess), reflecting the respiratory consequence of hyperammonemia and accumulation of titratable organic acids, respectively
• Plasma amino acid analysis showing elevation of glutamine and alanine and low-to-normal citrulline
• Urine organic acid analysis showing elevations of carboxylase substrates and related metabolites suggestive of multiple carboxylase deficiency: 3-OH propionate, propionylglycine, methylcitrate and lactate, beta-hydroxybutyrate, and acetoacetate
• While newborn screening using tandem mass spectrometry can theoretically detect carboxylase substrates (specifically C3 and C5OH levels as seen in multiple carboxylase deficiency), they were unremarkable in some of the affected individuals reported to date [
• Liver transaminases, albumin, and clotting factors have been normal in the affected individuals reported to date.
## Suggestive Findings
Significant elevation of plasma ammonia, lactate, and ketones (with concomitant increased urinary ketones). Hypoglycemia can also be seen.
Complex acid-base status that includes respiratory alkalosis and metabolic acidosis (with decreased bicarbonate and base excess), reflecting the respiratory consequence of hyperammonemia and accumulation of titratable organic acids, respectively
Plasma amino acid analysis showing elevation of glutamine and alanine and low-to-normal citrulline
Urine organic acid analysis showing elevations of carboxylase substrates and related metabolites suggestive of multiple carboxylase deficiency: 3-OH propionate, propionylglycine, methylcitrate and lactate, beta-hydroxybutyrate, and acetoacetate
While newborn screening using tandem mass spectrometry can theoretically detect carboxylase substrates (specifically C3 and C5OH levels as seen in multiple carboxylase deficiency), they were unremarkable in some of the affected individuals reported to date [
Liver transaminases, albumin, and clotting factors have been normal in the affected individuals reported to date.
• Significant elevation of plasma ammonia, lactate, and ketones (with concomitant increased urinary ketones). Hypoglycemia can also be seen.
• Complex acid-base status that includes respiratory alkalosis and metabolic acidosis (with decreased bicarbonate and base excess), reflecting the respiratory consequence of hyperammonemia and accumulation of titratable organic acids, respectively
• Plasma amino acid analysis showing elevation of glutamine and alanine and low-to-normal citrulline
• Urine organic acid analysis showing elevations of carboxylase substrates and related metabolites suggestive of multiple carboxylase deficiency: 3-OH propionate, propionylglycine, methylcitrate and lactate, beta-hydroxybutyrate, and acetoacetate
• Significant elevation of plasma ammonia, lactate, and ketones (with concomitant increased urinary ketones). Hypoglycemia can also be seen.
• Complex acid-base status that includes respiratory alkalosis and metabolic acidosis (with decreased bicarbonate and base excess), reflecting the respiratory consequence of hyperammonemia and accumulation of titratable organic acids, respectively
• Plasma amino acid analysis showing elevation of glutamine and alanine and low-to-normal citrulline
• Urine organic acid analysis showing elevations of carboxylase substrates and related metabolites suggestive of multiple carboxylase deficiency: 3-OH propionate, propionylglycine, methylcitrate and lactate, beta-hydroxybutyrate, and acetoacetate
•
• While newborn screening using tandem mass spectrometry can theoretically detect carboxylase substrates (specifically C3 and C5OH levels as seen in multiple carboxylase deficiency), they were unremarkable in some of the affected individuals reported to date [
• Liver transaminases, albumin, and clotting factors have been normal in the affected individuals reported to date.
• While newborn screening using tandem mass spectrometry can theoretically detect carboxylase substrates (specifically C3 and C5OH levels as seen in multiple carboxylase deficiency), they were unremarkable in some of the affected individuals reported to date [
• Liver transaminases, albumin, and clotting factors have been normal in the affected individuals reported to date.
• Significant elevation of plasma ammonia, lactate, and ketones (with concomitant increased urinary ketones). Hypoglycemia can also be seen.
• Complex acid-base status that includes respiratory alkalosis and metabolic acidosis (with decreased bicarbonate and base excess), reflecting the respiratory consequence of hyperammonemia and accumulation of titratable organic acids, respectively
• Plasma amino acid analysis showing elevation of glutamine and alanine and low-to-normal citrulline
• Urine organic acid analysis showing elevations of carboxylase substrates and related metabolites suggestive of multiple carboxylase deficiency: 3-OH propionate, propionylglycine, methylcitrate and lactate, beta-hydroxybutyrate, and acetoacetate
• While newborn screening using tandem mass spectrometry can theoretically detect carboxylase substrates (specifically C3 and C5OH levels as seen in multiple carboxylase deficiency), they were unremarkable in some of the affected individuals reported to date [
• Liver transaminases, albumin, and clotting factors have been normal in the affected individuals reported to date.
## Establishing the Diagnosis
The diagnosis of carbonic anhydrase VA (CA-VA) deficiency
Note: Identification of biallelic
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Carbonic Anhydrase VA Deficiency
See
See
Data derived from
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Carbonic Anhydrase VA Deficiency
See
See
Data derived from
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
## Clinical Characteristics
Most children with carbonic anhydrase VA (CA-VA) deficiency reported to date have presented during the newborn period (day 2 of life) or in early childhood (up to age 20 months) with hyperammonemic encephalopathy (i.e., lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma) [
Data on long-term follow up are limited as the oldest known affected individual is only an adolescent (as of 2021). Almost all of the other affected individuals reported (total number still <20) show normal psychomotor development and no further episodes of metabolic crisis. Only four individuals have shown mild learning difficulties and/or delayed gross and fine motor skills.
Genotype-phenotype correlations remain to be determined. Of note, because of the high rate of parental consanguinity most affected individuals are homozygous for a pathogenic variant.
Interestingly, for family 3 reported by
Prevalence is currently unknown. Fewer than 20 affected individuals have been described to date; however, some underdiagnosis must be assumed based on available published data [
Of note, a high proportion of affected individuals have been born to consanguineous parents from the Indian subcontinent (India, Pakistan, and Sri Lanka) due to the recurrent variant,
## Clinical Description
Most children with carbonic anhydrase VA (CA-VA) deficiency reported to date have presented during the newborn period (day 2 of life) or in early childhood (up to age 20 months) with hyperammonemic encephalopathy (i.e., lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma) [
Data on long-term follow up are limited as the oldest known affected individual is only an adolescent (as of 2021). Almost all of the other affected individuals reported (total number still <20) show normal psychomotor development and no further episodes of metabolic crisis. Only four individuals have shown mild learning difficulties and/or delayed gross and fine motor skills.
## Genotype-Phenotype Correlations
Genotype-phenotype correlations remain to be determined. Of note, because of the high rate of parental consanguinity most affected individuals are homozygous for a pathogenic variant.
Interestingly, for family 3 reported by
## Prevalence
Prevalence is currently unknown. Fewer than 20 affected individuals have been described to date; however, some underdiagnosis must be assumed based on available published data [
Of note, a high proportion of affected individuals have been born to consanguineous parents from the Indian subcontinent (India, Pakistan, and Sri Lanka) due to the recurrent variant,
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders to consider in the differential diagnosis of carbonic anhydrase VA (CA-VA) deficiency are summarized in
Disorders of Interest in the Differential Diagnosis of CA-VA Deficiency
AR = autosomal recessive; CPS1 = carbamoylphosphate synthetase I; DD = developmental delay; MOI = mode of inheritance; NAGS = N-acetyl glutamate synthase; nl = normal
Three clinical types are recognized: Type A (infantile form), in which most affected children die in infancy or early childhood; Type B (severe neonatal form), in which affected infants have hepatomegaly, pyramidal tract signs, and abnormal movement and die within the first three months of life; and Type C (intermittent/benign form), in which affected individuals have normal or mildly delayed neurologic development and episodic metabolic acidosis.
The biochemical profiles of the disorders to consider in the differential diagnosis of CA-VA deficiency are summarized in
Comparison of Biochemical Findings in CA-VA Deficiency and Other Inborn Errors of Metabolism in the Differential Diagnosis
↑ = elevated; ↓ = decreased; CA-VA = carbonic anhydrase VA; CPS1 = carbamoyl phosphate synthetase 1; NAGS = N-acetyl-glutamate synthase; Nl = normal; PC = pyruvate carboxylase; UQCRC2 = ubiquinol-cytochrome
HCO3 as low as 5 mmol/L and base excess as low as -21 found in some affected individuals
Low C0 (free carnitine) and elevated C2, C3, and C5OH
Elevated ketones, dicarboxylic acids, and tricarboxylic acid cycle intermediates
Glutamine levels are elevated in CA-VA deficiency but normal to decreased in PC deficiency.
Citrulline levels are decreased to normal in CA-VA deficiency but often elevated in PC deficiency.
Lysine levels are normal, and 2-ketoglutarate and other Krebs cycle intermediates are relatively mildly elevated in CA-VA deficiency. In PC deficiency, lysine is elevated and 2-ketoglutarate and other Krebs cycle metabolites are decreased.
The biochemical profiles in children with CA-VA deficiency support a predominant effect of (secondary) CPS1 deficiency vs PC deficiency.
The significantly higher level of PCC and 3MCC metabolites in (even well-controlled) individuals with the two former disorders compared to those with CA-VA deficiency during metabolic decompensation;
The presence of secondary CPS1 deficiency (high plasma glutamine and low plasma citrulline) as the (likely) major cause of hyperammonemia in CA-VA deficiency;
The presence of acetyl-CoA carboxylase deficiency in HCS deficiency and biotinidase deficiency. Individuals with CA-VA deficiency exhibited normal levels of free fatty acids and total and free carnitine, as well as normal acylcarnitine profiles (data not shown), mostly likely as a result of the activity of the cytosolic acetyl-CoA carboxylase 2 isoform that is not affected by impaired provision of mitochondrial HCO
Absence of hyperlactatemia in urea cycle defects;
Presence of multiple carboxylase deficiency metabolites in CA-VA deficiency.
• Glutamine levels are elevated in CA-VA deficiency but normal to decreased in PC deficiency.
• Citrulline levels are decreased to normal in CA-VA deficiency but often elevated in PC deficiency.
• Lysine levels are normal, and 2-ketoglutarate and other Krebs cycle intermediates are relatively mildly elevated in CA-VA deficiency. In PC deficiency, lysine is elevated and 2-ketoglutarate and other Krebs cycle metabolites are decreased.
• The significantly higher level of PCC and 3MCC metabolites in (even well-controlled) individuals with the two former disorders compared to those with CA-VA deficiency during metabolic decompensation;
• The presence of secondary CPS1 deficiency (high plasma glutamine and low plasma citrulline) as the (likely) major cause of hyperammonemia in CA-VA deficiency;
• The presence of acetyl-CoA carboxylase deficiency in HCS deficiency and biotinidase deficiency. Individuals with CA-VA deficiency exhibited normal levels of free fatty acids and total and free carnitine, as well as normal acylcarnitine profiles (data not shown), mostly likely as a result of the activity of the cytosolic acetyl-CoA carboxylase 2 isoform that is not affected by impaired provision of mitochondrial HCO
• Absence of hyperlactatemia in urea cycle defects;
• Presence of multiple carboxylase deficiency metabolites in CA-VA deficiency.
## Clinical Findings
Disorders to consider in the differential diagnosis of carbonic anhydrase VA (CA-VA) deficiency are summarized in
Disorders of Interest in the Differential Diagnosis of CA-VA Deficiency
AR = autosomal recessive; CPS1 = carbamoylphosphate synthetase I; DD = developmental delay; MOI = mode of inheritance; NAGS = N-acetyl glutamate synthase; nl = normal
Three clinical types are recognized: Type A (infantile form), in which most affected children die in infancy or early childhood; Type B (severe neonatal form), in which affected infants have hepatomegaly, pyramidal tract signs, and abnormal movement and die within the first three months of life; and Type C (intermittent/benign form), in which affected individuals have normal or mildly delayed neurologic development and episodic metabolic acidosis.
## Laboratory Findings
The biochemical profiles of the disorders to consider in the differential diagnosis of CA-VA deficiency are summarized in
Comparison of Biochemical Findings in CA-VA Deficiency and Other Inborn Errors of Metabolism in the Differential Diagnosis
↑ = elevated; ↓ = decreased; CA-VA = carbonic anhydrase VA; CPS1 = carbamoyl phosphate synthetase 1; NAGS = N-acetyl-glutamate synthase; Nl = normal; PC = pyruvate carboxylase; UQCRC2 = ubiquinol-cytochrome
HCO3 as low as 5 mmol/L and base excess as low as -21 found in some affected individuals
Low C0 (free carnitine) and elevated C2, C3, and C5OH
Elevated ketones, dicarboxylic acids, and tricarboxylic acid cycle intermediates
Glutamine levels are elevated in CA-VA deficiency but normal to decreased in PC deficiency.
Citrulline levels are decreased to normal in CA-VA deficiency but often elevated in PC deficiency.
Lysine levels are normal, and 2-ketoglutarate and other Krebs cycle intermediates are relatively mildly elevated in CA-VA deficiency. In PC deficiency, lysine is elevated and 2-ketoglutarate and other Krebs cycle metabolites are decreased.
The biochemical profiles in children with CA-VA deficiency support a predominant effect of (secondary) CPS1 deficiency vs PC deficiency.
The significantly higher level of PCC and 3MCC metabolites in (even well-controlled) individuals with the two former disorders compared to those with CA-VA deficiency during metabolic decompensation;
The presence of secondary CPS1 deficiency (high plasma glutamine and low plasma citrulline) as the (likely) major cause of hyperammonemia in CA-VA deficiency;
The presence of acetyl-CoA carboxylase deficiency in HCS deficiency and biotinidase deficiency. Individuals with CA-VA deficiency exhibited normal levels of free fatty acids and total and free carnitine, as well as normal acylcarnitine profiles (data not shown), mostly likely as a result of the activity of the cytosolic acetyl-CoA carboxylase 2 isoform that is not affected by impaired provision of mitochondrial HCO
Absence of hyperlactatemia in urea cycle defects;
Presence of multiple carboxylase deficiency metabolites in CA-VA deficiency.
• Glutamine levels are elevated in CA-VA deficiency but normal to decreased in PC deficiency.
• Citrulline levels are decreased to normal in CA-VA deficiency but often elevated in PC deficiency.
• Lysine levels are normal, and 2-ketoglutarate and other Krebs cycle intermediates are relatively mildly elevated in CA-VA deficiency. In PC deficiency, lysine is elevated and 2-ketoglutarate and other Krebs cycle metabolites are decreased.
• The significantly higher level of PCC and 3MCC metabolites in (even well-controlled) individuals with the two former disorders compared to those with CA-VA deficiency during metabolic decompensation;
• The presence of secondary CPS1 deficiency (high plasma glutamine and low plasma citrulline) as the (likely) major cause of hyperammonemia in CA-VA deficiency;
• The presence of acetyl-CoA carboxylase deficiency in HCS deficiency and biotinidase deficiency. Individuals with CA-VA deficiency exhibited normal levels of free fatty acids and total and free carnitine, as well as normal acylcarnitine profiles (data not shown), mostly likely as a result of the activity of the cytosolic acetyl-CoA carboxylase 2 isoform that is not affected by impaired provision of mitochondrial HCO
• Absence of hyperlactatemia in urea cycle defects;
• Presence of multiple carboxylase deficiency metabolites in CA-VA deficiency.
## Management
No clinical practice guidelines for carbonic anhydrase VA (CA-VA) deficiency have been published.
To establish the extent of disease and needs in an individual diagnosed with carbonic anhydrase VA (CA-VA) deficiency, the following evaluations are recommended:
Measurement of serum lactate, plasma ammonia, serum glucose, blood gases, plasma amino acids, blood acylcarnitines, urine ketone bodies, and urine organic acid profiles (during periods of illness; when stable for monitoring, preferably fasting)
Liver function parameters (coagulation, albumin, AST, ALT) as acute liver failure can occur in the urea cycle disorders, which are metabolically similar
Consideration of:
Brain MRI to define extent of or to exclude brain edema
Neurodevelopmental testing
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of CA-VA deficiency in order to facilitate medical and personal decision making
Always provide IV fluids (with glucose at maintenance doses) and extra calories via IV lipids; restrict protein intake if plasma ammonia is elevated.
Always monitor plasma ammonia, serum lactate, serum glucose, blood gases, electrolytes, and liver parameters.
Consider administration of carglumic acid (which – though not approved yet for this indication – enhances CPS1 activity and thus partially compensates for reduced HCO
Other ammonia-lowering medications such as sodium benzoate would also be reasonable; however, to date no conclusive information has been published.
Use a sick day formula (i.e., with extra calories and lipids, but limited proteins).
Monitor plasma ammonia, serum glucose, blood gases, serum lactate, and plasma amino acids (frequency according to patient's clinical state and physician's expertise).
There is no evidence to date that use of a special diet and/or cofactor (zinc) treatment during periods of wellness prevents metabolic decompensations.
Follow up during infancy and early childhood with a metabolic disease specialist every three to six months for physical and neurologic examinations.
Consider neurodevelopmental testing and measurement of the following: plasma ammonia and amino acids (to check for chronic hyperammonemia and citrulline deficiency as well as general nutritional state); serum lactate and glucose; blood gases; liver parameters; and urine organic acids.
If asymptomatic and no further episodes, monitoring can be relaxed during childhood but a sick day regime/emergency plan should be provided and followed.
Acetazolamide should be avoided, as it inhibits carbonic anhydrase activity.
If anti-seizure medication is necessary, avoid topiramate based on its action as a carbonic anhydrase inhibitor.
It is appropriate to clarify the genetic status of all sibs of an affected individual in order to identify those who would benefit from prompt treatment when symptoms appear.
Of note, in some families, asymptomatic (older) sibs were found to have biallelic
See
Avoidance of severe catabolism for a pregnant woman with CA-VA deficiency seems prudent.
Search
• Measurement of serum lactate, plasma ammonia, serum glucose, blood gases, plasma amino acids, blood acylcarnitines, urine ketone bodies, and urine organic acid profiles (during periods of illness; when stable for monitoring, preferably fasting)
• Liver function parameters (coagulation, albumin, AST, ALT) as acute liver failure can occur in the urea cycle disorders, which are metabolically similar
• Consideration of:
• Brain MRI to define extent of or to exclude brain edema
• Neurodevelopmental testing
• Brain MRI to define extent of or to exclude brain edema
• Neurodevelopmental testing
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of CA-VA deficiency in order to facilitate medical and personal decision making
• Brain MRI to define extent of or to exclude brain edema
• Neurodevelopmental testing
• Always provide IV fluids (with glucose at maintenance doses) and extra calories via IV lipids; restrict protein intake if plasma ammonia is elevated.
• Always monitor plasma ammonia, serum lactate, serum glucose, blood gases, electrolytes, and liver parameters.
• Consider administration of carglumic acid (which – though not approved yet for this indication – enhances CPS1 activity and thus partially compensates for reduced HCO
• Other ammonia-lowering medications such as sodium benzoate would also be reasonable; however, to date no conclusive information has been published.
• Use a sick day formula (i.e., with extra calories and lipids, but limited proteins).
• Monitor plasma ammonia, serum glucose, blood gases, serum lactate, and plasma amino acids (frequency according to patient's clinical state and physician's expertise).
• There is no evidence to date that use of a special diet and/or cofactor (zinc) treatment during periods of wellness prevents metabolic decompensations.
• Consider neurodevelopmental testing and measurement of the following: plasma ammonia and amino acids (to check for chronic hyperammonemia and citrulline deficiency as well as general nutritional state); serum lactate and glucose; blood gases; liver parameters; and urine organic acids.
• If asymptomatic and no further episodes, monitoring can be relaxed during childhood but a sick day regime/emergency plan should be provided and followed.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with carbonic anhydrase VA (CA-VA) deficiency, the following evaluations are recommended:
Measurement of serum lactate, plasma ammonia, serum glucose, blood gases, plasma amino acids, blood acylcarnitines, urine ketone bodies, and urine organic acid profiles (during periods of illness; when stable for monitoring, preferably fasting)
Liver function parameters (coagulation, albumin, AST, ALT) as acute liver failure can occur in the urea cycle disorders, which are metabolically similar
Consideration of:
Brain MRI to define extent of or to exclude brain edema
Neurodevelopmental testing
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of CA-VA deficiency in order to facilitate medical and personal decision making
• Measurement of serum lactate, plasma ammonia, serum glucose, blood gases, plasma amino acids, blood acylcarnitines, urine ketone bodies, and urine organic acid profiles (during periods of illness; when stable for monitoring, preferably fasting)
• Liver function parameters (coagulation, albumin, AST, ALT) as acute liver failure can occur in the urea cycle disorders, which are metabolically similar
• Consideration of:
• Brain MRI to define extent of or to exclude brain edema
• Neurodevelopmental testing
• Brain MRI to define extent of or to exclude brain edema
• Neurodevelopmental testing
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of CA-VA deficiency in order to facilitate medical and personal decision making
• Brain MRI to define extent of or to exclude brain edema
• Neurodevelopmental testing
## Treatment of Manifestations
Always provide IV fluids (with glucose at maintenance doses) and extra calories via IV lipids; restrict protein intake if plasma ammonia is elevated.
Always monitor plasma ammonia, serum lactate, serum glucose, blood gases, electrolytes, and liver parameters.
Consider administration of carglumic acid (which – though not approved yet for this indication – enhances CPS1 activity and thus partially compensates for reduced HCO
Other ammonia-lowering medications such as sodium benzoate would also be reasonable; however, to date no conclusive information has been published.
Use a sick day formula (i.e., with extra calories and lipids, but limited proteins).
Monitor plasma ammonia, serum glucose, blood gases, serum lactate, and plasma amino acids (frequency according to patient's clinical state and physician's expertise).
There is no evidence to date that use of a special diet and/or cofactor (zinc) treatment during periods of wellness prevents metabolic decompensations.
• Always provide IV fluids (with glucose at maintenance doses) and extra calories via IV lipids; restrict protein intake if plasma ammonia is elevated.
• Always monitor plasma ammonia, serum lactate, serum glucose, blood gases, electrolytes, and liver parameters.
• Consider administration of carglumic acid (which – though not approved yet for this indication – enhances CPS1 activity and thus partially compensates for reduced HCO
• Other ammonia-lowering medications such as sodium benzoate would also be reasonable; however, to date no conclusive information has been published.
• Use a sick day formula (i.e., with extra calories and lipids, but limited proteins).
• Monitor plasma ammonia, serum glucose, blood gases, serum lactate, and plasma amino acids (frequency according to patient's clinical state and physician's expertise).
• There is no evidence to date that use of a special diet and/or cofactor (zinc) treatment during periods of wellness prevents metabolic decompensations.
## Surveillance
Follow up during infancy and early childhood with a metabolic disease specialist every three to six months for physical and neurologic examinations.
Consider neurodevelopmental testing and measurement of the following: plasma ammonia and amino acids (to check for chronic hyperammonemia and citrulline deficiency as well as general nutritional state); serum lactate and glucose; blood gases; liver parameters; and urine organic acids.
If asymptomatic and no further episodes, monitoring can be relaxed during childhood but a sick day regime/emergency plan should be provided and followed.
• Consider neurodevelopmental testing and measurement of the following: plasma ammonia and amino acids (to check for chronic hyperammonemia and citrulline deficiency as well as general nutritional state); serum lactate and glucose; blood gases; liver parameters; and urine organic acids.
• If asymptomatic and no further episodes, monitoring can be relaxed during childhood but a sick day regime/emergency plan should be provided and followed.
## Agents/Circumstances to Avoid
Acetazolamide should be avoided, as it inhibits carbonic anhydrase activity.
If anti-seizure medication is necessary, avoid topiramate based on its action as a carbonic anhydrase inhibitor.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of all sibs of an affected individual in order to identify those who would benefit from prompt treatment when symptoms appear.
Of note, in some families, asymptomatic (older) sibs were found to have biallelic
See
## Pregnancy Management
Avoidance of severe catabolism for a pregnant woman with CA-VA deficiency seems prudent.
## Therapies Under Investigation
Search
## Genetic Counseling
Carbonic anhydrase VA (CA-VA) deficiency is inherited in an autosomal recessive manner.
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
A 25% chance of inheriting two
Note: In some families, asymptomatic (older) sibs with biallelic
A 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier;
A 25% chance of inheriting neither pathogenic variant being unaffected and not a carrier.
Clinical status of sibs cannot be used to refine their genetic risk as asymptomatic (older) sibs with biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have or are at risk of having one or two
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• A 25% chance of inheriting two
• Note: In some families, asymptomatic (older) sibs with biallelic
• A 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier;
• A 25% chance of inheriting neither pathogenic variant being unaffected and not a carrier.
• A 25% chance of inheriting two
• Note: In some families, asymptomatic (older) sibs with biallelic
• A 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier;
• A 25% chance of inheriting neither pathogenic variant being unaffected and not a carrier.
• Clinical status of sibs cannot be used to refine their genetic risk as asymptomatic (older) sibs with biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A 25% chance of inheriting two
• Note: In some families, asymptomatic (older) sibs with biallelic
• A 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier;
• A 25% chance of inheriting neither pathogenic variant being unaffected and not a carrier.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have or are at risk of having one or two
## Mode of Inheritance
Carbonic anhydrase VA (CA-VA) deficiency is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
A 25% chance of inheriting two
Note: In some families, asymptomatic (older) sibs with biallelic
A 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier;
A 25% chance of inheriting neither pathogenic variant being unaffected and not a carrier.
Clinical status of sibs cannot be used to refine their genetic risk as asymptomatic (older) sibs with biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• A 25% chance of inheriting two
• Note: In some families, asymptomatic (older) sibs with biallelic
• A 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier;
• A 25% chance of inheriting neither pathogenic variant being unaffected and not a carrier.
• A 25% chance of inheriting two
• Note: In some families, asymptomatic (older) sibs with biallelic
• A 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier;
• A 25% chance of inheriting neither pathogenic variant being unaffected and not a carrier.
• Clinical status of sibs cannot be used to refine their genetic risk as asymptomatic (older) sibs with biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A 25% chance of inheriting two
• Note: In some families, asymptomatic (older) sibs with biallelic
• A 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier;
• A 25% chance of inheriting neither pathogenic variant being unaffected and not a carrier.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have or are at risk of having one or two
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have or are at risk of having one or two
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
• United Kingdom
•
## Molecular Genetics
Carbonic Anhydrase VA Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Carbonic Anhydrase VA Deficiency (
Carbonic anhydrase VA (CA-VA) comprises two domains: (1) the alpha carbonic anhydrase domain, which spans from amino acid position 33 to 296; (2) the carbonic anhydrase, alpha-class, conserved site (within the aforementioned domain), which spans from amino acid position 141 to 157. Both domains are important for catalyzing the reversible hydration of carbon dioxide to bicarbonate.
Acute decompensations are consistent with dysfunction of all four enzymes to which CA-VA provides bicarbonate as substrate in mitochondria:
Carbamoyl phosphate synthetase 1 (CPS1) encoded by
The three biotin-dependent carboxylases:
Propionyl-CoA carboxylase (PCC) encoded by
3-methylcrotonyl-CoA carboxylase (3MCC) encoded by
Pyruvate carboxylase (PC) encoded by
The authors propose several explanations for the relatively benign clinical course observed in children with carbonic anhydrase VA deficiency:
The overlapping function of CA-VB may help prevent deleterious sequelae of reduced CA-VA activity [
Some bicarbonate is produced via the non-enzymatic reaction, even in the absence of carbonic anhydrases; thus, during stable periods, this may be sufficient for the four different bicarbonate-requiring intra-mitochondrial enzymes to function normally.
Notable
Variants listed in the table have been provided by the authors.
• Carbamoyl phosphate synthetase 1 (CPS1) encoded by
• The three biotin-dependent carboxylases:
• Propionyl-CoA carboxylase (PCC) encoded by
• 3-methylcrotonyl-CoA carboxylase (3MCC) encoded by
• Pyruvate carboxylase (PC) encoded by
• Propionyl-CoA carboxylase (PCC) encoded by
• 3-methylcrotonyl-CoA carboxylase (3MCC) encoded by
• Pyruvate carboxylase (PC) encoded by
• Propionyl-CoA carboxylase (PCC) encoded by
• 3-methylcrotonyl-CoA carboxylase (3MCC) encoded by
• Pyruvate carboxylase (PC) encoded by
• The overlapping function of CA-VB may help prevent deleterious sequelae of reduced CA-VA activity [
• Some bicarbonate is produced via the non-enzymatic reaction, even in the absence of carbonic anhydrases; thus, during stable periods, this may be sufficient for the four different bicarbonate-requiring intra-mitochondrial enzymes to function normally.
## Molecular Pathogenesis
Carbonic anhydrase VA (CA-VA) comprises two domains: (1) the alpha carbonic anhydrase domain, which spans from amino acid position 33 to 296; (2) the carbonic anhydrase, alpha-class, conserved site (within the aforementioned domain), which spans from amino acid position 141 to 157. Both domains are important for catalyzing the reversible hydration of carbon dioxide to bicarbonate.
Acute decompensations are consistent with dysfunction of all four enzymes to which CA-VA provides bicarbonate as substrate in mitochondria:
Carbamoyl phosphate synthetase 1 (CPS1) encoded by
The three biotin-dependent carboxylases:
Propionyl-CoA carboxylase (PCC) encoded by
3-methylcrotonyl-CoA carboxylase (3MCC) encoded by
Pyruvate carboxylase (PC) encoded by
The authors propose several explanations for the relatively benign clinical course observed in children with carbonic anhydrase VA deficiency:
The overlapping function of CA-VB may help prevent deleterious sequelae of reduced CA-VA activity [
Some bicarbonate is produced via the non-enzymatic reaction, even in the absence of carbonic anhydrases; thus, during stable periods, this may be sufficient for the four different bicarbonate-requiring intra-mitochondrial enzymes to function normally.
Notable
Variants listed in the table have been provided by the authors.
• Carbamoyl phosphate synthetase 1 (CPS1) encoded by
• The three biotin-dependent carboxylases:
• Propionyl-CoA carboxylase (PCC) encoded by
• 3-methylcrotonyl-CoA carboxylase (3MCC) encoded by
• Pyruvate carboxylase (PC) encoded by
• Propionyl-CoA carboxylase (PCC) encoded by
• 3-methylcrotonyl-CoA carboxylase (3MCC) encoded by
• Pyruvate carboxylase (PC) encoded by
• Propionyl-CoA carboxylase (PCC) encoded by
• 3-methylcrotonyl-CoA carboxylase (3MCC) encoded by
• Pyruvate carboxylase (PC) encoded by
• The overlapping function of CA-VB may help prevent deleterious sequelae of reduced CA-VA activity [
• Some bicarbonate is produced via the non-enzymatic reaction, even in the absence of carbonic anhydrases; thus, during stable periods, this may be sufficient for the four different bicarbonate-requiring intra-mitochondrial enzymes to function normally.
## Chapter Notes
TIDE (
Clara van Karnebeek, MD, PhD is a pediatrician and biochemical geneticist who dedicates her research to enhancing early diagnosis and treatment of inborn errors of metabolism to prevent intellectual developmental disabilities.
Johannes Häberle, MD is a neonatologist and metabolic pediatrician who specializes in the diagnosis and treatment of urea cycle defects and related disorders with hyperammonemia.
We gratefully acknowledge Casper Shyr, PhD student (University of British Columbia, Vancouver, Canada) for his contributions to the molecular genetics section of this paper.
26 August 2021 (bp) Comprehensive update posted live
2 April 2015 (me) Review posted live
8 September 2014 (cvk) Original submission
• 26 August 2021 (bp) Comprehensive update posted live
• 2 April 2015 (me) Review posted live
• 8 September 2014 (cvk) Original submission
## Author Notes
TIDE (
Clara van Karnebeek, MD, PhD is a pediatrician and biochemical geneticist who dedicates her research to enhancing early diagnosis and treatment of inborn errors of metabolism to prevent intellectual developmental disabilities.
Johannes Häberle, MD is a neonatologist and metabolic pediatrician who specializes in the diagnosis and treatment of urea cycle defects and related disorders with hyperammonemia.
## Acknowledgments
We gratefully acknowledge Casper Shyr, PhD student (University of British Columbia, Vancouver, Canada) for his contributions to the molecular genetics section of this paper.
## Revision History
26 August 2021 (bp) Comprehensive update posted live
2 April 2015 (me) Review posted live
8 September 2014 (cvk) Original submission
• 26 August 2021 (bp) Comprehensive update posted live
• 2 April 2015 (me) Review posted live
• 8 September 2014 (cvk) Original submission
## References
## Literature Cited
|
[
"C Diez-Fernandez, V Rüfenacht, S Santra, AM Lund, R Santer, M Lindner, T Tangeraas, C Unsinn, P de Lonlay, A Burlina, CD van Karnebeek, J Häberle. Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis.. Genet Med. 2016;18:991-1000",
"J. Häberle. Clinical and biochemical aspects of primary and secondary hyperammonemic disorders.. Arch Biochem Biophys 2013;536:101-8",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"A Marwaha, J Ibrahim, T Rice, N Hamwi, CA Rupar, D Cresswell, C Prasad, A Schulze. Two cases of carbonic anhydrase VA deficiency-An ultrarare metabolic decompensation syndrome presenting with hyperammonemia, lactic acidosis, ketonuria, and good clinical outcome.. JIMD Rep. 2020;57:9-14",
"Y Nagao, JR Batanian, MF Clemente, WS Sly. Genomic organization of the human gene (CA5) and pseudogene for mitochondrial carbonic anhydrase V and their localization to chromosomes 16q and 16p.. Genomics. 1995;28:477-84",
"A Olgac, CS Kasapkara, M Kilic, EY Keskin, G Sandal, DS Cram, J Haberle, D Torun. Carbonic anhydrase VA deficiency: a very rare case of hyperammonemic encephalopathy.. J Pediatr Endocrinol Metab. 2020;33:1349-52",
"GN Shah, TS Rubbelke, J Hendin, H Nguyen, A Waheed, JD Shoemaker, WS Sly. Targeted mutagenesis of mitochondrial carbonic anhydrases VA and VB implicates both in ammonia detoxification and glucose metabolism.. Proc Natl Acad Sci USA. 2013;110:7423-8",
"PD Stenson, M Mort, EV Ball, K Evans, M Hayden, S Heywood, M Hussain, AD Phillips, DN Cooper. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies.. Hum Genet. 2017;136:665-77",
"CDM van Karnebeek, WS Sly, CJ Ross, R Salvarinova, J Yaplito-Lee, S Santra, C Shyr, GA Horvath, P Eydoux, AM Lehman, V Bernard, T Newlove, H Ukpeh, A Chakrapani, MA Preece, S Ball, J Pitt, HD Vallance, M Coulter-Mackie, H Nguyen, L-H Zhang, AP Bhavsar, G Sinclair, A Waheed, WW Wasserman, S Stockler-Ipsiroglu. Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood.. Am J Hum Genet. 2014;94:453-61"
] |
2/4/2015
|
26/8/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
cach
|
cach
|
[
"CACH/VWM",
"Leukoencephalopathy with Vanishing White Matter",
"Leukoencephalopathy with Vanishing White Matter",
"CACH/VWM",
"Translation initiation factor eIF2B subunit alpha",
"Translation initiation factor eIF2B subunit beta",
"Translation initiation factor eIF2B subunit delta",
"Translation initiation factor eIF2B subunit epsilon",
"Translation initiation factor eIF2B subunit gamma",
"EIF2B1",
"EIF2B2",
"EIF2B3",
"EIF2B4",
"EIF2B5",
"Childhood Ataxia with Central Nervous System Hypomyelination / Vanishing White Matter"
] |
Childhood Ataxia with Central Nervous System Hypomyelination / Vanishing White Matter
|
Marjo S van der Knaap, Anne Fogli, Odile Boespflug-Tanguy, Truus EM Abbink, Raphael Schiffmann
|
Summary Childhood ataxia with central nervous system hypomyelination / vanishing white matter (CACH/VWM) is characterized by ataxia, spasticity, and variable optic atrophy. The phenotypic range includes a prenatal/congenital form, a subacute infantile form (onset age <1 year), an early childhood-onset form (onset age 1 to <4 years), a late childhood-/juvenile-onset form (onset age 4 to <18 years), and an adult-onset form (onset ≥18 years). The prenatal/congenital form is characterized by severe encephalopathy. In the later-onset forms initial motor and intellectual development is normal or mildly delayed, followed by neurologic deterioration with a chronic progressive or subacute course. While in childhood-onset forms motor deterioration dominates, in adult-onset forms cognitive decline and personality changes dominate. Chronic progressive decline can be exacerbated by rapid deterioration during febrile illnesses or following head trauma or major surgical procedures, or by acute and extreme fright. The diagnosis of CACH/VWM can be established in an individual with typical clinical findings, characteristic abnormalities on cranial MRI, and identification of biallelic pathogenic variants in one of five genes ( CACH/VWM is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variants in an affected relative have been identified.
|
## Diagnosis
Childhood ataxia with central nervous system hypomyelination / vanishing white matter (CACH/VWM)
Antenatal/early-infantile form:
Oligohydramnios
Intrauterine growth restriction
Severe encephalopathy
Microcephaly
Contractures
Cataract
Pancreatitis
Hepatosplenomegaly
Renal hypoplasia
Later-onset form:
Initial motor and intellectual development is normal or mildly delayed.
Neurologic deterioration has a chronic progressive or subacute course. Episodes of subacute deterioration may follow minor infection or minor head trauma and may lead to lethargy or coma.
Truncal and appendicular ataxia
Spasticity with increased tendon reflexes
Peripheral nervous system is usually not involved.
Optic atrophy may develop.
Epilepsy may occur but is not the predominant sign of the disease except in an acute situation.
In children, intellectual abilities may be affected but not to the same degree as motor functions. Alteration in intellectual abilities associated with behavioral changes can be the initial symptom in adult-onset forms.
Ovarian failure may be present as primary or secondary amenorrhea [
Routine cerebrospinal fluid (CSF) analysis is normal.
Glycine is often elevated.
The cerebral hemispheric white matter is symmetrically and diffusely abnormal.
Part of the abnormal white matter has a signal intensity close to or the same as CSF on T
On T
The MRI abnormalities are present in all affected individuals regardless of age of onset and are even present in asymptomatic affected sibs of a proband, although in presymptomatic and early symptomatic individuals the cerebral white matter may be abnormal on MRI, but not yet CSF-like. Over time, increasing amounts of white matter vanish and are replaced with CSF; cystic breakdown of the white matter is seen on proton density or FLAIR images [
Severe cerebral atrophy can be observed in adult-onset forms with slow progression. Cranial CT scan is of limited use and usually shows diffuse and symmetric hypodensity of the cerebral hemispheric white matter with no calcifications.
The diagnosis of CACH/VWM
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of CACH/VWM is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of CACH/VWM, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
When the diagnosis of CACH/VWM is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Childhood Ataxia with Central Nervous System Hypomyelination / Vanishing White Matter (CACH/VWM)
Genes are listed in alphabetic order.
See
All or almost all individuals with CACH/VWM have biallelic pathogenic variants identified in one of the five associated genes [
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
This number reflects the number of unique variants reported. Some variants are recurrent (see
A single multigene deletion including
* Testing is on a research basis only.
• Antenatal/early-infantile form:
• Oligohydramnios
• Intrauterine growth restriction
• Severe encephalopathy
• Microcephaly
• Contractures
• Cataract
• Pancreatitis
• Hepatosplenomegaly
• Renal hypoplasia
• Oligohydramnios
• Intrauterine growth restriction
• Severe encephalopathy
• Microcephaly
• Contractures
• Cataract
• Pancreatitis
• Hepatosplenomegaly
• Renal hypoplasia
• Later-onset form:
• Initial motor and intellectual development is normal or mildly delayed.
• Neurologic deterioration has a chronic progressive or subacute course. Episodes of subacute deterioration may follow minor infection or minor head trauma and may lead to lethargy or coma.
• Truncal and appendicular ataxia
• Spasticity with increased tendon reflexes
• Peripheral nervous system is usually not involved.
• Optic atrophy may develop.
• Epilepsy may occur but is not the predominant sign of the disease except in an acute situation.
• In children, intellectual abilities may be affected but not to the same degree as motor functions. Alteration in intellectual abilities associated with behavioral changes can be the initial symptom in adult-onset forms.
• Ovarian failure may be present as primary or secondary amenorrhea [
• Initial motor and intellectual development is normal or mildly delayed.
• Neurologic deterioration has a chronic progressive or subacute course. Episodes of subacute deterioration may follow minor infection or minor head trauma and may lead to lethargy or coma.
• Truncal and appendicular ataxia
• Spasticity with increased tendon reflexes
• Peripheral nervous system is usually not involved.
• Optic atrophy may develop.
• Epilepsy may occur but is not the predominant sign of the disease except in an acute situation.
• In children, intellectual abilities may be affected but not to the same degree as motor functions. Alteration in intellectual abilities associated with behavioral changes can be the initial symptom in adult-onset forms.
• Ovarian failure may be present as primary or secondary amenorrhea [
• Oligohydramnios
• Intrauterine growth restriction
• Severe encephalopathy
• Microcephaly
• Contractures
• Cataract
• Pancreatitis
• Hepatosplenomegaly
• Renal hypoplasia
• Initial motor and intellectual development is normal or mildly delayed.
• Neurologic deterioration has a chronic progressive or subacute course. Episodes of subacute deterioration may follow minor infection or minor head trauma and may lead to lethargy or coma.
• Truncal and appendicular ataxia
• Spasticity with increased tendon reflexes
• Peripheral nervous system is usually not involved.
• Optic atrophy may develop.
• Epilepsy may occur but is not the predominant sign of the disease except in an acute situation.
• In children, intellectual abilities may be affected but not to the same degree as motor functions. Alteration in intellectual abilities associated with behavioral changes can be the initial symptom in adult-onset forms.
• Ovarian failure may be present as primary or secondary amenorrhea [
• Routine cerebrospinal fluid (CSF) analysis is normal.
• Glycine is often elevated.
• The cerebral hemispheric white matter is symmetrically and diffusely abnormal.
• Part of the abnormal white matter has a signal intensity close to or the same as CSF on T
• On T
• The MRI abnormalities are present in all affected individuals regardless of age of onset and are even present in asymptomatic affected sibs of a proband, although in presymptomatic and early symptomatic individuals the cerebral white matter may be abnormal on MRI, but not yet CSF-like. Over time, increasing amounts of white matter vanish and are replaced with CSF; cystic breakdown of the white matter is seen on proton density or FLAIR images [
• Severe cerebral atrophy can be observed in adult-onset forms with slow progression. Cranial CT scan is of limited use and usually shows diffuse and symmetric hypodensity of the cerebral hemispheric white matter with no calcifications.
## Suggestive Findings
Childhood ataxia with central nervous system hypomyelination / vanishing white matter (CACH/VWM)
Antenatal/early-infantile form:
Oligohydramnios
Intrauterine growth restriction
Severe encephalopathy
Microcephaly
Contractures
Cataract
Pancreatitis
Hepatosplenomegaly
Renal hypoplasia
Later-onset form:
Initial motor and intellectual development is normal or mildly delayed.
Neurologic deterioration has a chronic progressive or subacute course. Episodes of subacute deterioration may follow minor infection or minor head trauma and may lead to lethargy or coma.
Truncal and appendicular ataxia
Spasticity with increased tendon reflexes
Peripheral nervous system is usually not involved.
Optic atrophy may develop.
Epilepsy may occur but is not the predominant sign of the disease except in an acute situation.
In children, intellectual abilities may be affected but not to the same degree as motor functions. Alteration in intellectual abilities associated with behavioral changes can be the initial symptom in adult-onset forms.
Ovarian failure may be present as primary or secondary amenorrhea [
Routine cerebrospinal fluid (CSF) analysis is normal.
Glycine is often elevated.
The cerebral hemispheric white matter is symmetrically and diffusely abnormal.
Part of the abnormal white matter has a signal intensity close to or the same as CSF on T
On T
The MRI abnormalities are present in all affected individuals regardless of age of onset and are even present in asymptomatic affected sibs of a proband, although in presymptomatic and early symptomatic individuals the cerebral white matter may be abnormal on MRI, but not yet CSF-like. Over time, increasing amounts of white matter vanish and are replaced with CSF; cystic breakdown of the white matter is seen on proton density or FLAIR images [
Severe cerebral atrophy can be observed in adult-onset forms with slow progression. Cranial CT scan is of limited use and usually shows diffuse and symmetric hypodensity of the cerebral hemispheric white matter with no calcifications.
• Antenatal/early-infantile form:
• Oligohydramnios
• Intrauterine growth restriction
• Severe encephalopathy
• Microcephaly
• Contractures
• Cataract
• Pancreatitis
• Hepatosplenomegaly
• Renal hypoplasia
• Oligohydramnios
• Intrauterine growth restriction
• Severe encephalopathy
• Microcephaly
• Contractures
• Cataract
• Pancreatitis
• Hepatosplenomegaly
• Renal hypoplasia
• Later-onset form:
• Initial motor and intellectual development is normal or mildly delayed.
• Neurologic deterioration has a chronic progressive or subacute course. Episodes of subacute deterioration may follow minor infection or minor head trauma and may lead to lethargy or coma.
• Truncal and appendicular ataxia
• Spasticity with increased tendon reflexes
• Peripheral nervous system is usually not involved.
• Optic atrophy may develop.
• Epilepsy may occur but is not the predominant sign of the disease except in an acute situation.
• In children, intellectual abilities may be affected but not to the same degree as motor functions. Alteration in intellectual abilities associated with behavioral changes can be the initial symptom in adult-onset forms.
• Ovarian failure may be present as primary or secondary amenorrhea [
• Initial motor and intellectual development is normal or mildly delayed.
• Neurologic deterioration has a chronic progressive or subacute course. Episodes of subacute deterioration may follow minor infection or minor head trauma and may lead to lethargy or coma.
• Truncal and appendicular ataxia
• Spasticity with increased tendon reflexes
• Peripheral nervous system is usually not involved.
• Optic atrophy may develop.
• Epilepsy may occur but is not the predominant sign of the disease except in an acute situation.
• In children, intellectual abilities may be affected but not to the same degree as motor functions. Alteration in intellectual abilities associated with behavioral changes can be the initial symptom in adult-onset forms.
• Ovarian failure may be present as primary or secondary amenorrhea [
• Oligohydramnios
• Intrauterine growth restriction
• Severe encephalopathy
• Microcephaly
• Contractures
• Cataract
• Pancreatitis
• Hepatosplenomegaly
• Renal hypoplasia
• Initial motor and intellectual development is normal or mildly delayed.
• Neurologic deterioration has a chronic progressive or subacute course. Episodes of subacute deterioration may follow minor infection or minor head trauma and may lead to lethargy or coma.
• Truncal and appendicular ataxia
• Spasticity with increased tendon reflexes
• Peripheral nervous system is usually not involved.
• Optic atrophy may develop.
• Epilepsy may occur but is not the predominant sign of the disease except in an acute situation.
• In children, intellectual abilities may be affected but not to the same degree as motor functions. Alteration in intellectual abilities associated with behavioral changes can be the initial symptom in adult-onset forms.
• Ovarian failure may be present as primary or secondary amenorrhea [
• Routine cerebrospinal fluid (CSF) analysis is normal.
• Glycine is often elevated.
• The cerebral hemispheric white matter is symmetrically and diffusely abnormal.
• Part of the abnormal white matter has a signal intensity close to or the same as CSF on T
• On T
• The MRI abnormalities are present in all affected individuals regardless of age of onset and are even present in asymptomatic affected sibs of a proband, although in presymptomatic and early symptomatic individuals the cerebral white matter may be abnormal on MRI, but not yet CSF-like. Over time, increasing amounts of white matter vanish and are replaced with CSF; cystic breakdown of the white matter is seen on proton density or FLAIR images [
• Severe cerebral atrophy can be observed in adult-onset forms with slow progression. Cranial CT scan is of limited use and usually shows diffuse and symmetric hypodensity of the cerebral hemispheric white matter with no calcifications.
## Establishing the Diagnosis
The diagnosis of CACH/VWM
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of CACH/VWM is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of CACH/VWM, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
When the diagnosis of CACH/VWM is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Childhood Ataxia with Central Nervous System Hypomyelination / Vanishing White Matter (CACH/VWM)
Genes are listed in alphabetic order.
See
All or almost all individuals with CACH/VWM have biallelic pathogenic variants identified in one of the five associated genes [
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
This number reflects the number of unique variants reported. Some variants are recurrent (see
A single multigene deletion including
* Testing is on a research basis only.
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of CACH/VWM, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
## Option 2
When the diagnosis of CACH/VWM is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Childhood Ataxia with Central Nervous System Hypomyelination / Vanishing White Matter (CACH/VWM)
Genes are listed in alphabetic order.
See
All or almost all individuals with CACH/VWM have biallelic pathogenic variants identified in one of the five associated genes [
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
This number reflects the number of unique variants reported. Some variants are recurrent (see
A single multigene deletion including
* Testing is on a research basis only.
## Clinical Characteristics
Childhood ataxia with central nervous system hypomyelination / vanishing white matter (CACH/VWM) phenotypes range from a congenital or early-infantile form (onset age <1 year) to an early childhood-onset form (onset age 1 to <4 years), a late-childhood/juvenile-onset form (onset age 4 to <18 years), and an adult-onset form (onset ≥18 years [
The rate of disease progression depends on the age of onset. For individuals with disease onset before age four years, the decline is in general more rapid and more severe the earlier the onset. For onset after age four years, the disease course is generally slower and milder and life span is longer. For this later-onset group, however, variation in severity is wide and does not correlate with specific age at onset [
The clinical course is rapidly and relentlessly downhill; the adverse effect of stress factors is less clear. So far, all infants with neonatal presentation have died within the first year of life [
A specific infantile-onset phenotype was described as "Cree leukoencephalopathy" because of its occurrence in the native North American Cree and Chippewayan indigenous population [
Subsequently, generally progressive deterioration results in increasing difficulty in walking, tremor, spasticity with hyperreflexia, dysarthria, and seizures. Once a child becomes nonambulatory, the clinical course may remain stable for several years. Swallowing difficulties and optic atrophy develop late in the disease.
Head circumference is usually normal; however, severe progressive macrocephaly occurring after age two years has been reported [
The time course of disease progression varies among individuals even within the same family, ranging from rapid progression with death occurring one to five years after onset to very slow progression with death occurring decades after onset.
Asymptomatic and minimally symptomatic adults with two pathogenic variants in one of the genes and a typically affected sib have also been described [
No statistically significant differences have been observed for individuals with pathogenic variants in
Although intrafamilial variability exists, correlation between certain homozygous pathogenic variants and age of onset and disease severity has been described [
In individuals homozygous for the
Certain
Certain
Some adults who are homozygous or compound heterozygous for two disease-causing pathogenic variants in the same gene may be asymptomatic for prolonged periods of time [
"Cree leukoencephalopathy," described in the native North American Cree and Chippewayan indigenous population, is now recognized to be an infantile form of CACH/VWM [
The prevalence of CACH/VWM is not known; it is considered one of the more common leukodystrophies. In the Netherlands, the live-birth incidence was recently shown to be 1:80,000 [
• In individuals homozygous for the
• Certain
• Certain
## Clinical Description
Childhood ataxia with central nervous system hypomyelination / vanishing white matter (CACH/VWM) phenotypes range from a congenital or early-infantile form (onset age <1 year) to an early childhood-onset form (onset age 1 to <4 years), a late-childhood/juvenile-onset form (onset age 4 to <18 years), and an adult-onset form (onset ≥18 years [
The rate of disease progression depends on the age of onset. For individuals with disease onset before age four years, the decline is in general more rapid and more severe the earlier the onset. For onset after age four years, the disease course is generally slower and milder and life span is longer. For this later-onset group, however, variation in severity is wide and does not correlate with specific age at onset [
The clinical course is rapidly and relentlessly downhill; the adverse effect of stress factors is less clear. So far, all infants with neonatal presentation have died within the first year of life [
A specific infantile-onset phenotype was described as "Cree leukoencephalopathy" because of its occurrence in the native North American Cree and Chippewayan indigenous population [
Subsequently, generally progressive deterioration results in increasing difficulty in walking, tremor, spasticity with hyperreflexia, dysarthria, and seizures. Once a child becomes nonambulatory, the clinical course may remain stable for several years. Swallowing difficulties and optic atrophy develop late in the disease.
Head circumference is usually normal; however, severe progressive macrocephaly occurring after age two years has been reported [
The time course of disease progression varies among individuals even within the same family, ranging from rapid progression with death occurring one to five years after onset to very slow progression with death occurring decades after onset.
Asymptomatic and minimally symptomatic adults with two pathogenic variants in one of the genes and a typically affected sib have also been described [
## Phenotype Correlations by Gene
No statistically significant differences have been observed for individuals with pathogenic variants in
## Genotype-Phenotype Correlations
Although intrafamilial variability exists, correlation between certain homozygous pathogenic variants and age of onset and disease severity has been described [
In individuals homozygous for the
Certain
Certain
• In individuals homozygous for the
• Certain
• Certain
## Penetrance
Some adults who are homozygous or compound heterozygous for two disease-causing pathogenic variants in the same gene may be asymptomatic for prolonged periods of time [
## Nomenclature
"Cree leukoencephalopathy," described in the native North American Cree and Chippewayan indigenous population, is now recognized to be an infantile form of CACH/VWM [
## Prevalence
The prevalence of CACH/VWM is not known; it is considered one of the more common leukodystrophies. In the Netherlands, the live-birth incidence was recently shown to be 1:80,000 [
## Genetically Related (Allelic) Disorders
Thus far, all individuals with eIF2B-related disease have a leukodystrophy; no other phenotypes have been observed.
A contiguous gene deletion that included
## Differential Diagnosis
Other Disorders Affecting the White Matter Diffusely During Childhood to Consider in the Differential Diagnosis of CACH/VWM
Extensive or diffuse cerebral WM changes
Involvement of the corpus callosum connecting lesions on both sides
Involvement of long descending tracts
WM signal changes have a frontal predominance.
The cystic degeneration may affect the subcortical or deep WM.
Basal ganglia & thalamic abnormalities are frequently present.
Contrast enhancement of characteristic structures often facilitates diagnosis.
Diffusely abnormal & mildly swollen cerebral hemispheric WM that does not show signs of diffuse rarefaction or cystic degeneration
Subcortical cysts are almost always present in the anterior temporal area & often in other regions.
Cysts are best seen on proton density & FLAIR.
MRI abnormalities may be similar to those seen in CACH/VWM, but WM cysts are typically well delineated (in contrast to CACH/VWM).
Prominent & diffuse WM rarefaction & cystic degeneration may be seen in mitochondrial disorders.
Diffuse hyperintensity of WM on T
There is no WM rarefaction of cystic degeneration.
In addition, central nerve conduction evaluated w/evoked potentials is always severely affected even at an early stage of the disease.
AD = autosomal dominant; AR = autosomal recessive; CACH/VWM = childhood ataxia with central nervous system / hypomyelination / vanishing white matter; MOI = mode of inheritance; mt = mitochondrial; WM = white matter; XL = X-linked
Biallelic pathogenic variants in
Mitochondrial diseases are a clinically heterogeneous group of disorders that can be caused by mutation of genes encoded by either nuclear DNA or mitochondrial DNA (mtDNA).
See
Available data suggest that multiple sclerosis is inherited as a complex multifactorial disorder that results from the interaction of genetic and environmental factors.
• Extensive or diffuse cerebral WM changes
• Involvement of the corpus callosum connecting lesions on both sides
• Involvement of long descending tracts
• WM signal changes have a frontal predominance.
• The cystic degeneration may affect the subcortical or deep WM.
• Basal ganglia & thalamic abnormalities are frequently present.
• Contrast enhancement of characteristic structures often facilitates diagnosis.
• Diffusely abnormal & mildly swollen cerebral hemispheric WM that does not show signs of diffuse rarefaction or cystic degeneration
• Subcortical cysts are almost always present in the anterior temporal area & often in other regions.
• Cysts are best seen on proton density & FLAIR.
• MRI abnormalities may be similar to those seen in CACH/VWM, but WM cysts are typically well delineated (in contrast to CACH/VWM).
• Prominent & diffuse WM rarefaction & cystic degeneration may be seen in mitochondrial disorders.
• Diffuse hyperintensity of WM on T
• There is no WM rarefaction of cystic degeneration.
• In addition, central nerve conduction evaluated w/evoked potentials is always severely affected even at an early stage of the disease.
## Management
To establish the extent of disease and needs in an individual diagnosed with childhood ataxia with central nervous system hypomyelination / vanishing white matter (CACH/VWM), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Brain MRI
Ophthalmologic examination
Neurologic examination
Physical therapy/occupational therapy assessment as needed
Consultation with a clinical geneticist and/or genetic counselor
Note: If an individual is diagnosed while asymptomatic, either because of an affected sib or as an incidental finding on exome sequencing, the above evaluations and the recommendations in
The following are appropriate:
Physical therapy and rehabilitation for motor dysfunction (mainly spasticity and ataxia)
Ankle-foot orthotics in individuals with hypotonia and weakness of ankle dorsiflexors
Anti-seizure medication for treatment of seizures and abnormalities of behavior and mood
Considering the known adverse effect of fever, it is important to prevent infections and fever as much as possible (e.g., through the use of vaccinations, including anti-flu vaccination); low-dose maintenance antibiotics during winter, antibiotics for minor infections, and antipyretics for fever are appropriate. For children, wearing a helmet while outside helps minimize the effects of possible head trauma.
Close surveillance for several days following head trauma or major surgical procedure with anesthesia is indicated because neurologic deterioration (presumably stress related) may follow.
Avoid the following:
Contact sports and other activities with a high risk of head trauma
Stressful emotional and physical situations (e.g., acute fright, fever and other causes of extreme temperatures, major surgery)
See
Search
In general, corticosteriods and intravenous gamma globulin are not effective in the treatment of CACH/VWM. Corticosteriods have been used with inconsistent results in acute situations, including intractable status epilepticus.
• Brain MRI
• Ophthalmologic examination
• Neurologic examination
• Physical therapy/occupational therapy assessment as needed
• Consultation with a clinical geneticist and/or genetic counselor
• Physical therapy and rehabilitation for motor dysfunction (mainly spasticity and ataxia)
• Ankle-foot orthotics in individuals with hypotonia and weakness of ankle dorsiflexors
• Anti-seizure medication for treatment of seizures and abnormalities of behavior and mood
• Contact sports and other activities with a high risk of head trauma
• Stressful emotional and physical situations (e.g., acute fright, fever and other causes of extreme temperatures, major surgery)
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with childhood ataxia with central nervous system hypomyelination / vanishing white matter (CACH/VWM), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Brain MRI
Ophthalmologic examination
Neurologic examination
Physical therapy/occupational therapy assessment as needed
Consultation with a clinical geneticist and/or genetic counselor
Note: If an individual is diagnosed while asymptomatic, either because of an affected sib or as an incidental finding on exome sequencing, the above evaluations and the recommendations in
• Brain MRI
• Ophthalmologic examination
• Neurologic examination
• Physical therapy/occupational therapy assessment as needed
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
The following are appropriate:
Physical therapy and rehabilitation for motor dysfunction (mainly spasticity and ataxia)
Ankle-foot orthotics in individuals with hypotonia and weakness of ankle dorsiflexors
Anti-seizure medication for treatment of seizures and abnormalities of behavior and mood
• Physical therapy and rehabilitation for motor dysfunction (mainly spasticity and ataxia)
• Ankle-foot orthotics in individuals with hypotonia and weakness of ankle dorsiflexors
• Anti-seizure medication for treatment of seizures and abnormalities of behavior and mood
## Prevention of Secondary Complications
Considering the known adverse effect of fever, it is important to prevent infections and fever as much as possible (e.g., through the use of vaccinations, including anti-flu vaccination); low-dose maintenance antibiotics during winter, antibiotics for minor infections, and antipyretics for fever are appropriate. For children, wearing a helmet while outside helps minimize the effects of possible head trauma.
## Surveillance
Close surveillance for several days following head trauma or major surgical procedure with anesthesia is indicated because neurologic deterioration (presumably stress related) may follow.
## Agents/Circumstances to Avoid
Avoid the following:
Contact sports and other activities with a high risk of head trauma
Stressful emotional and physical situations (e.g., acute fright, fever and other causes of extreme temperatures, major surgery)
• Contact sports and other activities with a high risk of head trauma
• Stressful emotional and physical situations (e.g., acute fright, fever and other causes of extreme temperatures, major surgery)
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Other
In general, corticosteriods and intravenous gamma globulin are not effective in the treatment of CACH/VWM. Corticosteriods have been used with inconsistent results in acute situations, including intractable status epilepticus.
## Genetic Counseling
Childhood ataxia with central nervous system hypomyelination / vanishing white matter (CACH/VWM) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., carriers of one CACH/VWM-causing pathogenic variant).
Heterozygotes (carriers) are asymptomatic. No clinical or MRI abnormalities have been found in carriers of pathogenic variants in
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Age of onset of neurologic signs can differ from one individual to another within the same family. Therefore, a neurologically asymptomatic sib of an affected individual may have biallelic pathogenic variants and be at high risk of developing the disease. The large majority of (if not all) apparently asymptomatic individuals appear to have the extensive white matter abnormalities characteristic of the syndrome on head MRI, and may have very mild learning, cognitive, or behavioral disabilities. Note: Although both the childhood and juvenile forms have been observed in sibs [
Heterozygotes (carriers) are asymptomatic. No clinical or MRI abnormalities have been found in carriers of a CACH/VWM-causing pathogenic variant
Carrier testing for at-risk relatives requires prior identification of the CACH/VWM-causing pathogenic variants in the family.
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of an affected individual and to young adults who are affected or at risk or are carriers.
Predictive testing for at-risk individuals is possible once the CACH/VWM-causing pathogenic variants have been identified in an affected family member.
Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
Predictive testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
Once the CACH/VWM-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one CACH/VWM-causing pathogenic variant).
• Heterozygotes (carriers) are asymptomatic. No clinical or MRI abnormalities have been found in carriers of pathogenic variants in
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Age of onset of neurologic signs can differ from one individual to another within the same family. Therefore, a neurologically asymptomatic sib of an affected individual may have biallelic pathogenic variants and be at high risk of developing the disease. The large majority of (if not all) apparently asymptomatic individuals appear to have the extensive white matter abnormalities characteristic of the syndrome on head MRI, and may have very mild learning, cognitive, or behavioral disabilities. Note: Although both the childhood and juvenile forms have been observed in sibs [
• Heterozygotes (carriers) are asymptomatic. No clinical or MRI abnormalities have been found in carriers of a CACH/VWM-causing pathogenic variant
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of an affected individual and to young adults who are affected or at risk or are carriers.
• Predictive testing for at-risk individuals is possible once the CACH/VWM-causing pathogenic variants have been identified in an affected family member.
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• Predictive testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
## Mode of Inheritance
Childhood ataxia with central nervous system hypomyelination / vanishing white matter (CACH/VWM) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one CACH/VWM-causing pathogenic variant).
Heterozygotes (carriers) are asymptomatic. No clinical or MRI abnormalities have been found in carriers of pathogenic variants in
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Age of onset of neurologic signs can differ from one individual to another within the same family. Therefore, a neurologically asymptomatic sib of an affected individual may have biallelic pathogenic variants and be at high risk of developing the disease. The large majority of (if not all) apparently asymptomatic individuals appear to have the extensive white matter abnormalities characteristic of the syndrome on head MRI, and may have very mild learning, cognitive, or behavioral disabilities. Note: Although both the childhood and juvenile forms have been observed in sibs [
Heterozygotes (carriers) are asymptomatic. No clinical or MRI abnormalities have been found in carriers of a CACH/VWM-causing pathogenic variant
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one CACH/VWM-causing pathogenic variant).
• Heterozygotes (carriers) are asymptomatic. No clinical or MRI abnormalities have been found in carriers of pathogenic variants in
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Age of onset of neurologic signs can differ from one individual to another within the same family. Therefore, a neurologically asymptomatic sib of an affected individual may have biallelic pathogenic variants and be at high risk of developing the disease. The large majority of (if not all) apparently asymptomatic individuals appear to have the extensive white matter abnormalities characteristic of the syndrome on head MRI, and may have very mild learning, cognitive, or behavioral disabilities. Note: Although both the childhood and juvenile forms have been observed in sibs [
• Heterozygotes (carriers) are asymptomatic. No clinical or MRI abnormalities have been found in carriers of a CACH/VWM-causing pathogenic variant
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the CACH/VWM-causing pathogenic variants in the family.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of an affected individual and to young adults who are affected or at risk or are carriers.
Predictive testing for at-risk individuals is possible once the CACH/VWM-causing pathogenic variants have been identified in an affected family member.
Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
Predictive testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of an affected individual and to young adults who are affected or at risk or are carriers.
• Predictive testing for at-risk individuals is possible once the CACH/VWM-causing pathogenic variants have been identified in an affected family member.
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• Predictive testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Once the CACH/VWM-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
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• United Kingdom
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## Molecular Genetics
Childhood Ataxia with Central Nervous System Hypomyelination / Vanishing White Matter: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Childhood Ataxia with Central Nervous System Hypomyelination / Vanishing White Matter (
The biologic importance of the eIF2B complex is evidenced by the following:
Yeast with null pathogenic variants for any of the five genes
Pathogenic variants that completely abolish eIF2B activity are probably lethal in the biallellic state in humans; nonsense variants are rare and only observed in compound heterozygotes in association with a pathogenic missense variant [
Affected individuals have decreased GEF activity (20%-77% of normal) [
Pathogenic variants in
Of note, decreased GEF activity leads to enhanced translation of specific mRNA of proteins, similar to the situation that occurs when a cell is under stress.
Childhood Ataxia with Central Nervous System Hypomyelination / Vanishing White Matter: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
Genes are in alphabetic order.
• Yeast with null pathogenic variants for any of the five genes
• Pathogenic variants that completely abolish eIF2B activity are probably lethal in the biallellic state in humans; nonsense variants are rare and only observed in compound heterozygotes in association with a pathogenic missense variant [
• Affected individuals have decreased GEF activity (20%-77% of normal) [
• Pathogenic variants in
## Molecular Pathogenesis
The biologic importance of the eIF2B complex is evidenced by the following:
Yeast with null pathogenic variants for any of the five genes
Pathogenic variants that completely abolish eIF2B activity are probably lethal in the biallellic state in humans; nonsense variants are rare and only observed in compound heterozygotes in association with a pathogenic missense variant [
Affected individuals have decreased GEF activity (20%-77% of normal) [
Pathogenic variants in
Of note, decreased GEF activity leads to enhanced translation of specific mRNA of proteins, similar to the situation that occurs when a cell is under stress.
Childhood Ataxia with Central Nervous System Hypomyelination / Vanishing White Matter: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
Genes are in alphabetic order.
• Yeast with null pathogenic variants for any of the five genes
• Pathogenic variants that completely abolish eIF2B activity are probably lethal in the biallellic state in humans; nonsense variants are rare and only observed in compound heterozygotes in association with a pathogenic missense variant [
• Affected individuals have decreased GEF activity (20%-77% of normal) [
• Pathogenic variants in
## References
## Literature Cited
## Chapter Notes
4 April 2019 (sw) Comprehensive update posted live
24 May 2012 (me) Comprehensive update posted live
9 February 2010 (me) Comprehensive update posted live
30 July 2007 (me) Comprehensive update posted live
20 February 2003 (me) Review posted live
19 November 2002 (pb) Original submission
• 4 April 2019 (sw) Comprehensive update posted live
• 24 May 2012 (me) Comprehensive update posted live
• 9 February 2010 (me) Comprehensive update posted live
• 30 July 2007 (me) Comprehensive update posted live
• 20 February 2003 (me) Review posted live
• 19 November 2002 (pb) Original submission
## Revision History
4 April 2019 (sw) Comprehensive update posted live
24 May 2012 (me) Comprehensive update posted live
9 February 2010 (me) Comprehensive update posted live
30 July 2007 (me) Comprehensive update posted live
20 February 2003 (me) Review posted live
19 November 2002 (pb) Original submission
• 4 April 2019 (sw) Comprehensive update posted live
• 24 May 2012 (me) Comprehensive update posted live
• 9 February 2010 (me) Comprehensive update posted live
• 30 July 2007 (me) Comprehensive update posted live
• 20 February 2003 (me) Review posted live
• 19 November 2002 (pb) Original submission
MRI of an individual with the classic form of CACH/VWM
Figure 1. Diffuse hypointensity of the white matter on T
Figure 2. Increased signal intensity in the same white matter area on T
Figure 3. Cavitation in the abnormal white matter seen on the FLAIR images. Note the absence of cerebral atrophy.
Parasagittal T
|
[] |
20/2/2003
|
4/4/2019
|
9/8/2012
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cact-def
|
cact-def
|
[
"CACT Deficiency",
"CACT Deficiency",
"Mitochondrial carnitine/acylcarnitine carrier protein",
"SLC25A20",
"Carnitine-Acylcarnitine Translocase Deficiency"
] |
Carnitine-Acylcarnitine Translocase Deficiency
|
J Andres Morales Corado, Chung U Lee, Gregory M Enns
|
Summary Carnitine-acylcarnitine translocase (CACT) is a critical component of the carnitine shuttle, which facilitates the transfer of long-chain fatty acylcarnitines across the inner mitochondrial membrane. CACT deficiency causes a defect in mitochondrial long-chain fatty acid β-oxidation, with variable clinical severity. Severe neonatal-onset disease is most common, with symptoms evident within two days after birth; attenuated cases may present in the first months of life. Hyperammonemia and cardiac arrhythmia are prominent in early-onset disease, with high rates of cardiac arrest. Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis. Univentricular or biventricular hypertrophic cardiomyopathy, ranging from mild to severe, may respond to appropriate dietary and medical therapies. Hyperammonemia is difficult to treat and is an important determinant of long-term neurocognitive outcome. Affected individuals with early-onset disease typically experience brain injury at presentation, and have recurrent hyperammonemia leading to developmental delay / intellectual disability. Affected individuals with later-onset disease have milder symptoms and are less likely to experience recurrent hyperammonemia, allowing a better developmental outcome. Prompt treatment of the presenting episode to prevent hypoglycemic, hypoxic, or hyperammonemic brain injury may allow normal growth and development. Characteristic elevation of long-chain acylcarnitines C16, C18, and C18:1 on acylcarnitine profile suggests a diagnosis of CACT or CPT II deficiency. The diagnosis of CACT deficiency is confirmed by identification of biallelic pathogenic variants in CACT deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
## Diagnosis
Carnitine acylcarnitine translocase (CACT) is a part of the carnitine shuttle that is localized to the inner mitochondrial membrane. It transfers long-chain acylcarnitines formed by the action of carnitine palmitoyl-transferase I (CPT1) in the outer mitochondrial membrane into the mitochondrial matrix in exchange for free carnitine. These acylcarnitines are then converted into acyl-CoA by carnitine palmitoyl-transferase 2 (CPT2) to enter β-oxidation [
No consensus clinical diagnostic criteria for carnitine-acylcarnitine translocase (CACT) deficiency have been published.
C16 and C18:1 acylcarnitine values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing, as these metabolites could also be elevated in carnitine palmitoyltransferase II (CPT2) deficiency (see
Most individuals with the severe early-onset phenotype will already be symptomatic by the time a newborn screening result is available. After a positive newborn screening test, the newborn should be evaluated immediately and a follow-up plasma acylcarnitine profile obtained [
If the follow-up biochemical testing supports the likelihood of CACT deficiency, additional testing is required to establish the diagnosis (see
Medical interventions should be put in place immediately on receipt of an abnormal NBS result, while additional testing is performed to establish a definitive diagnosis of CACT deficiency.
Arrange for an immediate clinical evaluation to include:
Clinical assessment for poor feeding, lethargy, hypotonia, cardiac insufficiency, respiratory distress, and hepatomegaly;
Measurement of screening serum glucose, ammonia, creatine kinase (CK), and transaminase levels.
If a newborn is symptomatic or has abnormal screening laboratory results, the following medical interventions should be initiated (see also
Admit to the hospital for further evaluation.
Initiate a diet based on a high carbohydrate intake and long-chain fatty acid restriction.
Start triheptanoin or medium-chain triglyceride (MCT) oil (if triheptanoin is not available).
Start carnitine supplementation.
If a newborn is asymptomatic and has normal screening laboratory results:
Provide counseling to the family regarding feeding, at-home monitoring of clinical status, and emergency procedures and contact information.
While awaiting diagnostic confirmation (see
Note: Decisions regarding medical interventions in this scenario are influenced by the specific initial screening results as well as turnaround time for confirmatory testing at the medical center involved.
NBS results returned after the onset of symptoms
NBS not performed
False negative NBS result
Caregivers not adherent to recommended treatment following a positive NBS result
Supportive (but nonspecific) clinical, imaging, and preliminary laboratory findings can include the following.
Poor feeding
Tachypnea
Cardiac arrhythmia and/or cardiac arrest
Seizures
Neurologic impairment, including encephalopathy, lethargy, and/or hypotonia
Muscle weakness
Hepatomegaly
Hypoketotic hypoglycemia
Hyperammonemia ranging from 85 to >1000 µmol/L
Elevated blood lactate
Metabolic acidosis
Elevated liver enzymes (AST, ALT) ± evidence of synthetic dysfunction (low albumin, elevated prothrombin, and elevated INR)
Elevated creatine kinase levels ranging from 190 to >25,000 U/L
Acylcarnitine profile demonstrating low free carnitine, elevated C16-, C16:1-, C18-, and C18:1-acylcarnitines (This profile is indistinguishable from CPT II deficiency, and thus follow-up testing is required to establish the diagnosis; see
Urine organic acid analysis demonstrating dicarboxylic aciduria with or without lactic aciduria
The diagnosis of CACT deficiency
Note: (1) Per ACMG variant interpretation criteria, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
When NBS results and other laboratory findings suggest the diagnosis of CACT deficiency, molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Carnitine-Acylcarnitine Translocase (CACT) Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes on 3p21.31 (e.g., those described
• Arrange for an immediate clinical evaluation to include:
• Clinical assessment for poor feeding, lethargy, hypotonia, cardiac insufficiency, respiratory distress, and hepatomegaly;
• Measurement of screening serum glucose, ammonia, creatine kinase (CK), and transaminase levels.
• Clinical assessment for poor feeding, lethargy, hypotonia, cardiac insufficiency, respiratory distress, and hepatomegaly;
• Measurement of screening serum glucose, ammonia, creatine kinase (CK), and transaminase levels.
• If a newborn is symptomatic or has abnormal screening laboratory results, the following medical interventions should be initiated (see also
• Admit to the hospital for further evaluation.
• Initiate a diet based on a high carbohydrate intake and long-chain fatty acid restriction.
• Start triheptanoin or medium-chain triglyceride (MCT) oil (if triheptanoin is not available).
• Start carnitine supplementation.
• Admit to the hospital for further evaluation.
• Initiate a diet based on a high carbohydrate intake and long-chain fatty acid restriction.
• Start triheptanoin or medium-chain triglyceride (MCT) oil (if triheptanoin is not available).
• Start carnitine supplementation.
• If a newborn is asymptomatic and has normal screening laboratory results:
• Provide counseling to the family regarding feeding, at-home monitoring of clinical status, and emergency procedures and contact information.
• While awaiting diagnostic confirmation (see
• Provide counseling to the family regarding feeding, at-home monitoring of clinical status, and emergency procedures and contact information.
• While awaiting diagnostic confirmation (see
• Clinical assessment for poor feeding, lethargy, hypotonia, cardiac insufficiency, respiratory distress, and hepatomegaly;
• Measurement of screening serum glucose, ammonia, creatine kinase (CK), and transaminase levels.
• Admit to the hospital for further evaluation.
• Initiate a diet based on a high carbohydrate intake and long-chain fatty acid restriction.
• Start triheptanoin or medium-chain triglyceride (MCT) oil (if triheptanoin is not available).
• Start carnitine supplementation.
• Provide counseling to the family regarding feeding, at-home monitoring of clinical status, and emergency procedures and contact information.
• While awaiting diagnostic confirmation (see
• NBS results returned after the onset of symptoms
• NBS not performed
• False negative NBS result
• Caregivers not adherent to recommended treatment following a positive NBS result
• Poor feeding
• Tachypnea
• Cardiac arrhythmia and/or cardiac arrest
• Seizures
• Neurologic impairment, including encephalopathy, lethargy, and/or hypotonia
• Muscle weakness
• Hepatomegaly
• Hypoketotic hypoglycemia
• Hyperammonemia ranging from 85 to >1000 µmol/L
• Elevated blood lactate
• Metabolic acidosis
• Elevated liver enzymes (AST, ALT) ± evidence of synthetic dysfunction (low albumin, elevated prothrombin, and elevated INR)
• Elevated creatine kinase levels ranging from 190 to >25,000 U/L
• Acylcarnitine profile demonstrating low free carnitine, elevated C16-, C16:1-, C18-, and C18:1-acylcarnitines (This profile is indistinguishable from CPT II deficiency, and thus follow-up testing is required to establish the diagnosis; see
• Urine organic acid analysis demonstrating dicarboxylic aciduria with or without lactic aciduria
• For an introduction to multigene panels click
## Suggestive Findings
C16 and C18:1 acylcarnitine values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing, as these metabolites could also be elevated in carnitine palmitoyltransferase II (CPT2) deficiency (see
Most individuals with the severe early-onset phenotype will already be symptomatic by the time a newborn screening result is available. After a positive newborn screening test, the newborn should be evaluated immediately and a follow-up plasma acylcarnitine profile obtained [
If the follow-up biochemical testing supports the likelihood of CACT deficiency, additional testing is required to establish the diagnosis (see
Medical interventions should be put in place immediately on receipt of an abnormal NBS result, while additional testing is performed to establish a definitive diagnosis of CACT deficiency.
Arrange for an immediate clinical evaluation to include:
Clinical assessment for poor feeding, lethargy, hypotonia, cardiac insufficiency, respiratory distress, and hepatomegaly;
Measurement of screening serum glucose, ammonia, creatine kinase (CK), and transaminase levels.
If a newborn is symptomatic or has abnormal screening laboratory results, the following medical interventions should be initiated (see also
Admit to the hospital for further evaluation.
Initiate a diet based on a high carbohydrate intake and long-chain fatty acid restriction.
Start triheptanoin or medium-chain triglyceride (MCT) oil (if triheptanoin is not available).
Start carnitine supplementation.
If a newborn is asymptomatic and has normal screening laboratory results:
Provide counseling to the family regarding feeding, at-home monitoring of clinical status, and emergency procedures and contact information.
While awaiting diagnostic confirmation (see
Note: Decisions regarding medical interventions in this scenario are influenced by the specific initial screening results as well as turnaround time for confirmatory testing at the medical center involved.
NBS results returned after the onset of symptoms
NBS not performed
False negative NBS result
Caregivers not adherent to recommended treatment following a positive NBS result
Supportive (but nonspecific) clinical, imaging, and preliminary laboratory findings can include the following.
Poor feeding
Tachypnea
Cardiac arrhythmia and/or cardiac arrest
Seizures
Neurologic impairment, including encephalopathy, lethargy, and/or hypotonia
Muscle weakness
Hepatomegaly
Hypoketotic hypoglycemia
Hyperammonemia ranging from 85 to >1000 µmol/L
Elevated blood lactate
Metabolic acidosis
Elevated liver enzymes (AST, ALT) ± evidence of synthetic dysfunction (low albumin, elevated prothrombin, and elevated INR)
Elevated creatine kinase levels ranging from 190 to >25,000 U/L
Acylcarnitine profile demonstrating low free carnitine, elevated C16-, C16:1-, C18-, and C18:1-acylcarnitines (This profile is indistinguishable from CPT II deficiency, and thus follow-up testing is required to establish the diagnosis; see
Urine organic acid analysis demonstrating dicarboxylic aciduria with or without lactic aciduria
• Arrange for an immediate clinical evaluation to include:
• Clinical assessment for poor feeding, lethargy, hypotonia, cardiac insufficiency, respiratory distress, and hepatomegaly;
• Measurement of screening serum glucose, ammonia, creatine kinase (CK), and transaminase levels.
• Clinical assessment for poor feeding, lethargy, hypotonia, cardiac insufficiency, respiratory distress, and hepatomegaly;
• Measurement of screening serum glucose, ammonia, creatine kinase (CK), and transaminase levels.
• If a newborn is symptomatic or has abnormal screening laboratory results, the following medical interventions should be initiated (see also
• Admit to the hospital for further evaluation.
• Initiate a diet based on a high carbohydrate intake and long-chain fatty acid restriction.
• Start triheptanoin or medium-chain triglyceride (MCT) oil (if triheptanoin is not available).
• Start carnitine supplementation.
• Admit to the hospital for further evaluation.
• Initiate a diet based on a high carbohydrate intake and long-chain fatty acid restriction.
• Start triheptanoin or medium-chain triglyceride (MCT) oil (if triheptanoin is not available).
• Start carnitine supplementation.
• If a newborn is asymptomatic and has normal screening laboratory results:
• Provide counseling to the family regarding feeding, at-home monitoring of clinical status, and emergency procedures and contact information.
• While awaiting diagnostic confirmation (see
• Provide counseling to the family regarding feeding, at-home monitoring of clinical status, and emergency procedures and contact information.
• While awaiting diagnostic confirmation (see
• Clinical assessment for poor feeding, lethargy, hypotonia, cardiac insufficiency, respiratory distress, and hepatomegaly;
• Measurement of screening serum glucose, ammonia, creatine kinase (CK), and transaminase levels.
• Admit to the hospital for further evaluation.
• Initiate a diet based on a high carbohydrate intake and long-chain fatty acid restriction.
• Start triheptanoin or medium-chain triglyceride (MCT) oil (if triheptanoin is not available).
• Start carnitine supplementation.
• Provide counseling to the family regarding feeding, at-home monitoring of clinical status, and emergency procedures and contact information.
• While awaiting diagnostic confirmation (see
• NBS results returned after the onset of symptoms
• NBS not performed
• False negative NBS result
• Caregivers not adherent to recommended treatment following a positive NBS result
• Poor feeding
• Tachypnea
• Cardiac arrhythmia and/or cardiac arrest
• Seizures
• Neurologic impairment, including encephalopathy, lethargy, and/or hypotonia
• Muscle weakness
• Hepatomegaly
• Hypoketotic hypoglycemia
• Hyperammonemia ranging from 85 to >1000 µmol/L
• Elevated blood lactate
• Metabolic acidosis
• Elevated liver enzymes (AST, ALT) ± evidence of synthetic dysfunction (low albumin, elevated prothrombin, and elevated INR)
• Elevated creatine kinase levels ranging from 190 to >25,000 U/L
• Acylcarnitine profile demonstrating low free carnitine, elevated C16-, C16:1-, C18-, and C18:1-acylcarnitines (This profile is indistinguishable from CPT II deficiency, and thus follow-up testing is required to establish the diagnosis; see
• Urine organic acid analysis demonstrating dicarboxylic aciduria with or without lactic aciduria
## Establishing the Diagnosis
The diagnosis of CACT deficiency
Note: (1) Per ACMG variant interpretation criteria, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
When NBS results and other laboratory findings suggest the diagnosis of CACT deficiency, molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Carnitine-Acylcarnitine Translocase (CACT) Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes on 3p21.31 (e.g., those described
• For an introduction to multigene panels click
## Clinical Characteristics
Individuals with carnitine-acylcarnitine translocase (CACT) deficiency can experience variable clinical severity. To date, just over 100 individuals have been reported with CACT deficiency. Two phenotypes have been described: a severe neonatal-onset form and a later-onset form.
The clinical features of severe CACT deficiency generally present around age two days, prior to receipt of the newborn screening result. Clinical features include poor feeding, hypotonia, lethargy, arrhythmias, hypoketotic hypoglycemia, hyperammonemia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis [
First-degree atrioventricular block
Left bundle branch block
Right bundle branch block
Broad complex tachyarrhythmia
Atrial flutter
Hepatomegaly may be present at the time of diagnosis or may develop months later [
Steatohepatitis, hepatomegaly, gallstones, and liver fibrosis have been reported as potential longer-term complications [
Chronic diarrhea has also been reported.
One individual had upper gastrointestinal bleeding, possibly secondary to chronic liver disease [
In those who survive longer term, there continues to be a risk for acute metabolic decompensation, particularly in the presence of metabolic stressors such as acute illnesses or fasting periods (e.g., due to surgical procedures) [
Chronic or recurrent hyperammonemia is a major factor in neurologic outcome.
Other chronic health issues include elevated CK levels (hyperCKemia), cardiac arrhythmias, and cardiomyopathy [
A small group of affected individuals experience symptoms after age one month; a fraction of these manifest symptoms after age one year [
Select Features of Later-Onset Carnitine-Acylcarnitine Translocase (CACT) Deficiency at Time of Diagnosis
Clinical features in individuals who have the later-onset form are similar to those seen in the neonatal-onset form, but with symptoms (hypoketotic hypoglycemia, hyperammonemia, muscle weakness, hypotonia, lethargy) that are typically milder. For some affected individuals, the first manifestation of CACT deficiency was heart failure and ventricular tachycardia [
There is less risk of chronic hyperammonemia and, although rare, long-term survival into adulthood with normal neurocognitive progress has been described [
Only one known individual with the later-onset form has remained asymptomatic into adulthood [
Affected individuals who have one pathogenic c.199-10T>G allele and another pathogenic variant on the other allele tend to have severe clinical features, with no apparent correlation to survival [
The c.199-10T>G pathogenic variant is the most common pathogenic variant described to date, and the most common pathogenic variant observed in individuals of East Asian and Southeast Asian descent, suggesting a possible founder effect [
In the past, CACT deficiency was also referred to as:
CATR deficiency, a different acronym that also stands for carnitine-acylcarnitine translocase deficiency [
Carnitine-acylcarnitine carrier (CAC) deficiency [
To date, 89 individuals with the neonatal-onset form of CACT deficiency and 14 individuals with the later-onset form have been described.
Based on newborn screening data, the estimated incidence of CACT in an aggregate population of individuals from Australia, Germany, and the United States is approximately 1:750,000-1:2,000,000 [
• First-degree atrioventricular block
• Left bundle branch block
• Right bundle branch block
• Broad complex tachyarrhythmia
• Atrial flutter
• Hepatomegaly may be present at the time of diagnosis or may develop months later [
• Steatohepatitis, hepatomegaly, gallstones, and liver fibrosis have been reported as potential longer-term complications [
• Chronic diarrhea has also been reported.
• One individual had upper gastrointestinal bleeding, possibly secondary to chronic liver disease [
• In those who survive longer term, there continues to be a risk for acute metabolic decompensation, particularly in the presence of metabolic stressors such as acute illnesses or fasting periods (e.g., due to surgical procedures) [
• Chronic or recurrent hyperammonemia is a major factor in neurologic outcome.
• Other chronic health issues include elevated CK levels (hyperCKemia), cardiac arrhythmias, and cardiomyopathy [
• There is less risk of chronic hyperammonemia and, although rare, long-term survival into adulthood with normal neurocognitive progress has been described [
• Only one known individual with the later-onset form has remained asymptomatic into adulthood [
• Affected individuals who have one pathogenic c.199-10T>G allele and another pathogenic variant on the other allele tend to have severe clinical features, with no apparent correlation to survival [
• The c.199-10T>G pathogenic variant is the most common pathogenic variant described to date, and the most common pathogenic variant observed in individuals of East Asian and Southeast Asian descent, suggesting a possible founder effect [
• CATR deficiency, a different acronym that also stands for carnitine-acylcarnitine translocase deficiency [
• Carnitine-acylcarnitine carrier (CAC) deficiency [
## Clinical Description
Individuals with carnitine-acylcarnitine translocase (CACT) deficiency can experience variable clinical severity. To date, just over 100 individuals have been reported with CACT deficiency. Two phenotypes have been described: a severe neonatal-onset form and a later-onset form.
The clinical features of severe CACT deficiency generally present around age two days, prior to receipt of the newborn screening result. Clinical features include poor feeding, hypotonia, lethargy, arrhythmias, hypoketotic hypoglycemia, hyperammonemia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis [
First-degree atrioventricular block
Left bundle branch block
Right bundle branch block
Broad complex tachyarrhythmia
Atrial flutter
Hepatomegaly may be present at the time of diagnosis or may develop months later [
Steatohepatitis, hepatomegaly, gallstones, and liver fibrosis have been reported as potential longer-term complications [
Chronic diarrhea has also been reported.
One individual had upper gastrointestinal bleeding, possibly secondary to chronic liver disease [
In those who survive longer term, there continues to be a risk for acute metabolic decompensation, particularly in the presence of metabolic stressors such as acute illnesses or fasting periods (e.g., due to surgical procedures) [
Chronic or recurrent hyperammonemia is a major factor in neurologic outcome.
Other chronic health issues include elevated CK levels (hyperCKemia), cardiac arrhythmias, and cardiomyopathy [
A small group of affected individuals experience symptoms after age one month; a fraction of these manifest symptoms after age one year [
Select Features of Later-Onset Carnitine-Acylcarnitine Translocase (CACT) Deficiency at Time of Diagnosis
Clinical features in individuals who have the later-onset form are similar to those seen in the neonatal-onset form, but with symptoms (hypoketotic hypoglycemia, hyperammonemia, muscle weakness, hypotonia, lethargy) that are typically milder. For some affected individuals, the first manifestation of CACT deficiency was heart failure and ventricular tachycardia [
There is less risk of chronic hyperammonemia and, although rare, long-term survival into adulthood with normal neurocognitive progress has been described [
Only one known individual with the later-onset form has remained asymptomatic into adulthood [
• First-degree atrioventricular block
• Left bundle branch block
• Right bundle branch block
• Broad complex tachyarrhythmia
• Atrial flutter
• Hepatomegaly may be present at the time of diagnosis or may develop months later [
• Steatohepatitis, hepatomegaly, gallstones, and liver fibrosis have been reported as potential longer-term complications [
• Chronic diarrhea has also been reported.
• One individual had upper gastrointestinal bleeding, possibly secondary to chronic liver disease [
• In those who survive longer term, there continues to be a risk for acute metabolic decompensation, particularly in the presence of metabolic stressors such as acute illnesses or fasting periods (e.g., due to surgical procedures) [
• Chronic or recurrent hyperammonemia is a major factor in neurologic outcome.
• Other chronic health issues include elevated CK levels (hyperCKemia), cardiac arrhythmias, and cardiomyopathy [
• There is less risk of chronic hyperammonemia and, although rare, long-term survival into adulthood with normal neurocognitive progress has been described [
• Only one known individual with the later-onset form has remained asymptomatic into adulthood [
## Severe Neonatal Form
The clinical features of severe CACT deficiency generally present around age two days, prior to receipt of the newborn screening result. Clinical features include poor feeding, hypotonia, lethargy, arrhythmias, hypoketotic hypoglycemia, hyperammonemia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis [
First-degree atrioventricular block
Left bundle branch block
Right bundle branch block
Broad complex tachyarrhythmia
Atrial flutter
Hepatomegaly may be present at the time of diagnosis or may develop months later [
Steatohepatitis, hepatomegaly, gallstones, and liver fibrosis have been reported as potential longer-term complications [
Chronic diarrhea has also been reported.
One individual had upper gastrointestinal bleeding, possibly secondary to chronic liver disease [
In those who survive longer term, there continues to be a risk for acute metabolic decompensation, particularly in the presence of metabolic stressors such as acute illnesses or fasting periods (e.g., due to surgical procedures) [
Chronic or recurrent hyperammonemia is a major factor in neurologic outcome.
Other chronic health issues include elevated CK levels (hyperCKemia), cardiac arrhythmias, and cardiomyopathy [
• First-degree atrioventricular block
• Left bundle branch block
• Right bundle branch block
• Broad complex tachyarrhythmia
• Atrial flutter
• Hepatomegaly may be present at the time of diagnosis or may develop months later [
• Steatohepatitis, hepatomegaly, gallstones, and liver fibrosis have been reported as potential longer-term complications [
• Chronic diarrhea has also been reported.
• One individual had upper gastrointestinal bleeding, possibly secondary to chronic liver disease [
• In those who survive longer term, there continues to be a risk for acute metabolic decompensation, particularly in the presence of metabolic stressors such as acute illnesses or fasting periods (e.g., due to surgical procedures) [
• Chronic or recurrent hyperammonemia is a major factor in neurologic outcome.
• Other chronic health issues include elevated CK levels (hyperCKemia), cardiac arrhythmias, and cardiomyopathy [
## Later-Onset Form
A small group of affected individuals experience symptoms after age one month; a fraction of these manifest symptoms after age one year [
Select Features of Later-Onset Carnitine-Acylcarnitine Translocase (CACT) Deficiency at Time of Diagnosis
Clinical features in individuals who have the later-onset form are similar to those seen in the neonatal-onset form, but with symptoms (hypoketotic hypoglycemia, hyperammonemia, muscle weakness, hypotonia, lethargy) that are typically milder. For some affected individuals, the first manifestation of CACT deficiency was heart failure and ventricular tachycardia [
There is less risk of chronic hyperammonemia and, although rare, long-term survival into adulthood with normal neurocognitive progress has been described [
Only one known individual with the later-onset form has remained asymptomatic into adulthood [
• There is less risk of chronic hyperammonemia and, although rare, long-term survival into adulthood with normal neurocognitive progress has been described [
• Only one known individual with the later-onset form has remained asymptomatic into adulthood [
## Genotype-Phenotype Correlations
Affected individuals who have one pathogenic c.199-10T>G allele and another pathogenic variant on the other allele tend to have severe clinical features, with no apparent correlation to survival [
The c.199-10T>G pathogenic variant is the most common pathogenic variant described to date, and the most common pathogenic variant observed in individuals of East Asian and Southeast Asian descent, suggesting a possible founder effect [
• Affected individuals who have one pathogenic c.199-10T>G allele and another pathogenic variant on the other allele tend to have severe clinical features, with no apparent correlation to survival [
• The c.199-10T>G pathogenic variant is the most common pathogenic variant described to date, and the most common pathogenic variant observed in individuals of East Asian and Southeast Asian descent, suggesting a possible founder effect [
## Neonatal-Onset Form
Affected individuals who have one pathogenic c.199-10T>G allele and another pathogenic variant on the other allele tend to have severe clinical features, with no apparent correlation to survival [
The c.199-10T>G pathogenic variant is the most common pathogenic variant described to date, and the most common pathogenic variant observed in individuals of East Asian and Southeast Asian descent, suggesting a possible founder effect [
• Affected individuals who have one pathogenic c.199-10T>G allele and another pathogenic variant on the other allele tend to have severe clinical features, with no apparent correlation to survival [
• The c.199-10T>G pathogenic variant is the most common pathogenic variant described to date, and the most common pathogenic variant observed in individuals of East Asian and Southeast Asian descent, suggesting a possible founder effect [
## Milder Neonatal-Onset or Later-Onset Form
## Nomenclature
In the past, CACT deficiency was also referred to as:
CATR deficiency, a different acronym that also stands for carnitine-acylcarnitine translocase deficiency [
Carnitine-acylcarnitine carrier (CAC) deficiency [
• CATR deficiency, a different acronym that also stands for carnitine-acylcarnitine translocase deficiency [
• Carnitine-acylcarnitine carrier (CAC) deficiency [
## Prevalence
To date, 89 individuals with the neonatal-onset form of CACT deficiency and 14 individuals with the later-onset form have been described.
Based on newborn screening data, the estimated incidence of CACT in an aggregate population of individuals from Australia, Germany, and the United States is approximately 1:750,000-1:2,000,000 [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Carnitine-Acylcarnitine Translocase Deficiency
AR = autosomal recessive; CACT = carnitine-acylcarnitine translocase; MOI = mode of inheritance; NBS = newborn screening
## Management
No consensus clinical practice guidelines for carnitine-acylcarnitine translocase (CACT) deficiency have been published.
When CACT deficiency is suspected during the diagnostic evaluation (i.e., due to elevated C16 and C18:1 on acylcarnitine profile), metabolic treatment should be initiated immediately.
Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (i.e., malnutrition, growth failure, obesity) require a multidisciplinary approach including multiple subspecialists, with oversight and expertise from a specialized metabolic center.
To establish the extent of disease and needs in an individual diagnosed with CACT deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis of Carnitine-Acylcarnitine Translocase (CACT) Deficiency
Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended)
Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
EKG to assess for arrhythmia
Echocardiogram to assess for cardiomyopathy & cardiac dysfunction
Consider referral to cardiologist.
Plasma AST, ALT, hepatic synthetic function tests (albumin, prothrombin, INR, platelet count)
Abdominal ultrasound to assess for hepatomegaly & nephromegaly (rare)
Referral to hepatologist as clinically indicated
Serum BUN, creatinine &/or cystatin C, electrolytes
Abdominal ultrasound to assess for nephromegaly (rare) & hepatomegaly
Referral to nephrologist as clinically indicated
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CK = creatine kinase; MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist
After a new diagnosis of CACT deficiency in a child, the closest hospital and local pediatrician should also be informed.
Implantation of a pacemaker may be considered (see
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
All children with CACT deficiency require the supervision of a specialist metabolic dietitian with experience in managing diet in individuals with long-chain fatty acid oxidation disorders (LC-FAODs). Management may differ between centers, but dietetic management of CACT deficiency typically follows the general principles of management of severe LC-FAODs.
Routine Daily Treatment in Individuals with Carnitine-Acylcarnitine Translocase (CACT) Deficiency
Oils such as walnut or flaxseed are prescribed to meet essential fatty acid requirements.
Skimmed breast milk has been used to limit its long-chain fatty acid content to 6%-7% of total calories.
Provide frequent meals & limit overnight fasting to inhibit lipolysis.
Duration of fasting interval depends on severity of illness & age of affected person
Continuous overnight feeds may be recommended in infancy & early childhood to restrict overnight fasting.
Late-night uncooked cornstarch may be used instead of continuous overnight feeds in older or less severely affected persons
Synthetic medium-chain fatty acid w/7 carbons; provides 2 acetyl-CoA molecules, a 3-carbon propionyl-CoA, & 4 5-carbon ketone bodies
The provision of both even- & odd-chain ketone bodies → superior TCA cycle anaplerosis.
However, evidence for triheptanoin use in CACT deficiency is limited.
Its safety & efficacy have been described in 5 patients, 3 of whom presented w/cardiogenic shock.
Excluded from the initial open-label multicenter safety & efficacy study, persons w/CACT deficiency were then included in the extension study, suggesting a reduction of major clinical events (MCE) rate.
Triheptanoin may contribute to osmotic diarrhea.
Allows energy generation & ketogenesis through β-oxidation of medium-chain fatty acids
Fatty acyl moieties of C10 length or longer (which are dependent on the carnitine shuttle) account for 20%-50% of total fatty acids in most commercially available MCT formulas. Partial utilization of these may be the reason ketogenesis on MCT formula is suboptimal in CACT deficiency. Some centers thus prefer a fat-free formula supplemented w/C8 oil.
MCT may contribute to osmotic diarrhea.
Carnitine supplementation in LC-FAO has been controversial due to previous mouse models showing signs of cardiotoxicity following L-carnitine administration.
However, cumulative experience in persons w/CACT suggests that supplementation does not → cardiotoxicity.
Additionally, carnitine can facilitate export of excess (& sometimes toxic) long-chain fatty acyl CoA as acylcarnitines & improve levels of free carnitine.
May contribute to osmotic diarrhea
Ammonia scavengers (sodium benzoate, sodium phenylbutyrate) are of limited efficacy in this condition.
Carbaglu (
CACT deficiency has been proposed to ↓ acetyl-CoA & therefore NAG (essential in the urea cycle).
High dietary carbohydrate intake appears necessary to prevent chronic recurrent hyperammonemia but may → excessive weight gain & steatohepatitis.
Feeding difficulties are common in early childhood.
Gastrostomy placement allows provision of enteral emergency regimen to ensure adequate caloric intake during illness.
Physical therapy
Occupational/feeding therapy
Aggressive rehab therapy
NAG = N-acetylglutamate; TCA = tricarboxylic acid
Emergency Outpatient Treatment in Individuals with Carnitine-Acylcarnitine Translocase (CACT) Deficiency
Carbohydrate supplementation orally or via tube feed
↑ carnitine supplementation
Trial of outpatient treatment at home for up to 12 hrs could be considered based on degree of symptoms.
Reassessment (every ~2 hrs) for clinical changes
Fever <38.5°C (101°F); enteral or gastrostomy tube feeding tolerated without recurrent vomiting or diarrhea; absence of neurologic symptoms (altered consciousness, irritability, hypotonia, dystonia)
Stringent guidelines to quantify carbohydrate/caloric requirements are available to guide nutritional arrangements in the outpatient setting, with some centers recommending provision of carbohydrate-rich beverages every two hours, with frequent reassessment.
Temporarily increasing L-carnitine doses (e.g., to 200 mg/kg/day in infants) may be considered [
Alterations in mentation/alertness, fever, and enteral feeding tolerance; discuss any new or evolving clinical features with the designated center of expertise for inherited metabolic diseases.
Some classes of antiemetics can be used safely on an occasional basis to temporarily improve enteral tolerance of food and beverages at home or during transfer to hospital.
Acute manifestations (e.g., lethargy, encephalopathy, seizures, or progressive coma), often occurring in the setting of intercurrent illness and/or inadequate caloric intake, should be managed symptomatically and with generous caloric support in a hospital setting, with aggressive treatment and supportive care of any identified or clinically suspected metabolic stressors (see
Acute Inpatient Treatment in Individuals with Carnitine-Acylcarnitine Translocase (CACT) Deficiency
Administer high-energy (dextrose-containing) fluids & (if needed) insulin for mgmt of hyperglycemia.
IV L-carnitine supplementation
Address electrolytes & pH imbalances w/IV fluid mgmt.
Obtain blood glucose, electrolytes, BUN, creatinine, AST/ALT, albumin, blood gases, serum ammonia, total CK level, & plasma acylcarnitine profile.
Cardiac monitoring is indicated.
Ongoing assessment of hemodynamic status & for new neurologic signs is critical.
Use of carnitine supplementation is controversial (see
Inadequate or delayed start of emergency treatment → high risk of consequent long-term neurodisability.
Place a cardiac monitor.
Obtain an EKG.
Consider echocardiogram if not previously obtained or if signs of cardiac deterioration from baseline.
Consult a cardiologist; placement of a pacemaker may be considered.
Assess for rhabdomyolysis.
Improve caloric & fluid intake.
Administer IV fluids; consider initial saline bolus based on CK levels.
Avoid nephrotoxic medications or agents during this event.
Consult a nephrologist.
Initiate treatment above for ↑ catabolism.
Obtain serum ammonia levels.
Consult neurologist if evidence of seizure or signs of encephalopathy to consider EEG or neuroimaging.
Monitor free-flowing serum ammonia every 2-4 hrs or as clinically indicated.
Protein restriction is often unsuccessful; ↑ caloric intake through carbohydrates is most effective.
Although apparently w/o success, a few authors have used nitrogen scavengers (sodium benzoate, sodium phenylacetate or sodium phenylbutyrate) or intravenous arginine during initial presentation in the setting of persistently ↑ ammonia w/altered mental status (despite caloric optimization).
Extracorporeal ammonia clearance could be considered if medical therapy fails.
BUN = blood urea nitrogen; CK = creatine kinase; IV = intravenous
Inpatient emergency treatment should: (1) take place at the closest medical facility, (2) be started without delay, and (3) be supervised by physicians and specialist dietitians at the responsible metabolic center, who should be contacted without delay. While there may be different presenting symptoms (e.g., myalgia, fatigue), a complete evaluation including cardiac assessment and comprehensive laboratory tests should always be requested, as the patient's clinical status could progress in severity.
Intravenous glucose solutions should provide 12-15 g/kg/day glucose for infants and 10-12 g/kg/day for children 12 months - 6 years.
Use of insulin if hyperglycemia emerges; IV insulin given at a starting dose of 0.025 IU/kg/hour in the event of persistent hyperglycemia (>150-180 mg/dL in plasma, or glucosuria).
L-carnitine (with options to increase the dose) can be given intravenously, which enhances bioavailability.
Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with CACT deficiency together with pediatric metabolic experts, dietitians, psychologists, and social workers.
As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.
High carbohydrate intake (typically >60%), long-chain dietary fat restriction (<10%), and triheptanoin (Dojolvi
One of the most important components of management (as it relates to prevention of secondary complications) is education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see also
Prevention of Secondary Manifestations in Individuals with Carnitine-Acylcarnitine Translocase (CACT) Deficiency
Intensive & ongoing education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute encephalopathic crises
Treatment protocols & provision of emergency letters or cards to incl guidance for care in the event of illness while on vacation
MediAlert bracelets/pendants, or car seat stickers
Adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources); maintain medication required for maintenance & emergency treatment (carnitine, antipyretics) at home.
Provide written protocols for maintenance & emergency treatment to parents & primary care providers/pediatricians, teachers, & school staff.
Provide emergency letters/cards summarizing key information & principles of emergency treatment for CACT deficiency & incl contact info for primary treating metabolic center.
For any planned travel or vacations, consider contacting a center of expertise near the destination prior to travel.
Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional management).
Essential information including written treatment protocols should be in place in anticipation of possible future need for inpatient emergency treatment.
Parents or local hospitals should immediately inform the designated metabolic center if: (1) temperature rises >38.5°C (101°F); (2) vomiting/diarrhea or other symptoms of intercurrent illness develop; or (3) new neurologic symptoms appear.
Perioperative/perianesthetic management precautions may include visitations at specialist anesthetic clinics for affected individuals deemed to be at high risk for perioperative complications.
In addition to regular evaluations by a metabolic specialist and metabolic dietitian, the following are recommended.
Recommended Surveillance for Individuals with Carnitine-Acylcarnitine Translocase (CACT) Deficiency
Neonates: every 2 wks
Infants age 2 mos – 1 yr: every 1-3 mos
Children ≥ 1 year: every 3-6 mos
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; CK = creatine kinase; CRP = C-reactive protein
CRP is used as an inflammatory marker in the authors' practice, in conjunction with prealbumin. Prealbumin has a shorter half-life (2 to 3 days) than albumin and is thus a more favorable marker for acute nutritional changes. Prealbumin levels could be affected (decreased) by the presence of an acute inflammatory process; CRP is required to rule out that possibility [
Avoid the following:
Prolonged fasting
Catabolic illness (fever, intercurrent infection)
Inadequate caloric provision during other stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)
Strenuous physical activity
Anesthetics that contain high doses of long-chain fatty acids, such as propofol, although use for short procedures is likely to be tolerated [
Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of CACT deficiency. For at-risk newborn sibs when prenatal testing was not performed: In parallel with newborn screening either test for the familial
See
Search
• Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended)
• Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
• EKG to assess for arrhythmia
• Echocardiogram to assess for cardiomyopathy & cardiac dysfunction
• Consider referral to cardiologist.
• Plasma AST, ALT, hepatic synthetic function tests (albumin, prothrombin, INR, platelet count)
• Abdominal ultrasound to assess for hepatomegaly & nephromegaly (rare)
• Referral to hepatologist as clinically indicated
• Serum BUN, creatinine &/or cystatin C, electrolytes
• Abdominal ultrasound to assess for nephromegaly (rare) & hepatomegaly
• Referral to nephrologist as clinically indicated
• Oils such as walnut or flaxseed are prescribed to meet essential fatty acid requirements.
• Skimmed breast milk has been used to limit its long-chain fatty acid content to 6%-7% of total calories.
• Provide frequent meals & limit overnight fasting to inhibit lipolysis.
• Duration of fasting interval depends on severity of illness & age of affected person
• Continuous overnight feeds may be recommended in infancy & early childhood to restrict overnight fasting.
• Late-night uncooked cornstarch may be used instead of continuous overnight feeds in older or less severely affected persons
• Synthetic medium-chain fatty acid w/7 carbons; provides 2 acetyl-CoA molecules, a 3-carbon propionyl-CoA, & 4 5-carbon ketone bodies
• The provision of both even- & odd-chain ketone bodies → superior TCA cycle anaplerosis.
• However, evidence for triheptanoin use in CACT deficiency is limited.
• Its safety & efficacy have been described in 5 patients, 3 of whom presented w/cardiogenic shock.
• Excluded from the initial open-label multicenter safety & efficacy study, persons w/CACT deficiency were then included in the extension study, suggesting a reduction of major clinical events (MCE) rate.
• Triheptanoin may contribute to osmotic diarrhea.
• Allows energy generation & ketogenesis through β-oxidation of medium-chain fatty acids
• Fatty acyl moieties of C10 length or longer (which are dependent on the carnitine shuttle) account for 20%-50% of total fatty acids in most commercially available MCT formulas. Partial utilization of these may be the reason ketogenesis on MCT formula is suboptimal in CACT deficiency. Some centers thus prefer a fat-free formula supplemented w/C8 oil.
• MCT may contribute to osmotic diarrhea.
• Carnitine supplementation in LC-FAO has been controversial due to previous mouse models showing signs of cardiotoxicity following L-carnitine administration.
• However, cumulative experience in persons w/CACT suggests that supplementation does not → cardiotoxicity.
• Additionally, carnitine can facilitate export of excess (& sometimes toxic) long-chain fatty acyl CoA as acylcarnitines & improve levels of free carnitine.
• May contribute to osmotic diarrhea
• Ammonia scavengers (sodium benzoate, sodium phenylbutyrate) are of limited efficacy in this condition.
• Carbaglu (
• CACT deficiency has been proposed to ↓ acetyl-CoA & therefore NAG (essential in the urea cycle).
• High dietary carbohydrate intake appears necessary to prevent chronic recurrent hyperammonemia but may → excessive weight gain & steatohepatitis.
• Feeding difficulties are common in early childhood.
• Gastrostomy placement allows provision of enteral emergency regimen to ensure adequate caloric intake during illness.
• Physical therapy
• Occupational/feeding therapy
• Aggressive rehab therapy
• Carbohydrate supplementation orally or via tube feed
• ↑ carnitine supplementation
• Trial of outpatient treatment at home for up to 12 hrs could be considered based on degree of symptoms.
• Reassessment (every ~2 hrs) for clinical changes
• Administer high-energy (dextrose-containing) fluids & (if needed) insulin for mgmt of hyperglycemia.
• IV L-carnitine supplementation
• Address electrolytes & pH imbalances w/IV fluid mgmt.
• Obtain blood glucose, electrolytes, BUN, creatinine, AST/ALT, albumin, blood gases, serum ammonia, total CK level, & plasma acylcarnitine profile.
• Cardiac monitoring is indicated.
• Ongoing assessment of hemodynamic status & for new neurologic signs is critical.
• Use of carnitine supplementation is controversial (see
• Inadequate or delayed start of emergency treatment → high risk of consequent long-term neurodisability.
• Place a cardiac monitor.
• Obtain an EKG.
• Consider echocardiogram if not previously obtained or if signs of cardiac deterioration from baseline.
• Consult a cardiologist; placement of a pacemaker may be considered.
• Assess for rhabdomyolysis.
• Improve caloric & fluid intake.
• Administer IV fluids; consider initial saline bolus based on CK levels.
• Avoid nephrotoxic medications or agents during this event.
• Consult a nephrologist.
• Initiate treatment above for ↑ catabolism.
• Obtain serum ammonia levels.
• Consult neurologist if evidence of seizure or signs of encephalopathy to consider EEG or neuroimaging.
• Monitor free-flowing serum ammonia every 2-4 hrs or as clinically indicated.
• Protein restriction is often unsuccessful; ↑ caloric intake through carbohydrates is most effective.
• Although apparently w/o success, a few authors have used nitrogen scavengers (sodium benzoate, sodium phenylacetate or sodium phenylbutyrate) or intravenous arginine during initial presentation in the setting of persistently ↑ ammonia w/altered mental status (despite caloric optimization).
• Extracorporeal ammonia clearance could be considered if medical therapy fails.
• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with CACT deficiency together with pediatric metabolic experts, dietitians, psychologists, and social workers.
• As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.
• Intensive & ongoing education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute encephalopathic crises
• Treatment protocols & provision of emergency letters or cards to incl guidance for care in the event of illness while on vacation
• MediAlert bracelets/pendants, or car seat stickers
• Adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources); maintain medication required for maintenance & emergency treatment (carnitine, antipyretics) at home.
• Provide written protocols for maintenance & emergency treatment to parents & primary care providers/pediatricians, teachers, & school staff.
• Provide emergency letters/cards summarizing key information & principles of emergency treatment for CACT deficiency & incl contact info for primary treating metabolic center.
• For any planned travel or vacations, consider contacting a center of expertise near the destination prior to travel.
• Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
• Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional management).
• Neonates: every 2 wks
• Infants age 2 mos – 1 yr: every 1-3 mos
• Children ≥ 1 year: every 3-6 mos
• Prolonged fasting
• Catabolic illness (fever, intercurrent infection)
• Inadequate caloric provision during other stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)
• Strenuous physical activity
• Anesthetics that contain high doses of long-chain fatty acids, such as propofol, although use for short procedures is likely to be tolerated [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CACT deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis of Carnitine-Acylcarnitine Translocase (CACT) Deficiency
Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended)
Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
EKG to assess for arrhythmia
Echocardiogram to assess for cardiomyopathy & cardiac dysfunction
Consider referral to cardiologist.
Plasma AST, ALT, hepatic synthetic function tests (albumin, prothrombin, INR, platelet count)
Abdominal ultrasound to assess for hepatomegaly & nephromegaly (rare)
Referral to hepatologist as clinically indicated
Serum BUN, creatinine &/or cystatin C, electrolytes
Abdominal ultrasound to assess for nephromegaly (rare) & hepatomegaly
Referral to nephrologist as clinically indicated
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CK = creatine kinase; MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist
After a new diagnosis of CACT deficiency in a child, the closest hospital and local pediatrician should also be informed.
Implantation of a pacemaker may be considered (see
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended)
• Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
• EKG to assess for arrhythmia
• Echocardiogram to assess for cardiomyopathy & cardiac dysfunction
• Consider referral to cardiologist.
• Plasma AST, ALT, hepatic synthetic function tests (albumin, prothrombin, INR, platelet count)
• Abdominal ultrasound to assess for hepatomegaly & nephromegaly (rare)
• Referral to hepatologist as clinically indicated
• Serum BUN, creatinine &/or cystatin C, electrolytes
• Abdominal ultrasound to assess for nephromegaly (rare) & hepatomegaly
• Referral to nephrologist as clinically indicated
## Treatment of Manifestations
All children with CACT deficiency require the supervision of a specialist metabolic dietitian with experience in managing diet in individuals with long-chain fatty acid oxidation disorders (LC-FAODs). Management may differ between centers, but dietetic management of CACT deficiency typically follows the general principles of management of severe LC-FAODs.
Routine Daily Treatment in Individuals with Carnitine-Acylcarnitine Translocase (CACT) Deficiency
Oils such as walnut or flaxseed are prescribed to meet essential fatty acid requirements.
Skimmed breast milk has been used to limit its long-chain fatty acid content to 6%-7% of total calories.
Provide frequent meals & limit overnight fasting to inhibit lipolysis.
Duration of fasting interval depends on severity of illness & age of affected person
Continuous overnight feeds may be recommended in infancy & early childhood to restrict overnight fasting.
Late-night uncooked cornstarch may be used instead of continuous overnight feeds in older or less severely affected persons
Synthetic medium-chain fatty acid w/7 carbons; provides 2 acetyl-CoA molecules, a 3-carbon propionyl-CoA, & 4 5-carbon ketone bodies
The provision of both even- & odd-chain ketone bodies → superior TCA cycle anaplerosis.
However, evidence for triheptanoin use in CACT deficiency is limited.
Its safety & efficacy have been described in 5 patients, 3 of whom presented w/cardiogenic shock.
Excluded from the initial open-label multicenter safety & efficacy study, persons w/CACT deficiency were then included in the extension study, suggesting a reduction of major clinical events (MCE) rate.
Triheptanoin may contribute to osmotic diarrhea.
Allows energy generation & ketogenesis through β-oxidation of medium-chain fatty acids
Fatty acyl moieties of C10 length or longer (which are dependent on the carnitine shuttle) account for 20%-50% of total fatty acids in most commercially available MCT formulas. Partial utilization of these may be the reason ketogenesis on MCT formula is suboptimal in CACT deficiency. Some centers thus prefer a fat-free formula supplemented w/C8 oil.
MCT may contribute to osmotic diarrhea.
Carnitine supplementation in LC-FAO has been controversial due to previous mouse models showing signs of cardiotoxicity following L-carnitine administration.
However, cumulative experience in persons w/CACT suggests that supplementation does not → cardiotoxicity.
Additionally, carnitine can facilitate export of excess (& sometimes toxic) long-chain fatty acyl CoA as acylcarnitines & improve levels of free carnitine.
May contribute to osmotic diarrhea
Ammonia scavengers (sodium benzoate, sodium phenylbutyrate) are of limited efficacy in this condition.
Carbaglu (
CACT deficiency has been proposed to ↓ acetyl-CoA & therefore NAG (essential in the urea cycle).
High dietary carbohydrate intake appears necessary to prevent chronic recurrent hyperammonemia but may → excessive weight gain & steatohepatitis.
Feeding difficulties are common in early childhood.
Gastrostomy placement allows provision of enteral emergency regimen to ensure adequate caloric intake during illness.
Physical therapy
Occupational/feeding therapy
Aggressive rehab therapy
NAG = N-acetylglutamate; TCA = tricarboxylic acid
Emergency Outpatient Treatment in Individuals with Carnitine-Acylcarnitine Translocase (CACT) Deficiency
Carbohydrate supplementation orally or via tube feed
↑ carnitine supplementation
Trial of outpatient treatment at home for up to 12 hrs could be considered based on degree of symptoms.
Reassessment (every ~2 hrs) for clinical changes
Fever <38.5°C (101°F); enteral or gastrostomy tube feeding tolerated without recurrent vomiting or diarrhea; absence of neurologic symptoms (altered consciousness, irritability, hypotonia, dystonia)
Stringent guidelines to quantify carbohydrate/caloric requirements are available to guide nutritional arrangements in the outpatient setting, with some centers recommending provision of carbohydrate-rich beverages every two hours, with frequent reassessment.
Temporarily increasing L-carnitine doses (e.g., to 200 mg/kg/day in infants) may be considered [
Alterations in mentation/alertness, fever, and enteral feeding tolerance; discuss any new or evolving clinical features with the designated center of expertise for inherited metabolic diseases.
Some classes of antiemetics can be used safely on an occasional basis to temporarily improve enteral tolerance of food and beverages at home or during transfer to hospital.
Acute manifestations (e.g., lethargy, encephalopathy, seizures, or progressive coma), often occurring in the setting of intercurrent illness and/or inadequate caloric intake, should be managed symptomatically and with generous caloric support in a hospital setting, with aggressive treatment and supportive care of any identified or clinically suspected metabolic stressors (see
Acute Inpatient Treatment in Individuals with Carnitine-Acylcarnitine Translocase (CACT) Deficiency
Administer high-energy (dextrose-containing) fluids & (if needed) insulin for mgmt of hyperglycemia.
IV L-carnitine supplementation
Address electrolytes & pH imbalances w/IV fluid mgmt.
Obtain blood glucose, electrolytes, BUN, creatinine, AST/ALT, albumin, blood gases, serum ammonia, total CK level, & plasma acylcarnitine profile.
Cardiac monitoring is indicated.
Ongoing assessment of hemodynamic status & for new neurologic signs is critical.
Use of carnitine supplementation is controversial (see
Inadequate or delayed start of emergency treatment → high risk of consequent long-term neurodisability.
Place a cardiac monitor.
Obtain an EKG.
Consider echocardiogram if not previously obtained or if signs of cardiac deterioration from baseline.
Consult a cardiologist; placement of a pacemaker may be considered.
Assess for rhabdomyolysis.
Improve caloric & fluid intake.
Administer IV fluids; consider initial saline bolus based on CK levels.
Avoid nephrotoxic medications or agents during this event.
Consult a nephrologist.
Initiate treatment above for ↑ catabolism.
Obtain serum ammonia levels.
Consult neurologist if evidence of seizure or signs of encephalopathy to consider EEG or neuroimaging.
Monitor free-flowing serum ammonia every 2-4 hrs or as clinically indicated.
Protein restriction is often unsuccessful; ↑ caloric intake through carbohydrates is most effective.
Although apparently w/o success, a few authors have used nitrogen scavengers (sodium benzoate, sodium phenylacetate or sodium phenylbutyrate) or intravenous arginine during initial presentation in the setting of persistently ↑ ammonia w/altered mental status (despite caloric optimization).
Extracorporeal ammonia clearance could be considered if medical therapy fails.
BUN = blood urea nitrogen; CK = creatine kinase; IV = intravenous
Inpatient emergency treatment should: (1) take place at the closest medical facility, (2) be started without delay, and (3) be supervised by physicians and specialist dietitians at the responsible metabolic center, who should be contacted without delay. While there may be different presenting symptoms (e.g., myalgia, fatigue), a complete evaluation including cardiac assessment and comprehensive laboratory tests should always be requested, as the patient's clinical status could progress in severity.
Intravenous glucose solutions should provide 12-15 g/kg/day glucose for infants and 10-12 g/kg/day for children 12 months - 6 years.
Use of insulin if hyperglycemia emerges; IV insulin given at a starting dose of 0.025 IU/kg/hour in the event of persistent hyperglycemia (>150-180 mg/dL in plasma, or glucosuria).
L-carnitine (with options to increase the dose) can be given intravenously, which enhances bioavailability.
Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with CACT deficiency together with pediatric metabolic experts, dietitians, psychologists, and social workers.
As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.
• Oils such as walnut or flaxseed are prescribed to meet essential fatty acid requirements.
• Skimmed breast milk has been used to limit its long-chain fatty acid content to 6%-7% of total calories.
• Provide frequent meals & limit overnight fasting to inhibit lipolysis.
• Duration of fasting interval depends on severity of illness & age of affected person
• Continuous overnight feeds may be recommended in infancy & early childhood to restrict overnight fasting.
• Late-night uncooked cornstarch may be used instead of continuous overnight feeds in older or less severely affected persons
• Synthetic medium-chain fatty acid w/7 carbons; provides 2 acetyl-CoA molecules, a 3-carbon propionyl-CoA, & 4 5-carbon ketone bodies
• The provision of both even- & odd-chain ketone bodies → superior TCA cycle anaplerosis.
• However, evidence for triheptanoin use in CACT deficiency is limited.
• Its safety & efficacy have been described in 5 patients, 3 of whom presented w/cardiogenic shock.
• Excluded from the initial open-label multicenter safety & efficacy study, persons w/CACT deficiency were then included in the extension study, suggesting a reduction of major clinical events (MCE) rate.
• Triheptanoin may contribute to osmotic diarrhea.
• Allows energy generation & ketogenesis through β-oxidation of medium-chain fatty acids
• Fatty acyl moieties of C10 length or longer (which are dependent on the carnitine shuttle) account for 20%-50% of total fatty acids in most commercially available MCT formulas. Partial utilization of these may be the reason ketogenesis on MCT formula is suboptimal in CACT deficiency. Some centers thus prefer a fat-free formula supplemented w/C8 oil.
• MCT may contribute to osmotic diarrhea.
• Carnitine supplementation in LC-FAO has been controversial due to previous mouse models showing signs of cardiotoxicity following L-carnitine administration.
• However, cumulative experience in persons w/CACT suggests that supplementation does not → cardiotoxicity.
• Additionally, carnitine can facilitate export of excess (& sometimes toxic) long-chain fatty acyl CoA as acylcarnitines & improve levels of free carnitine.
• May contribute to osmotic diarrhea
• Ammonia scavengers (sodium benzoate, sodium phenylbutyrate) are of limited efficacy in this condition.
• Carbaglu (
• CACT deficiency has been proposed to ↓ acetyl-CoA & therefore NAG (essential in the urea cycle).
• High dietary carbohydrate intake appears necessary to prevent chronic recurrent hyperammonemia but may → excessive weight gain & steatohepatitis.
• Feeding difficulties are common in early childhood.
• Gastrostomy placement allows provision of enteral emergency regimen to ensure adequate caloric intake during illness.
• Physical therapy
• Occupational/feeding therapy
• Aggressive rehab therapy
• Carbohydrate supplementation orally or via tube feed
• ↑ carnitine supplementation
• Trial of outpatient treatment at home for up to 12 hrs could be considered based on degree of symptoms.
• Reassessment (every ~2 hrs) for clinical changes
• Administer high-energy (dextrose-containing) fluids & (if needed) insulin for mgmt of hyperglycemia.
• IV L-carnitine supplementation
• Address electrolytes & pH imbalances w/IV fluid mgmt.
• Obtain blood glucose, electrolytes, BUN, creatinine, AST/ALT, albumin, blood gases, serum ammonia, total CK level, & plasma acylcarnitine profile.
• Cardiac monitoring is indicated.
• Ongoing assessment of hemodynamic status & for new neurologic signs is critical.
• Use of carnitine supplementation is controversial (see
• Inadequate or delayed start of emergency treatment → high risk of consequent long-term neurodisability.
• Place a cardiac monitor.
• Obtain an EKG.
• Consider echocardiogram if not previously obtained or if signs of cardiac deterioration from baseline.
• Consult a cardiologist; placement of a pacemaker may be considered.
• Assess for rhabdomyolysis.
• Improve caloric & fluid intake.
• Administer IV fluids; consider initial saline bolus based on CK levels.
• Avoid nephrotoxic medications or agents during this event.
• Consult a nephrologist.
• Initiate treatment above for ↑ catabolism.
• Obtain serum ammonia levels.
• Consult neurologist if evidence of seizure or signs of encephalopathy to consider EEG or neuroimaging.
• Monitor free-flowing serum ammonia every 2-4 hrs or as clinically indicated.
• Protein restriction is often unsuccessful; ↑ caloric intake through carbohydrates is most effective.
• Although apparently w/o success, a few authors have used nitrogen scavengers (sodium benzoate, sodium phenylacetate or sodium phenylbutyrate) or intravenous arginine during initial presentation in the setting of persistently ↑ ammonia w/altered mental status (despite caloric optimization).
• Extracorporeal ammonia clearance could be considered if medical therapy fails.
• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with CACT deficiency together with pediatric metabolic experts, dietitians, psychologists, and social workers.
• As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.
## Prevention of Primary Manifestations
High carbohydrate intake (typically >60%), long-chain dietary fat restriction (<10%), and triheptanoin (Dojolvi
## Prevention of Secondary Complications
One of the most important components of management (as it relates to prevention of secondary complications) is education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see also
Prevention of Secondary Manifestations in Individuals with Carnitine-Acylcarnitine Translocase (CACT) Deficiency
Intensive & ongoing education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute encephalopathic crises
Treatment protocols & provision of emergency letters or cards to incl guidance for care in the event of illness while on vacation
MediAlert bracelets/pendants, or car seat stickers
Adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources); maintain medication required for maintenance & emergency treatment (carnitine, antipyretics) at home.
Provide written protocols for maintenance & emergency treatment to parents & primary care providers/pediatricians, teachers, & school staff.
Provide emergency letters/cards summarizing key information & principles of emergency treatment for CACT deficiency & incl contact info for primary treating metabolic center.
For any planned travel or vacations, consider contacting a center of expertise near the destination prior to travel.
Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional management).
Essential information including written treatment protocols should be in place in anticipation of possible future need for inpatient emergency treatment.
Parents or local hospitals should immediately inform the designated metabolic center if: (1) temperature rises >38.5°C (101°F); (2) vomiting/diarrhea or other symptoms of intercurrent illness develop; or (3) new neurologic symptoms appear.
Perioperative/perianesthetic management precautions may include visitations at specialist anesthetic clinics for affected individuals deemed to be at high risk for perioperative complications.
• Intensive & ongoing education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute encephalopathic crises
• Treatment protocols & provision of emergency letters or cards to incl guidance for care in the event of illness while on vacation
• MediAlert bracelets/pendants, or car seat stickers
• Adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources); maintain medication required for maintenance & emergency treatment (carnitine, antipyretics) at home.
• Provide written protocols for maintenance & emergency treatment to parents & primary care providers/pediatricians, teachers, & school staff.
• Provide emergency letters/cards summarizing key information & principles of emergency treatment for CACT deficiency & incl contact info for primary treating metabolic center.
• For any planned travel or vacations, consider contacting a center of expertise near the destination prior to travel.
• Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
• Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional management).
## Surveillance
In addition to regular evaluations by a metabolic specialist and metabolic dietitian, the following are recommended.
Recommended Surveillance for Individuals with Carnitine-Acylcarnitine Translocase (CACT) Deficiency
Neonates: every 2 wks
Infants age 2 mos – 1 yr: every 1-3 mos
Children ≥ 1 year: every 3-6 mos
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; CK = creatine kinase; CRP = C-reactive protein
CRP is used as an inflammatory marker in the authors' practice, in conjunction with prealbumin. Prealbumin has a shorter half-life (2 to 3 days) than albumin and is thus a more favorable marker for acute nutritional changes. Prealbumin levels could be affected (decreased) by the presence of an acute inflammatory process; CRP is required to rule out that possibility [
• Neonates: every 2 wks
• Infants age 2 mos – 1 yr: every 1-3 mos
• Children ≥ 1 year: every 3-6 mos
## Agents/Circumstances to Avoid
Avoid the following:
Prolonged fasting
Catabolic illness (fever, intercurrent infection)
Inadequate caloric provision during other stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)
Strenuous physical activity
Anesthetics that contain high doses of long-chain fatty acids, such as propofol, although use for short procedures is likely to be tolerated [
• Prolonged fasting
• Catabolic illness (fever, intercurrent infection)
• Inadequate caloric provision during other stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)
• Strenuous physical activity
• Anesthetics that contain high doses of long-chain fatty acids, such as propofol, although use for short procedures is likely to be tolerated [
## Evaluation of Relatives at Risk
Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of CACT deficiency. For at-risk newborn sibs when prenatal testing was not performed: In parallel with newborn screening either test for the familial
See
## Therapies Under Investigation
Search
## Genetic Counseling
Carnitine-acylcarnitine translocase (CACT) deficiency is inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygous for an
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
See
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for an
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Carnitine-acylcarnitine translocase (CACT) deficiency is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for an
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are presumed to be heterozygous for an
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
## Related Genetic Counseling Issues
See
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
TEMPLE (Tools Enabling Metabolic Parents LEarning)
United Kingdom
United Kingdom
Health Resources & Services Administration
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• TEMPLE (Tools Enabling Metabolic Parents LEarning)
• United Kingdom
•
•
•
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•
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• United Kingdom
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• Health Resources & Services Administration
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## Molecular Genetics
Carnitine-Acylcarnitine Translocase Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Carnitine-Acylcarnitine Translocase Deficiency (
Fatty acid β-oxidation is an important pathway for energy production during times of stress or fasting, particularly in energy-demanding tissue such as cardiac muscle, skeletal muscle, and liver. Long-chain fatty acids require a carnitine shuttle system to be transported from the cytosol into the mitochondrial matrix for this purpose. Carnitine acylcarnitine translocase (CACT) transfers acylcarnitines formed by the action of carnitine palmitoyl-transferase I (CPT1) in the outer mitochondrial membrane into the mitochondrial matrix in exchange for free carnitine. These acylcarnitines are then converted into acyl-CoA by carnitine palmitoyl-transferase 2 (CPT2), to enter β-oxidation [
In CACT deficiency, fatty acid β-oxidation is not able to proceed normally and, therefore, the energy sources for essential body functions are limited. The organs primarily affected subsequently utilize other energy sources, such as glycogen and protein. As these metabolites are depleted, hypoglycemia, hyperammonemia, and rhabdomyolysis (due to protein catabolism) supervene.
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions.
## Molecular Pathogenesis
Fatty acid β-oxidation is an important pathway for energy production during times of stress or fasting, particularly in energy-demanding tissue such as cardiac muscle, skeletal muscle, and liver. Long-chain fatty acids require a carnitine shuttle system to be transported from the cytosol into the mitochondrial matrix for this purpose. Carnitine acylcarnitine translocase (CACT) transfers acylcarnitines formed by the action of carnitine palmitoyl-transferase I (CPT1) in the outer mitochondrial membrane into the mitochondrial matrix in exchange for free carnitine. These acylcarnitines are then converted into acyl-CoA by carnitine palmitoyl-transferase 2 (CPT2), to enter β-oxidation [
In CACT deficiency, fatty acid β-oxidation is not able to proceed normally and, therefore, the energy sources for essential body functions are limited. The organs primarily affected subsequently utilize other energy sources, such as glycogen and protein. As these metabolites are depleted, hypoglycemia, hyperammonemia, and rhabdomyolysis (due to protein catabolism) supervene.
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions.
## Chapter Notes
J Andres Morales Corado, MBBS, is an Assistant Professor of Pediatrics at Columbia University with interest and research focused on inborn errors of metabolism and their interaction with brain function, as well as bone genetic disorders and neurogenetic disorders.
Contact:
Chung U Lee, MD, is an Assistant Professor of Pediatrics and Program Director of the Medical Biochemical Genetics Fellowship Program at Stanford University with an interest and research focused in inborn errors of metabolism.
Gregory M Enns, MB ChB, is a Professor of Pediatrics and Director of the Biochemical Genetics Program at Stanford University with an interest in inborn errors of metabolism and research focused on mitochondrial disorders.
We would like to thank our patients and their families, as well as our team of registered dietitians: Lauren Bell, Temitope Pedro, Lisa Williams, and Jodi Wright for their outstanding care and collaboration on this chapter.
21 July 2022 (ma) Review posted live
18 February 2022 (jamc) Original submission
• 21 July 2022 (ma) Review posted live
• 18 February 2022 (jamc) Original submission
## Author Notes
J Andres Morales Corado, MBBS, is an Assistant Professor of Pediatrics at Columbia University with interest and research focused on inborn errors of metabolism and their interaction with brain function, as well as bone genetic disorders and neurogenetic disorders.
Contact:
Chung U Lee, MD, is an Assistant Professor of Pediatrics and Program Director of the Medical Biochemical Genetics Fellowship Program at Stanford University with an interest and research focused in inborn errors of metabolism.
Gregory M Enns, MB ChB, is a Professor of Pediatrics and Director of the Biochemical Genetics Program at Stanford University with an interest in inborn errors of metabolism and research focused on mitochondrial disorders.
## Acknowledgments
We would like to thank our patients and their families, as well as our team of registered dietitians: Lauren Bell, Temitope Pedro, Lisa Williams, and Jodi Wright for their outstanding care and collaboration on this chapter.
## Revision History
21 July 2022 (ma) Review posted live
18 February 2022 (jamc) Original submission
• 21 July 2022 (ma) Review posted live
• 18 February 2022 (jamc) Original submission
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] |
21/7/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
cadasil
|
cadasil
|
[
"Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy",
"Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy",
"Neurogenic locus notch homolog protein 3",
"NOTCH3",
"CADASIL"
] |
CADASIL
|
Remco J Hack, Julie Rutten, Saskia AJ Lesnik Oberstein
|
Summary CADASIL ( The diagnosis of CADASIL is established in a proband either by identification of a heterozygous pathogenic variant in CADASIL is inherited in an autosomal dominant manner. Most affected individuals have an affected parent;
|
## Diagnosis
There are no generally accepted diagnostic criteria for CADASIL (
CADASIL
Transient ischemic attacks and ischemic stroke
Cognitive impairment, manifesting initially with executive dysfunction, with a concurrent stepwise deterioration due to recurrent strokes to vascular dementia
Migraine with aura, with a mean age of onset of 30 years
Psychiatric disturbances, most frequently mood disturbances and apathy
Symmetric and progressive white matter hyperintensities, often involving the anterior temporal lobes and external capsules
Lacunes of presumed vascular origin
Recent subcortical infarcts
Dilated perivascular spaces, sometimes referred to as subcortical lacunar lesions
Brain atrophy
Cerebral microbleeds
The diagnosis of CADASIL
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of CADASIL is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of CADASIL, molecular genetic testing approaches can include
Perform sequence analysis first. If a biallelic pathogenic variant is identified, consider gene-targeted deletion/duplication analysis to determine if an unidentified exon deletion or duplication is present.
Note: Biallelic
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by stroke and/or dementia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in CADASIL
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
When all exons coding for epidermal growth factor-like repeats (see
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The diagnosis can be confirmed by ultrastructural analysis of small arterioles obtained, for example, by skin biopsy [
The combined analysis by electron microscopy and immunohistochemistry, when interpreted by an experienced (neuro)pathologist, usually allows for a conclusive CADASIL diagnosis [
• Transient ischemic attacks and ischemic stroke
• Cognitive impairment, manifesting initially with executive dysfunction, with a concurrent stepwise deterioration due to recurrent strokes to vascular dementia
• Migraine with aura, with a mean age of onset of 30 years
• Psychiatric disturbances, most frequently mood disturbances and apathy
• Symmetric and progressive white matter hyperintensities, often involving the anterior temporal lobes and external capsules
• Lacunes of presumed vascular origin
• Recent subcortical infarcts
• Dilated perivascular spaces, sometimes referred to as subcortical lacunar lesions
• Brain atrophy
• Cerebral microbleeds
• Perform sequence analysis first. If a biallelic pathogenic variant is identified, consider gene-targeted deletion/duplication analysis to determine if an unidentified exon deletion or duplication is present.
• Note: Biallelic
• For an introduction to multigene panels click
## Suggestive Findings
CADASIL
Transient ischemic attacks and ischemic stroke
Cognitive impairment, manifesting initially with executive dysfunction, with a concurrent stepwise deterioration due to recurrent strokes to vascular dementia
Migraine with aura, with a mean age of onset of 30 years
Psychiatric disturbances, most frequently mood disturbances and apathy
Symmetric and progressive white matter hyperintensities, often involving the anterior temporal lobes and external capsules
Lacunes of presumed vascular origin
Recent subcortical infarcts
Dilated perivascular spaces, sometimes referred to as subcortical lacunar lesions
Brain atrophy
Cerebral microbleeds
• Transient ischemic attacks and ischemic stroke
• Cognitive impairment, manifesting initially with executive dysfunction, with a concurrent stepwise deterioration due to recurrent strokes to vascular dementia
• Migraine with aura, with a mean age of onset of 30 years
• Psychiatric disturbances, most frequently mood disturbances and apathy
• Symmetric and progressive white matter hyperintensities, often involving the anterior temporal lobes and external capsules
• Lacunes of presumed vascular origin
• Recent subcortical infarcts
• Dilated perivascular spaces, sometimes referred to as subcortical lacunar lesions
• Brain atrophy
• Cerebral microbleeds
## Establishing the Diagnosis
The diagnosis of CADASIL
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of CADASIL is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of CADASIL, molecular genetic testing approaches can include
Perform sequence analysis first. If a biallelic pathogenic variant is identified, consider gene-targeted deletion/duplication analysis to determine if an unidentified exon deletion or duplication is present.
Note: Biallelic
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by stroke and/or dementia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in CADASIL
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
When all exons coding for epidermal growth factor-like repeats (see
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The diagnosis can be confirmed by ultrastructural analysis of small arterioles obtained, for example, by skin biopsy [
The combined analysis by electron microscopy and immunohistochemistry, when interpreted by an experienced (neuro)pathologist, usually allows for a conclusive CADASIL diagnosis [
• Perform sequence analysis first. If a biallelic pathogenic variant is identified, consider gene-targeted deletion/duplication analysis to determine if an unidentified exon deletion or duplication is present.
• Note: Biallelic
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of CADASIL, molecular genetic testing approaches can include
Perform sequence analysis first. If a biallelic pathogenic variant is identified, consider gene-targeted deletion/duplication analysis to determine if an unidentified exon deletion or duplication is present.
Note: Biallelic
For an introduction to multigene panels click
• Perform sequence analysis first. If a biallelic pathogenic variant is identified, consider gene-targeted deletion/duplication analysis to determine if an unidentified exon deletion or duplication is present.
• Note: Biallelic
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by stroke and/or dementia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in CADASIL
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
When all exons coding for epidermal growth factor-like repeats (see
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Skin Biopsy
The diagnosis can be confirmed by ultrastructural analysis of small arterioles obtained, for example, by skin biopsy [
The combined analysis by electron microscopy and immunohistochemistry, when interpreted by an experienced (neuro)pathologist, usually allows for a conclusive CADASIL diagnosis [
## Clinical Characteristics
CADASIL is a disease of the small to medium-sized arteries, mainly affecting the brain. The presenting symptoms, age at onset, and disease progression in CADASIL are variable, both between and within families. The disease is characterized by five main symptoms: transient ischemic attacks and recurrent ischemic strokes; cognitive decline; migraine with aura; mood disturbance; and apathy.
Ischemic episodes typically present as a classic lacunar syndrome (pure motor stroke, ataxic hemiparesis/dysarthria-clumsy hand syndrome, pure sensory stroke, sensorimotor stroke), but other lacunar syndromes (brain stem or hemispheric) are also observed [
Strokes involving the territory of a large artery have occasionally been reported. However, whether these are coincidental observations, or whether (certain sub-populations of) individuals with CADASIL are at increased risk for large vessel stroke, is unclear [
The pattern of cognitive dysfunction is initially characterized by deficits in executive function (timed measures and measures of error monitoring), verbal fluency, and memory with benefit from clues [
Data on the long-term prognosis in CADASIL come from a large study of 411 individuals [
The median survival time of men was significantly shorter than expected from German life tables, whereas the median survival time of women was not significantly reduced. The reason for this difference is not known; possible explanations include sex hormones, sex differences in risk factor control, medical management, social support, and socioeconomic factors.
In individuals age 20-30 years, distinctive white matter hyperintensities often first appear in the anterior temporal lobes, when the rest of the white matter, except for periventricular caps, appears unaffected [
In the course of the disease, the load of white matter hyperintensity lesions increases, eventually coalescing to the point where, in some elderly individuals, normal-appearing white matter is barely distinguishable [
White matter hyperintensities in the temporal lobe and external capsule are characteristic for CADASIL but not always present [
In symptomatic individuals, white matter hyperintensities are symmetrically distributed and located in the periventricular and deep white matter. Within the white matter, the frontal lobe is the site with the highest lesion load, followed by the temporal and parietal lobes [
The majority of lacunes develop at the edge of white matter hyperintensities and proximal to white matter hyperintensities along the course of perforating vessels supplying the respective brain region [
Brain atrophy appears to result from accumulation of lacunes and widespread microstructural alterations within the brain [
Lacunes and brain atrophy are strongly correlated with clinical severity and clinical worsening in individuals with CADASIL [
Dilated perivascular spaces are found in approximately 70%-80% of affected individuals [
Cerebral microbleeds (CMB) are reported in approximately one third of affected individuals [
Smaller studies have described genotype-phenotype correlations for specific pathogenic variants [
In general, affected individuals with cysteine-altering pathogenic variants in epidermal growth-factor like repeat (EGFr) domains 1-6 of NOTCH3 have a 12-year earlier onset of stroke, lower survival, and increased white matter hyperintensity volume, consistent with the more severe classic CADASIL presentation, compared to those with a cysteine-altering pathogenic variant in EGFr domains 7-34. The mean survival time was 68.5 and 76.9 years, respectively [
There is conflicting evidence about the effect of pathogenic variants in the ligand-binding domain of
Pathogenic variants in EGFr domains 1-6 appear to be fully penetrant and are usually associated with the classic CADASIL phenotype. However, there is variability in disease severity.
Pathogenic variants in EGFr domains 7-34 have a much higher population frequency (~1:300) [
Previous descriptions of families with "hereditary multi-infarct dementia," "chronic familial vascular encephalopathy," and "familial subcortical dementia" represent early reports of CADASIL.
While most published information on individuals with CADASIL originates from Europe, CADASIL has been observed on all continents. Multiple small and national European registries have estimated the minimum prevalence at between two and four per 100,000 [
Recently, it was found that the frequency of
• In individuals age 20-30 years, distinctive white matter hyperintensities often first appear in the anterior temporal lobes, when the rest of the white matter, except for periventricular caps, appears unaffected [
• In the course of the disease, the load of white matter hyperintensity lesions increases, eventually coalescing to the point where, in some elderly individuals, normal-appearing white matter is barely distinguishable [
• White matter hyperintensities in the temporal lobe and external capsule are characteristic for CADASIL but not always present [
• In symptomatic individuals, white matter hyperintensities are symmetrically distributed and located in the periventricular and deep white matter. Within the white matter, the frontal lobe is the site with the highest lesion load, followed by the temporal and parietal lobes [
• The majority of lacunes develop at the edge of white matter hyperintensities and proximal to white matter hyperintensities along the course of perforating vessels supplying the respective brain region [
• Brain atrophy appears to result from accumulation of lacunes and widespread microstructural alterations within the brain [
• Lacunes and brain atrophy are strongly correlated with clinical severity and clinical worsening in individuals with CADASIL [
• Dilated perivascular spaces are found in approximately 70%-80% of affected individuals [
• Cerebral microbleeds (CMB) are reported in approximately one third of affected individuals [
## Clinical Description
CADASIL is a disease of the small to medium-sized arteries, mainly affecting the brain. The presenting symptoms, age at onset, and disease progression in CADASIL are variable, both between and within families. The disease is characterized by five main symptoms: transient ischemic attacks and recurrent ischemic strokes; cognitive decline; migraine with aura; mood disturbance; and apathy.
Ischemic episodes typically present as a classic lacunar syndrome (pure motor stroke, ataxic hemiparesis/dysarthria-clumsy hand syndrome, pure sensory stroke, sensorimotor stroke), but other lacunar syndromes (brain stem or hemispheric) are also observed [
Strokes involving the territory of a large artery have occasionally been reported. However, whether these are coincidental observations, or whether (certain sub-populations of) individuals with CADASIL are at increased risk for large vessel stroke, is unclear [
The pattern of cognitive dysfunction is initially characterized by deficits in executive function (timed measures and measures of error monitoring), verbal fluency, and memory with benefit from clues [
Data on the long-term prognosis in CADASIL come from a large study of 411 individuals [
The median survival time of men was significantly shorter than expected from German life tables, whereas the median survival time of women was not significantly reduced. The reason for this difference is not known; possible explanations include sex hormones, sex differences in risk factor control, medical management, social support, and socioeconomic factors.
In individuals age 20-30 years, distinctive white matter hyperintensities often first appear in the anterior temporal lobes, when the rest of the white matter, except for periventricular caps, appears unaffected [
In the course of the disease, the load of white matter hyperintensity lesions increases, eventually coalescing to the point where, in some elderly individuals, normal-appearing white matter is barely distinguishable [
White matter hyperintensities in the temporal lobe and external capsule are characteristic for CADASIL but not always present [
In symptomatic individuals, white matter hyperintensities are symmetrically distributed and located in the periventricular and deep white matter. Within the white matter, the frontal lobe is the site with the highest lesion load, followed by the temporal and parietal lobes [
The majority of lacunes develop at the edge of white matter hyperintensities and proximal to white matter hyperintensities along the course of perforating vessels supplying the respective brain region [
Brain atrophy appears to result from accumulation of lacunes and widespread microstructural alterations within the brain [
Lacunes and brain atrophy are strongly correlated with clinical severity and clinical worsening in individuals with CADASIL [
Dilated perivascular spaces are found in approximately 70%-80% of affected individuals [
Cerebral microbleeds (CMB) are reported in approximately one third of affected individuals [
• In individuals age 20-30 years, distinctive white matter hyperintensities often first appear in the anterior temporal lobes, when the rest of the white matter, except for periventricular caps, appears unaffected [
• In the course of the disease, the load of white matter hyperintensity lesions increases, eventually coalescing to the point where, in some elderly individuals, normal-appearing white matter is barely distinguishable [
• White matter hyperintensities in the temporal lobe and external capsule are characteristic for CADASIL but not always present [
• In symptomatic individuals, white matter hyperintensities are symmetrically distributed and located in the periventricular and deep white matter. Within the white matter, the frontal lobe is the site with the highest lesion load, followed by the temporal and parietal lobes [
• The majority of lacunes develop at the edge of white matter hyperintensities and proximal to white matter hyperintensities along the course of perforating vessels supplying the respective brain region [
• Brain atrophy appears to result from accumulation of lacunes and widespread microstructural alterations within the brain [
• Lacunes and brain atrophy are strongly correlated with clinical severity and clinical worsening in individuals with CADASIL [
• Dilated perivascular spaces are found in approximately 70%-80% of affected individuals [
• Cerebral microbleeds (CMB) are reported in approximately one third of affected individuals [
## Genotype-Phenotype Correlations
Smaller studies have described genotype-phenotype correlations for specific pathogenic variants [
In general, affected individuals with cysteine-altering pathogenic variants in epidermal growth-factor like repeat (EGFr) domains 1-6 of NOTCH3 have a 12-year earlier onset of stroke, lower survival, and increased white matter hyperintensity volume, consistent with the more severe classic CADASIL presentation, compared to those with a cysteine-altering pathogenic variant in EGFr domains 7-34. The mean survival time was 68.5 and 76.9 years, respectively [
There is conflicting evidence about the effect of pathogenic variants in the ligand-binding domain of
## Penetrance
Pathogenic variants in EGFr domains 1-6 appear to be fully penetrant and are usually associated with the classic CADASIL phenotype. However, there is variability in disease severity.
Pathogenic variants in EGFr domains 7-34 have a much higher population frequency (~1:300) [
## Nomenclature
Previous descriptions of families with "hereditary multi-infarct dementia," "chronic familial vascular encephalopathy," and "familial subcortical dementia" represent early reports of CADASIL.
## Prevalence
While most published information on individuals with CADASIL originates from Europe, CADASIL has been observed on all continents. Multiple small and national European registries have estimated the minimum prevalence at between two and four per 100,000 [
Recently, it was found that the frequency of
## Genetically Related (Allelic) Disorders
Heterozygous truncating pathogenic variants in
A
## Differential Diagnosis
The differential diagnosis of CADASIL includes
The clinical characteristics and MRI abnormalities in these conditions may resemble those of CADASIL. The presence of temporopolar MRI lesions, the absence of optic nerve and spinal cord involvement, the absence of oligoclonal bands in the cerebrospinal fluid, and the absence of hypertension are critical in this regard [
Clinical Signs and MRI Abnormalities of Sporadic/Multifactorial Disorders in the Differential Diagnosis of CADASIL
Optic neuritis
Spinal cord involvement
Internuclear ophthalmoplegia
Lhermitte sign
Heat sensitivity
Age of onset: 15-50 yrs
Juxtacortical WMH
Dawson fingers
Spinal cord, corpus callosum & U-fibers involvement
Gadolinium enhancement of lesions
Hypertension
Absence of AD or AR inheritance in family history
Age of onset: >65 yrs
Involvement of temporal pole is rare
Involvement of external capsule occurs less frequently
Subacute headache
Multifocal neurologic deficits
Signs & symptoms suggestive of systemic vaculitis (peripheral neuropathy, fever, weight loss, rash, & night sweats)
May occur at any age; median age at diagnosis: 50 yrs
Multifocal infarcts in different vascular territories
Diffuse gadolinium enhanced lesions
Spinal cord: 5% of affected individuals
Optic nerve: rare
AD = autosomal dominant; AR = autosomal recessive; CSF = cerebrospinal fluid; WMH = white matter hyperintensities
Several inherited disorders are associated with acute ischemic events (or stroke-like episodes in the case of MELAS) and cerebral white matter hyperintensities on MRI. These disorders can be distinguished from CADASIL by the associated clinical signs, MRI, mode of inheritance, and appropriate laboratory investigations (particularly, molecular genetic testing) (see
Clinical Signs and MRI Abnormalities of Inherited Disorders to Consider in the Differential Diagnosis of CADASIL
Onset in childhood & adolescence
Periodic severe pain in extremities
Angiokeratoma
Renal insufficiency
Hypohidrosis
Cardiac involvement
Corneal opacities
Onset in adulthood & later
Cardiomyopathy
Renal disease
Cerebrovascular disease
Exclusive involvement of pulvinar thought to be characteristic
Ischemic strokes predominantly located in vertebrobasilar system
Vertebrobasilar dolichoectasia
Onset age: 20-30 yrs (spastic gait)
Spastic gait
Premature alopecia
Severe low back pain & deforming spondylosis
Spinal spondylosis
In advanced stage: "arc" sign (involvement of pontocerebellar tract)
Onset age: 50-70 yrs (stroke)
Alopecia, spondylosis, & low back pain reported (less frequently than in CARASIL)
Onset age: 2-10 yrs
Anorexia
Recurrent vomiting
Short stature
Generalized tonic-clonic seizures
Proximal limb weakness
Sensorineural hearing loss
Stroke-like episodes of cortical blindness and/or altered consciousness from age ~40 yrs
↑ T
Swollen gyri
Gadolinium enhancement of lesions
Slow spreading of stroke-like lesions
Age of onset: 40-60 yrs
Intracerebral hemorrhage
Muscle cramps
Xerostomia
Keratoconjuctivitis sicca
Therapy-resistant hypertension
Psychomotor retardation
Infantile hemiplegia
Intracerebral hemorrhage
Seizures
Intracerebral hemorrhage
Opthalmologic abnormalities
Renal abnormalities
Cardiovascular abnormalties
Muscle cramps
Porencephaly
Schizencephaly
Deep & lobar intracerebral hemorrhage
Cerebral calcification
Cerebellar atrophy
Intracranial aneurysms
AD = autosomal dominant; AR = autosomal recessive; Mat = maternal; MOI = mode of inheritance; WMH = white matter hyperintensities; XL = X-linked
CARASIL =
Pathogenic variants known to cause MELAS have been identified in other mtDNA tRNA genes including
CARASAL = cathepsin A–related arteriopathy with strokes and leukoencephalopathy [
• Optic neuritis
• Spinal cord involvement
• Internuclear ophthalmoplegia
• Lhermitte sign
• Heat sensitivity
• Age of onset: 15-50 yrs
• Juxtacortical WMH
• Dawson fingers
• Spinal cord, corpus callosum & U-fibers involvement
• Gadolinium enhancement of lesions
• Hypertension
• Absence of AD or AR inheritance in family history
• Age of onset: >65 yrs
• Involvement of temporal pole is rare
• Involvement of external capsule occurs less frequently
• Subacute headache
• Multifocal neurologic deficits
• Signs & symptoms suggestive of systemic vaculitis (peripheral neuropathy, fever, weight loss, rash, & night sweats)
• May occur at any age; median age at diagnosis: 50 yrs
• Multifocal infarcts in different vascular territories
• Diffuse gadolinium enhanced lesions
• Spinal cord: 5% of affected individuals
• Optic nerve: rare
• Onset in childhood & adolescence
• Periodic severe pain in extremities
• Angiokeratoma
• Renal insufficiency
• Hypohidrosis
• Cardiac involvement
• Corneal opacities
• Onset in adulthood & later
• Cardiomyopathy
• Renal disease
• Cerebrovascular disease
• Exclusive involvement of pulvinar thought to be characteristic
• Ischemic strokes predominantly located in vertebrobasilar system
• Vertebrobasilar dolichoectasia
• Onset age: 20-30 yrs (spastic gait)
• Spastic gait
• Premature alopecia
• Severe low back pain & deforming spondylosis
• Spinal spondylosis
• In advanced stage: "arc" sign (involvement of pontocerebellar tract)
• Onset age: 50-70 yrs (stroke)
• Alopecia, spondylosis, & low back pain reported (less frequently than in CARASIL)
• Onset age: 2-10 yrs
• Anorexia
• Recurrent vomiting
• Short stature
• Generalized tonic-clonic seizures
• Proximal limb weakness
• Sensorineural hearing loss
• Stroke-like episodes of cortical blindness and/or altered consciousness from age ~40 yrs
• ↑ T
• Swollen gyri
• Gadolinium enhancement of lesions
• Slow spreading of stroke-like lesions
• Age of onset: 40-60 yrs
• Intracerebral hemorrhage
• Muscle cramps
• Xerostomia
• Keratoconjuctivitis sicca
• Therapy-resistant hypertension
• Psychomotor retardation
• Infantile hemiplegia
• Intracerebral hemorrhage
• Seizures
• Intracerebral hemorrhage
• Opthalmologic abnormalities
• Renal abnormalities
• Cardiovascular abnormalties
• Muscle cramps
• Porencephaly
• Schizencephaly
• Deep & lobar intracerebral hemorrhage
• Cerebral calcification
• Cerebellar atrophy
• Intracranial aneurysms
## Sporadic/Multifactorial Disorders
The clinical characteristics and MRI abnormalities in these conditions may resemble those of CADASIL. The presence of temporopolar MRI lesions, the absence of optic nerve and spinal cord involvement, the absence of oligoclonal bands in the cerebrospinal fluid, and the absence of hypertension are critical in this regard [
Clinical Signs and MRI Abnormalities of Sporadic/Multifactorial Disorders in the Differential Diagnosis of CADASIL
Optic neuritis
Spinal cord involvement
Internuclear ophthalmoplegia
Lhermitte sign
Heat sensitivity
Age of onset: 15-50 yrs
Juxtacortical WMH
Dawson fingers
Spinal cord, corpus callosum & U-fibers involvement
Gadolinium enhancement of lesions
Hypertension
Absence of AD or AR inheritance in family history
Age of onset: >65 yrs
Involvement of temporal pole is rare
Involvement of external capsule occurs less frequently
Subacute headache
Multifocal neurologic deficits
Signs & symptoms suggestive of systemic vaculitis (peripheral neuropathy, fever, weight loss, rash, & night sweats)
May occur at any age; median age at diagnosis: 50 yrs
Multifocal infarcts in different vascular territories
Diffuse gadolinium enhanced lesions
Spinal cord: 5% of affected individuals
Optic nerve: rare
AD = autosomal dominant; AR = autosomal recessive; CSF = cerebrospinal fluid; WMH = white matter hyperintensities
• Optic neuritis
• Spinal cord involvement
• Internuclear ophthalmoplegia
• Lhermitte sign
• Heat sensitivity
• Age of onset: 15-50 yrs
• Juxtacortical WMH
• Dawson fingers
• Spinal cord, corpus callosum & U-fibers involvement
• Gadolinium enhancement of lesions
• Hypertension
• Absence of AD or AR inheritance in family history
• Age of onset: >65 yrs
• Involvement of temporal pole is rare
• Involvement of external capsule occurs less frequently
• Subacute headache
• Multifocal neurologic deficits
• Signs & symptoms suggestive of systemic vaculitis (peripheral neuropathy, fever, weight loss, rash, & night sweats)
• May occur at any age; median age at diagnosis: 50 yrs
• Multifocal infarcts in different vascular territories
• Diffuse gadolinium enhanced lesions
• Spinal cord: 5% of affected individuals
• Optic nerve: rare
## Inherited Disorders
Several inherited disorders are associated with acute ischemic events (or stroke-like episodes in the case of MELAS) and cerebral white matter hyperintensities on MRI. These disorders can be distinguished from CADASIL by the associated clinical signs, MRI, mode of inheritance, and appropriate laboratory investigations (particularly, molecular genetic testing) (see
Clinical Signs and MRI Abnormalities of Inherited Disorders to Consider in the Differential Diagnosis of CADASIL
Onset in childhood & adolescence
Periodic severe pain in extremities
Angiokeratoma
Renal insufficiency
Hypohidrosis
Cardiac involvement
Corneal opacities
Onset in adulthood & later
Cardiomyopathy
Renal disease
Cerebrovascular disease
Exclusive involvement of pulvinar thought to be characteristic
Ischemic strokes predominantly located in vertebrobasilar system
Vertebrobasilar dolichoectasia
Onset age: 20-30 yrs (spastic gait)
Spastic gait
Premature alopecia
Severe low back pain & deforming spondylosis
Spinal spondylosis
In advanced stage: "arc" sign (involvement of pontocerebellar tract)
Onset age: 50-70 yrs (stroke)
Alopecia, spondylosis, & low back pain reported (less frequently than in CARASIL)
Onset age: 2-10 yrs
Anorexia
Recurrent vomiting
Short stature
Generalized tonic-clonic seizures
Proximal limb weakness
Sensorineural hearing loss
Stroke-like episodes of cortical blindness and/or altered consciousness from age ~40 yrs
↑ T
Swollen gyri
Gadolinium enhancement of lesions
Slow spreading of stroke-like lesions
Age of onset: 40-60 yrs
Intracerebral hemorrhage
Muscle cramps
Xerostomia
Keratoconjuctivitis sicca
Therapy-resistant hypertension
Psychomotor retardation
Infantile hemiplegia
Intracerebral hemorrhage
Seizures
Intracerebral hemorrhage
Opthalmologic abnormalities
Renal abnormalities
Cardiovascular abnormalties
Muscle cramps
Porencephaly
Schizencephaly
Deep & lobar intracerebral hemorrhage
Cerebral calcification
Cerebellar atrophy
Intracranial aneurysms
AD = autosomal dominant; AR = autosomal recessive; Mat = maternal; MOI = mode of inheritance; WMH = white matter hyperintensities; XL = X-linked
CARASIL =
Pathogenic variants known to cause MELAS have been identified in other mtDNA tRNA genes including
CARASAL = cathepsin A–related arteriopathy with strokes and leukoencephalopathy [
• Onset in childhood & adolescence
• Periodic severe pain in extremities
• Angiokeratoma
• Renal insufficiency
• Hypohidrosis
• Cardiac involvement
• Corneal opacities
• Onset in adulthood & later
• Cardiomyopathy
• Renal disease
• Cerebrovascular disease
• Exclusive involvement of pulvinar thought to be characteristic
• Ischemic strokes predominantly located in vertebrobasilar system
• Vertebrobasilar dolichoectasia
• Onset age: 20-30 yrs (spastic gait)
• Spastic gait
• Premature alopecia
• Severe low back pain & deforming spondylosis
• Spinal spondylosis
• In advanced stage: "arc" sign (involvement of pontocerebellar tract)
• Onset age: 50-70 yrs (stroke)
• Alopecia, spondylosis, & low back pain reported (less frequently than in CARASIL)
• Onset age: 2-10 yrs
• Anorexia
• Recurrent vomiting
• Short stature
• Generalized tonic-clonic seizures
• Proximal limb weakness
• Sensorineural hearing loss
• Stroke-like episodes of cortical blindness and/or altered consciousness from age ~40 yrs
• ↑ T
• Swollen gyri
• Gadolinium enhancement of lesions
• Slow spreading of stroke-like lesions
• Age of onset: 40-60 yrs
• Intracerebral hemorrhage
• Muscle cramps
• Xerostomia
• Keratoconjuctivitis sicca
• Therapy-resistant hypertension
• Psychomotor retardation
• Infantile hemiplegia
• Intracerebral hemorrhage
• Seizures
• Intracerebral hemorrhage
• Opthalmologic abnormalities
• Renal abnormalities
• Cardiovascular abnormalties
• Muscle cramps
• Porencephaly
• Schizencephaly
• Deep & lobar intracerebral hemorrhage
• Cerebral calcification
• Cerebellar atrophy
• Intracranial aneurysms
## Management
To establish the extent of disease and needs in an individual diagnosed with CADASIL, the following evaluations are recommended, if they have not already been completed.
Recommended Evaluations Following Initial Diagnosis in Individuals with CADASIL
• Assess use of community or online
• Social work involvement for support
• Home nursing referral, if needed
Discussion of medical management options for individuals with CADASIL have been published [
Treatment of Manifestations in Individuals with CADASIL
IV = intravenous; TIA = transient ischemic attack
Triptans appear to have the same treatment responses and frequency of serious side effects in individuals with CADASIL as in the general migraine population [
No studies have been performed in individuals with CADASIL to determine the effect of the treatment of psychiatric disturbances (e.g. depression) with psychiatric drugs.
No treatment is of proven efficacy in preventing stroke, vascular dementia, or CADASIL disease progression.
Prevention of Primary Manifestations in Individuals with CADASIL
Such as aspirin and clopidogrel
No standard international surveillance guidelines for CADASIL exist. Several countries have developed CADASIL guidelines, such as the medical guideline for CADASIL published (in French) by the French Health Authority (HAS).
The interval at which individuals with CADASIL should be seen for follow up depends on the severity and type of symptoms and the needs of patients and their care givers.
Follow up by a neurologist with expertise in CADASIL is recommended from the time of diagnosis onward.
A consultation with a neuropsychiatrist is recommended when there are symptoms of depression, apathy, or other psychiatric manifestations.
Consultation of other medical specialists (e.g., rehabilitation physician, clinical geneticist, physical therapist, and psychologist) is as required.
The treatment effect of thrombolytic therapy (intravenous thrombolysis) is unknown in individuals with CADASIL. Studies performed in non-CADASIL populations show that increasing cerebral microbleed burden and increasing white matter hyperintensity lesion load is associated with an increased risk of intracerebral hemorrhage after thrombolytic therapy [
Oral anticoagulants could lead to an increased risk of intracerebral hemorrhage in individuals with CADASIL due to the presence of microbleeds [
Smoking increases the risk of stroke in individuals with CADASIL and should be avoided [
See
Fetuses affected with CADASIL are not at an increased risk for intrauterine complications or complications during/after delivery [
In a retrospective study, women with CADASIL were at increased risk for neurologic events in pregnancy during and shortly after delivery (puerperium) [
Case reports and small-scale observational studies have suggested a beneficial effect of acetazolamide on migraine [
Several therapeutic approaches are in pre-clinical development: testing in cells and mouse models including immunotherapy [
Search
Cross-sectional and longitudinal studies suggest that disease progression is faster in individuals with CADASIL who have increased blood pressure [
• Follow up by a neurologist with expertise in CADASIL is recommended from the time of diagnosis onward.
• A consultation with a neuropsychiatrist is recommended when there are symptoms of depression, apathy, or other psychiatric manifestations.
• Consultation of other medical specialists (e.g., rehabilitation physician, clinical geneticist, physical therapist, and psychologist) is as required.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CADASIL, the following evaluations are recommended, if they have not already been completed.
Recommended Evaluations Following Initial Diagnosis in Individuals with CADASIL
• Assess use of community or online
• Social work involvement for support
• Home nursing referral, if needed
## Treatment of Manifestations
Discussion of medical management options for individuals with CADASIL have been published [
Treatment of Manifestations in Individuals with CADASIL
IV = intravenous; TIA = transient ischemic attack
Triptans appear to have the same treatment responses and frequency of serious side effects in individuals with CADASIL as in the general migraine population [
No studies have been performed in individuals with CADASIL to determine the effect of the treatment of psychiatric disturbances (e.g. depression) with psychiatric drugs.
## Prevention of Primary Manifestations
No treatment is of proven efficacy in preventing stroke, vascular dementia, or CADASIL disease progression.
Prevention of Primary Manifestations in Individuals with CADASIL
Such as aspirin and clopidogrel
## Surveillance
No standard international surveillance guidelines for CADASIL exist. Several countries have developed CADASIL guidelines, such as the medical guideline for CADASIL published (in French) by the French Health Authority (HAS).
The interval at which individuals with CADASIL should be seen for follow up depends on the severity and type of symptoms and the needs of patients and their care givers.
Follow up by a neurologist with expertise in CADASIL is recommended from the time of diagnosis onward.
A consultation with a neuropsychiatrist is recommended when there are symptoms of depression, apathy, or other psychiatric manifestations.
Consultation of other medical specialists (e.g., rehabilitation physician, clinical geneticist, physical therapist, and psychologist) is as required.
• Follow up by a neurologist with expertise in CADASIL is recommended from the time of diagnosis onward.
• A consultation with a neuropsychiatrist is recommended when there are symptoms of depression, apathy, or other psychiatric manifestations.
• Consultation of other medical specialists (e.g., rehabilitation physician, clinical geneticist, physical therapist, and psychologist) is as required.
## Agents/Circumstances to Avoid
The treatment effect of thrombolytic therapy (intravenous thrombolysis) is unknown in individuals with CADASIL. Studies performed in non-CADASIL populations show that increasing cerebral microbleed burden and increasing white matter hyperintensity lesion load is associated with an increased risk of intracerebral hemorrhage after thrombolytic therapy [
Oral anticoagulants could lead to an increased risk of intracerebral hemorrhage in individuals with CADASIL due to the presence of microbleeds [
Smoking increases the risk of stroke in individuals with CADASIL and should be avoided [
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Fetuses affected with CADASIL are not at an increased risk for intrauterine complications or complications during/after delivery [
In a retrospective study, women with CADASIL were at increased risk for neurologic events in pregnancy during and shortly after delivery (puerperium) [
## Therapies Under Investigation
Case reports and small-scale observational studies have suggested a beneficial effect of acetazolamide on migraine [
Several therapeutic approaches are in pre-clinical development: testing in cells and mouse models including immunotherapy [
Search
## Other
Cross-sectional and longitudinal studies suggest that disease progression is faster in individuals with CADASIL who have increased blood pressure [
## Genetic Counseling
CADASIL is inherited in an autosomal dominant manner.
Most individuals diagnosed with CADASIL have an affected parent, although a negative family history is occasionally reported.
A proband with CADASIL may have the disorder as the result of a new pathogenic variant. Two individuals with
The recommended evaluation of apparently asymptomatic parents of an individual with CADASIL who has a known
An apparently negative family history cannot be confirmed until appropriate evaluations have been performed:
A family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
A review of family histories by
Biallelic pathogenic variants in
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
If one of the parents is affected, as is true for the vast majority of individuals with a
If the proband has biallelic
If the
If both parents are clinically unaffected but have not been tested for the
Each child of an individual with a
Each child of an individual who has biallelic
Predictive testing for at-risk relatives is possible once the
Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of CADASIL, it is appropriate to consider testing of symptomatic individuals regardless of age.
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspectives may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals diagnosed with CADASIL have an affected parent, although a negative family history is occasionally reported.
• A proband with CADASIL may have the disorder as the result of a new pathogenic variant. Two individuals with
• The recommended evaluation of apparently asymptomatic parents of an individual with CADASIL who has a known
• An apparently negative family history cannot be confirmed until appropriate evaluations have been performed:
• A family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
• A review of family histories by
• A family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
• A review of family histories by
• Biallelic pathogenic variants in
• A family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
• A review of family histories by
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If one of the parents is affected, as is true for the vast majority of individuals with a
• If the proband has biallelic
• If the
• If both parents are clinically unaffected but have not been tested for the
• Each child of an individual with a
• Each child of an individual who has biallelic
• Predictive testing for at-risk relatives is possible once the
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
CADASIL is inherited in an autosomal dominant manner.
## Risk to Family Members
Most individuals diagnosed with CADASIL have an affected parent, although a negative family history is occasionally reported.
A proband with CADASIL may have the disorder as the result of a new pathogenic variant. Two individuals with
The recommended evaluation of apparently asymptomatic parents of an individual with CADASIL who has a known
An apparently negative family history cannot be confirmed until appropriate evaluations have been performed:
A family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
A review of family histories by
Biallelic pathogenic variants in
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
If one of the parents is affected, as is true for the vast majority of individuals with a
If the proband has biallelic
If the
If both parents are clinically unaffected but have not been tested for the
Each child of an individual with a
Each child of an individual who has biallelic
• Most individuals diagnosed with CADASIL have an affected parent, although a negative family history is occasionally reported.
• A proband with CADASIL may have the disorder as the result of a new pathogenic variant. Two individuals with
• The recommended evaluation of apparently asymptomatic parents of an individual with CADASIL who has a known
• An apparently negative family history cannot be confirmed until appropriate evaluations have been performed:
• A family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
• A review of family histories by
• A family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
• A review of family histories by
• Biallelic pathogenic variants in
• A family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
• A review of family histories by
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If one of the parents is affected, as is true for the vast majority of individuals with a
• If the proband has biallelic
• If the
• If both parents are clinically unaffected but have not been tested for the
• Each child of an individual with a
• Each child of an individual who has biallelic
## Related Genetic Counseling Issues
Predictive testing for at-risk relatives is possible once the
Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of CADASIL, it is appropriate to consider testing of symptomatic individuals regardless of age.
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Predictive testing for at-risk relatives is possible once the
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspectives may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
110 Heathmoor Park Road
Halifax West Yorkshire HX2 9LP
United Kingdom
3605 Monument Drive
Round Rock TX 78681
10 Schalks Crossing Road
Suite 501A-133
Plainsboro NJ 08536
France
3605 Monument Drive
Round Rock TX 78681
•
• 110 Heathmoor Park Road
• Halifax West Yorkshire HX2 9LP
• United Kingdom
•
•
• 3605 Monument Drive
• Round Rock TX 78681
•
•
•
•
• 10 Schalks Crossing Road
• Suite 501A-133
• Plainsboro NJ 08536
•
•
• France
•
•
•
•
•
•
•
•
•
•
• 3605 Monument Drive
• Round Rock TX 78681
•
## Molecular Genetics
CADASIL: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CADASIL (
Approximately 70% of European individuals with a clinical CADASIL diagnosis have a pathogenic variant in one of the exons encoding EGFr domains 1-6 [
Of note, with a few exceptions [
A few splice site variants, insertions, and deletions, predicted to result in an uneven number of cysteine residues within EGFr, have been associated with disease [
Notable
Variants listed in the table have been provided by the authors.
Whether and which hypomorphic
Overall, evidence from studies in human, mice, and cell models indicates that neomorphic properties of mutant NOTCH3 protein drive CADASIL pathogenesis, whereas loss of NOTCH3 function does not play a pivotal role [
## Chapter Notes
Elles MJ Boon, PhD; Leiden University Medical Center (2006-2015)Martijn H Breuning, MD, PhD; Leiden University Medical Center (2000-2006)Martin Dichgans, MD, PhD; Ludwig-Maximilians-Universität München (2006-2012)J Haan, MD, PhD; Leiden University Medical Center (2000-2006)Remco J Hack, MD, PhD student; Leiden University Medical Center (2019-present)Saskia AJ Lesnik Oberstein, MD, PhD (2000-present)Julie Rutten, MD (2015-present)Gisela M Terwindt, MD, PhD; Leiden University Medical Center (2012-2015)
14 March 2019 (ma) Comprehensive update posted live
14 July 2016 (aa) Revision: Addition to
26 February 2015 (me) Comprehensive update posted live
28 June 2012 (me) Comprehensive update posted live
23 July 2009 (me) Comprehensive update posted live
21 November 2006 (me) Comprehensive update posted live
2 August 2004 (me) Comprehensive update posted live
23 August 2002 (me) Comprehensive update posted live
15 March 2000 (pb) Review posted live
January 2000 (slo) Original submission
• 14 March 2019 (ma) Comprehensive update posted live
• 14 July 2016 (aa) Revision: Addition to
• 26 February 2015 (me) Comprehensive update posted live
• 28 June 2012 (me) Comprehensive update posted live
• 23 July 2009 (me) Comprehensive update posted live
• 21 November 2006 (me) Comprehensive update posted live
• 2 August 2004 (me) Comprehensive update posted live
• 23 August 2002 (me) Comprehensive update posted live
• 15 March 2000 (pb) Review posted live
• January 2000 (slo) Original submission
## Author History
Elles MJ Boon, PhD; Leiden University Medical Center (2006-2015)Martijn H Breuning, MD, PhD; Leiden University Medical Center (2000-2006)Martin Dichgans, MD, PhD; Ludwig-Maximilians-Universität München (2006-2012)J Haan, MD, PhD; Leiden University Medical Center (2000-2006)Remco J Hack, MD, PhD student; Leiden University Medical Center (2019-present)Saskia AJ Lesnik Oberstein, MD, PhD (2000-present)Julie Rutten, MD (2015-present)Gisela M Terwindt, MD, PhD; Leiden University Medical Center (2012-2015)
## Revision History
14 March 2019 (ma) Comprehensive update posted live
14 July 2016 (aa) Revision: Addition to
26 February 2015 (me) Comprehensive update posted live
28 June 2012 (me) Comprehensive update posted live
23 July 2009 (me) Comprehensive update posted live
21 November 2006 (me) Comprehensive update posted live
2 August 2004 (me) Comprehensive update posted live
23 August 2002 (me) Comprehensive update posted live
15 March 2000 (pb) Review posted live
January 2000 (slo) Original submission
• 14 March 2019 (ma) Comprehensive update posted live
• 14 July 2016 (aa) Revision: Addition to
• 26 February 2015 (me) Comprehensive update posted live
• 28 June 2012 (me) Comprehensive update posted live
• 23 July 2009 (me) Comprehensive update posted live
• 21 November 2006 (me) Comprehensive update posted live
• 2 August 2004 (me) Comprehensive update posted live
• 23 August 2002 (me) Comprehensive update posted live
• 15 March 2000 (pb) Review posted live
• January 2000 (slo) Original submission
## References
Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available
## Published Guidelines / Consensus Statements
Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available
## Literature Cited
|
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"P Adib-Samii, G Brice, RJ Martin, HS Markus. Clinical spectrum of CADASIL and the effect of cardiovascular risk factors on phenotype: study in 200 consecutively recruited individuals.. Stroke 2010;41:630-4",
"F Alten, J Motte, C Ewering, N Osada, CR Clemens, EM Kadas, N Eter, F Paul, M Marziniak. Multimodal retinal vessel analysis in CADASIL patients.. PLoS One. 2014;9",
"K Amberla, M Waljas, S Tuominen, O Almkvist, M Poyhonen, S Tuisku, H Kalimo, M Viitanen. Insidious cognitive decline in CADASIL.. Stroke 2004;35:1598-602",
"JF Arboleda-Velasquez, F Lopera, E Lopez, MP Frosch, D Sepulveda-Falla, JE Gutierrez, S Vargas, M Medina, C Martinez De Arrieta, RV Lebo, SA Slaugenhaupt, RA Betensky, A Villegas, M Arcos-Burgos, D Rivera, JC Restrepo, KS Kosik. C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke.. Neurology. 2002;59:277-9",
"DP Auer, B Putz, C Gossl, G Elbel, T Gasser, M Dichgans. Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic encephalopathy: MR imaging study with statistical parametric group comparison.. Radiology 2001;218:443-51",
"EJ Belin de Chantemèle, K Retailleau, F Pinaud, E Vessières, A Bocquet, AL Guihot, B Lemaire, V Domenga, C Baufreton, L Loufrani, A Joutel, D Henrion. Notch3 is a major regulator of vascular tone in cerebral and tail resistance arteries.. Arterioscler Thromb Vasc Biol 2008;28:2216-24",
"M Bergmann, M Ebke, Y Yuan, W Brück, M Mugler, G Schwendemann. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): a morphological study of a German family.. Acta Neuropathol. 1996;92:341-50",
"A Bersano, G Bedini, HS Markus, P Vitali, E Colli-Tibaldi, F Taroni, C Gellera, S Baratta, L Mosca, P Carrera, M Ferrari, C Cereda, G Grieco, S Lanfranconi, F Mazucchelli, D Zarcone, ML De Lodovici, G Bono, GB Boncoraglio, EA Parati, MV Calloni, P Perrone, BM Bordo, C Motto, E Agostoni, A Pezzini, A Padovani, G Micieli, A Cavallini, G Molini, F Sasanelli, M Sessa, G Comi, N Checcarelli, M Carmerlingo, M Corato, S Marcheselli, L Fusi, G Grampa, D Uccellini, S Beretta, C Ferrarese, B Incorvaia, CS Tadeo, L Adobbati, V Silani, G Faragò, N Trobia, C Grond-Ginsbach, L Candelise. Lombardia GENS-group. The role of clinical and neuroimaging features in the diagnosis of CADASIL.. J Neurol. 2018;265:2934-43",
"S Bianchi, A Rufa, M Ragno, C D'Eramo, F Pescini, L Pantoni, A Cappelli, A Perretti, E Zicari, P Zolo, D Inzitari, MT Dotti, A Federico. High frequency of exon 10 mutations in the NOTCH3 gene in Italian CADASIL families: phenotypic peculiarities.. J Neurol. 2010;257:1039-42",
"S Bianchi, E Zicari, A Carluccio, I Di Donato, F Pescini, S Nannucci, R Valenti, M Ragno, D Inzitari, L Pantoni, A Federico, MT Dotti. CADASIL in central Italy: a retrospective clinical and genetic study in 229 patients.. J Neurol. 2015;262:134-41",
"MC Boelens, TJ Wu, BY Nabet, B Xu, Y Qiu, T Yoon, DJ Azzam, VC Twyman-Saint, BZ Wiemann, H Ishwaran, PJ Ter Brugge, J Jonkers, J Slingerland, AJ Minn. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways.. Cell 2014;159:499-513",
"R Bruening, M Dichgans, C Berchtenbreiter, T Yousry, KC Seelos, RH Wu, M Mayer, G Brix, M Reiser. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: decrease in regional cerebral blood volume in hyperintense subcortical lesions inversely correlates with disability and cognitive performance.. AJNR Am J Neuroradiol 2001;22:1268-74",
"F Buffon, R Porcher, K Hernandez, A Kurtz, S Pointeau, K Vahedi, MG Bousser, H Chabriat. Cognitive profile in CADASIL.. J Neurol Neurosurg Psychiatry. 2006;77:175-80",
"M Bugiani, SH Kevelam, HS Bakels, Q Waisfisz, C Ceuterick-de Groote, HW Niessen, TE Abbink, SA Lesnik Oberstein, MS van der Knaap. Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL).. Neurology. 2016;87:1777-86",
"H Chabriat, C Levy, H Taillia, MT Iba-Zizen, K Vahedi, A Joutel, E Tournier-Lasserve, MG Bousser. Patterns of MRI lesions in CADASIL.. Neurology 1998;51:452-7",
"H Chabriat, S Pappata, L Ostergaard, CA Clark, M Pachot-Clouard, K Vahedi, A Jobert, D Le Bihan, MG Bousser. Cerebral hemodynamics in CADASIL before and after acetazolamide challenge assessed with MRI bolus tracking.. Stroke 2000;31:1904-12",
"A Charidimou, C Karayiannis, TJ Song, DN Orken, V Thijs, R Lemmens, J Kim, SM Goh, TG Phan, C Soufan, RV Chandra, LA Slater, S Haji, V Mok, S Horstmann, KT Leung, Y Kawamura, N Sato, N Hasebe, T Saito, LKS Wong, Y Soo, R Veltkamp, KD Flemming, T Imaizumi, V Srikanth, JH Heo. Brain microbleeds, anticoagulation, and hemorrhage risk: Meta-analysis in stroke patients with AF.. Neurology. 2017a;89:2317-26",
"A Charidimou, M Pasi, M Fiorelli, S Shams, R von Kummer, L Pantoni, N Rost. Leukoaraiosis, cerebral hemorrhage, and outcome after intravenous thrombolysis for acute ischemic stroke: a meta-analysis (v1).. Stroke. 2016;47:2364-72",
"A Charidimou, G Turc, C Oppenheim. Yan S1, Scheitz JF, Erdur H, Klinger-Gratz PP, El-Koussy M, Takahashi W, Moriya Y, Wilson D, Kidwell CS, Saver JL, Sallem A, Moulin S, Edjlali-Goujon M, Thijs V, Fox Z, Shoamanesh A, Albers GW, Mattle HP, Benavente OR, Jäger HR, Ambler G, Aoki J, Baron JC, Kimura K, Kakuda W, Takizawa S, Jung S, Nolte CH, Lou M, Cordonnier C, Werring DJ. Microbleeds, cerebral hemorrhage, and functional outcome after stroke thrombolysis: individual patient data meta-analysis.. Stroke. 2017b;48:2084-90",
"S Chen, W Ni, XZ Yin, HQ Liu, C Lu, QJ Zheng, GX Zhao, YF Xu, L Wu, L Zhang, N Wang, HF Li, ZY Wu. Clinical features and mutation spectrum in Chinese patients with CADASIL: A multicenter retrospective study.. CNS Neurosci Ther. 2017;23:707-16",
"JC Choi, SK Song, JS Lee, SY Kang, JH Kang. Diversity of stroke presentation in CADASIL: study from patients harboring the predominant NOTCH3 mutation R544C.. J Stroke Cerebrovasc Dis 2013;22:126-31",
"E Cognat, C Baron-Menguy, V Domenga-Denier, S Cleophax, C Fouillade, M Monet-Leprêtre, M Dewerchin, A. Joutel. Archetypal Arg169Cys mutation in NOTCH3 does not drive the pathogenesis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy via a loss-of-function mechanism.. Stroke. 2014;45:842-9",
"E Coto, M Menendez, R Navarro, M Garcia-Castro, V Alvarez. A new de novo Notch3 mutation causing CADASIL.. Eur J Neurol 2006;13:628-31",
"R Cumurciuc, JP Guichard, D Reizine, F Gray, MG Bousser, H Chabriat. Dilation of Virchow-Robin spaces in CADASIL.. Eur J Neurol. 2006a;13:187-90",
"R Cumurciuc, P Henry, C Gobron, E Vicaut, MG Bousser, H Chabriat, K Vahedi. Electrocardiogram in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy patients without any clinical evidence of coronary artery disease: a case-control study.. Stroke 2006b;37:1100-2",
"R Cumurciuc, P Massin, M Paques, V Krisovic, A Gaudric, MG Bousser, H Chabriat. Retinal abnormalities in CADASIL: a retrospective study of 18 patients.. J Neurol Neurosurg Psychiatry 2004;75:1058-60",
"A del Río-Espínola, M Mendióroz, S Domingues-Montanari, P Pozo-Rosich, E Solé, J Fernández-Morales, I Fernández-Cadenas, J Montaner. CADASIL management or what to do when there is little one can do.. Expert Rev Neurother. 2009;9:197-210",
"DW Desmond, JT Moroney, T Lynch, S Chan, SS Chin, JP Mohr. The natural history of CADASIL: a pooled analysis of previously published cases.. Stroke. 1999;30:1230-3",
"M Dichgans. Cognition in CADASIL.. Stroke 2009;40:S45-7",
"M Dichgans, M Filippi, R Bruning, G Iannucci, C Berchtenbreiter, L Minicucci, I Uttner, A Crispin, H Ludwig, T Gasser, TA Yousry. Quantitative MRI in CADASIL: correlation with disability and cognitive performance.. Neurology 1999;52:1361-7",
"M Dichgans, J Herzog, T Gasser. NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL.. Neurology 2001;57:1714-7",
"M Dichgans, M Holtmannspotter, J Herzog, N Peters, M Bergmann, TA Yousry. Cerebral microbleeds in CADASIL: a gradient-echo magnetic resonance imaging and autopsy study.. Stroke 2002;33:67-71",
"M Dichgans, M Mayer, I Uttner, R Bruning, J Muller-Hocker, G Rungger, M Ebke, T Klockgether, T Gasser. The phenotypic spectrum of CADASIL: clinical findings in 102 cases.. Ann Neurol 1998;44:731-9",
"I Di Donato, S Bianchi, N De Stefano, M Dichgans, MT Dotti, M Duering, E Jouvent, AD Korczyn, SA Lesnik-Oberstein, A Malandrini, HS Markus, L Pantoni, S Penco, A Rufa, O Sinanović, D Stojanov, A Federico. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects.. BMC Med. 2017;15:41",
"V Domenga, P Fardoux, P Lacombe, M Monet, J Maciazek, LT Krebs, B Klonjkowski, E Berrou, M Mericskay, Z Li, E Tournier-Lasserve, T Gridley, A Joutel. Notch3 is required for arterial identity and maturation of vascular smooth muscle cells.. Genes Dev. 2004;18:2730-5",
"I Donnini, S Nannucci, R Valenti, F Pescini, S Bianchi, D Inzitari, L Pantoni. Acetazolamide for the prophylaxis of migraine in CADASIL: a preliminary experience.. J Headache Pain 2012;13:299-302",
"I Donnini, V Rinnoci, S Nannucci, R Valenti, F Pescini, G Mariani, S Bianchi, MT Dotti, A Federico, D Inzitari, L Pantoni. Pregnancy in CADASIL.. Acta Neurol Scand. 2017;136:668-71",
"M Duering, E Csanadi, B Gesierich, E Jouvent, D Hervé, S Seiler, B Belaroussi, S Ropele, R Schmidt, H Chabriat, M Dichgans. Incident lacunes preferentially localize to the edge of white matter hyperintensities: insights into the pathophysiology of cerebral small vessel disease.. Brain. 2013;136:2717-26",
"XJ Fang, M Yu, Y Wu, ZH Zhang, WW Wang, ZX Wang, Y Yuan. Study of Enhanced Depth Imaging Optical Coherence Tomography in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy.. Chin Med J (Engl) 2017;130:1042-8",
"A Federico, S Bianchi, MT Dotti. The spectrum of mutations for CADASIL diagnosis.. Neurol Sci 2005;26:117-24",
"AM Forteza, B Brozman, AA Rabinstein, JG Romano, WG Bradley. Acetazolamide for the treatment of migraine with aura in CADASIL.. Neurology. 2001;57:2144-5",
"Y Fujiwara, T Mizuno, C Okuyama, Y Nagakane, A Watanabe-Hosomi, M Kondo, N Kuriyama, T Tokuda, S Matsushima, T Nishimura, M Nakagawa. Simultaneous impairment of intracranial and peripheral artery vasoreactivity in CADASILpatients.. Cerebrovasc Dis. 2012;33:128-34",
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"F Gray, M Polivka, A Viswanathan, M Baudrimont, MG Bousser, H Chabriat. Apoptosis in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy.. J Neuropathol Exp Neurol. 2007;66:597-607",
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"S Guey, J Mawet, D Hervé, M Duering, O Godin, E Jouvent, C Opherk, N Alili, M Dichgans, H Chabriat. Prevalence and characteristics of migraine in CADASIL.. Cephalalgia. 2016;36:1038-47",
"J Haan, SA Lesnik Oberstein, MD Ferrari. Epilepsy in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.. Cerebrovasc Dis. 2007;24:316-7",
"C Haritoglou, JP Hoops, FH Stefani, P Mehraein, A Kampik, M Dichgans. Histopathological abnormalities in ocular blood vessels of CADASIL patients.. Am J Ophthalmol. 2004;138:302-5",
"M Holtmannspötter, N Peters, C Opherk, D Martin, J Herzog, H Bruckmann, P Samann, A Gschwendtner, M Dichgans. Diffusion magnetic resonance histograms as a surrogate marker and predictor of disease progression in CADASIL: a two-year follow-up study.. Stroke 2005;36:2559-65",
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"JG Jung, A Stoeck, B Guan, RC Wu, H Zhu, S Blackshaw, I Shih, TL Wang. Notch3 Interactome Analysis Identified WWP2 as a Negative Regulator of Notch3 Signaling in Ovarian Cancer.. PLoS Genet 2014;10",
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"F Pescini, S Nannucci, B Bertaccini, E Salvadori, S Bianchi, M Ragno, C Sarti, R Valenti, E Zicari, M Moretti, S Chiti, ML Stromillo, SN De, MT Dotti, A Federico, D Inzitari, L Pantoni. The Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Scale: a screening tool to select patients for NOTCH3 gene analysis.. Stroke 2012;43:2871-6",
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"T Pfefferkorn, S von Stuckrad-Barre, J Herzog, T Gasser, GF Hamann, M Dichgans. Reduced cerebrovascular CO(2) reactivity in CADASIL: A transcranial Doppler sonography study.. Stroke 2001;32:17-21",
"G Piccirillo, D Magrì, M Mitra, A Rufa, E Zicari, ML Stromillo, N De Stefano, MT Dotti. Increased QT variability in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.. Eur J Neurol. 2008;15:1216-21",
"E Pretegiani, F Rosini, MT Dotti, S Bianchi, A Federico, A Rufa. Visual system involvement in CADASIL.. J Stroke Cerebrovasc Dis. 2013;22:1377-84",
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"M Ragno, A Berbellini, G Cacchiò, A Manca, F Di Marzio, L Pianese, A De Rosa, S Silvestri, M Scarcella, G De Michele. Parkinsonism is a late, not rare, feature of CADASIL: a study on Italian patients carrying the R1006C mutation.. Stroke. 2013;44:1147-9",
"M Ragno, L Trojano, L Pianese, MV Boni, S Silvestri, V Mambelli, T Lorenzi, M Scarpelli, M Morroni. Renal involvement in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): report of a case with a six-year follow-up.. Histol Histopathol. 2012;27:1307-14",
"SS Razvi, R Davidson, I Bone, KW Muir. Is inadequate family history a barrier to diagnosis in CADASIL?. Acta Neurol Scand 2005a;112:323-6",
"SS Razvi, R Davidson, I Bone, KW Muir. The prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the west of Scotland.. J Neurol Neurosurg Psychiatry 2005b;76:739-41",
"S Reyes, A Viswanathan, O Godin, C Dufouil, S Benisty, K Hernandez, A Kurtz, E Jouvent, M O'Sullivan, V Czernecki, MG Bousser, M Dichgans, H Chabriat. Apathy: a major symptom in CADASIL.. Neurology 2009;72:905-10",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"S Roine, M Poyhonen, S Timonen, S Tuisku, R Marttila, R Sulkava, H Kalimo, M Viitanen. Neurologic symptoms are common during gestation and puerperium in CADASIL.. Neurology 2005;64:1441-3",
"MM Ruchoux, CA Maurage. CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.. J Neuropathol Exp Neurol 1997;56:947-64",
"A Rufa, F Guideri, M Acampa, G Cevenini, S Bianchi, N De Stefano, ML Stromillo, A Federico, MT Dotti. Cardiac autonomic nervous system and risk of arrhythmias in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).. Stroke. 2007;38:276-80",
"JW Rutten, EM Boon, MK Liem, JG Dauwerse, MJ Pont, E Vollebregt, AJ Maat-Kievit, HB Ginjaar, P Lakeman, SG van Duinen, GM Terwindt, SA Lesnik Oberstein. Hypomorphic NOTCH3 alleles do not cause CADASIL in humans.. Hum Mutat 2013;34:1486-9",
"JW Rutten, HG Dauwerse, G Gravesteijn, MJ van Belzen, J van der Grond, JM Polke, M Bernal-Quiros, SA Lesnik Oberstein. Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL.. Ann Clin Transl Neurol. 2016a;3:844-53",
"JW Rutten, HG Dauwerse, DJ Peters, A Goldfarb, H Venselaar, C Haffner, GJ van Ommen, AM Aartsma-Rus, SA Lesnik Oberstein. Therapeutic NOTCH3 cysteine correction in CADASIL using exon skipping: in vitro proof of concept.. Brain. 2016b;139:1123-35",
"JW Rutten, J Haan, GM Terwindt, SG van Duinen, EM Boon, SA Lesnik Oberstein. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL.. Expert Rev Mol Diagn. 2014;14:593-603",
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] |
15/3/2000
|
14/3/2019
|
14/7/2016
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
caffey
|
caffey
|
[
"Infantile Cortical Hyperostosis",
"Infantile Cortical Hyperostosis",
"Collagen alpha-1(I) chain",
"COL1A1",
"Caffey Disease"
] |
Caffey Disease
|
Andrea Guerin, Lucie Dupuis, Roberto Mendoza-Londono
|
Summary Caffey disease is characterized by massive subperiosteal new bone formation (usually involving the diaphyses of the long bones as well as the ribs, mandible, scapulae, and clavicles) typically associated with fever, soft-tissue swelling, and pain, with onset between birth and five months and spontaneous resolution by age two years. Recurrence of bone hyperostosis, fever, soft-tissue swelling, and pain can occur later in life. Adults with a history of Caffey disease in childhood may have joint laxity, skin hyperextensibility, hernias, short stature, and an increased risk for bone fractures and/or deformities. The diagnosis of Caffey disease is established in a proband with typical clinical and radiographic findings; identification of a heterozygous Caffey disease is inherited in an autosomal dominant manner. Some individuals diagnosed with Caffey disease have a parent who had Caffey disease in childhood; others have the disorder as the result of a
|
## Diagnosis
No consensus clinical diagnostic criteria for Caffey disease have been published.
Caffey disease
Irritability, fever, and/or pallor
Soft-tissue swelling and pain adjacent to involved bones (See
Subperiosteal cortical hyperostosis of the diaphyses of the long bones (with sparing of the epiphyses)
Subperiosteal cortical hyperostosis of the ribs, scapulae, clavicles, and mandible (See
Serum biochemical markers of inflammation (white blood cell count, erythrocyte sedimentation rate, C-reactive protein) have been elevated a few affected individuals [
Alkaline phosphatase may be elevated.
The diagnosis of Caffey disease
Molecular genetic testing approaches can include a combination of
When the phenotypic and laboratory findings suggest the diagnosis of Caffey disease, molecular genetic testing approaches can include
Note: To date, no large multiexon
For an introduction to multigene panels click
When the diagnosis of Caffey disease is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Caffey Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date, no large intragenic deletions/duplications have been reported in individuals with Caffey disease.
One individual with clinical and radiographic features of Caffey disease did not have an identified
• Irritability, fever, and/or pallor
• Soft-tissue swelling and pain adjacent to involved bones (See
• Subperiosteal cortical hyperostosis of the diaphyses of the long bones (with sparing of the epiphyses)
• Subperiosteal cortical hyperostosis of the ribs, scapulae, clavicles, and mandible (See
• Serum biochemical markers of inflammation (white blood cell count, erythrocyte sedimentation rate, C-reactive protein) have been elevated a few affected individuals [
• Alkaline phosphatase may be elevated.
• Note: To date, no large multiexon
• For an introduction to multigene panels click
## Suggestive Findings
Caffey disease
Irritability, fever, and/or pallor
Soft-tissue swelling and pain adjacent to involved bones (See
Subperiosteal cortical hyperostosis of the diaphyses of the long bones (with sparing of the epiphyses)
Subperiosteal cortical hyperostosis of the ribs, scapulae, clavicles, and mandible (See
Serum biochemical markers of inflammation (white blood cell count, erythrocyte sedimentation rate, C-reactive protein) have been elevated a few affected individuals [
Alkaline phosphatase may be elevated.
• Irritability, fever, and/or pallor
• Soft-tissue swelling and pain adjacent to involved bones (See
• Subperiosteal cortical hyperostosis of the diaphyses of the long bones (with sparing of the epiphyses)
• Subperiosteal cortical hyperostosis of the ribs, scapulae, clavicles, and mandible (See
• Serum biochemical markers of inflammation (white blood cell count, erythrocyte sedimentation rate, C-reactive protein) have been elevated a few affected individuals [
• Alkaline phosphatase may be elevated.
## Establishing the Diagnosis
The diagnosis of Caffey disease
Molecular genetic testing approaches can include a combination of
When the phenotypic and laboratory findings suggest the diagnosis of Caffey disease, molecular genetic testing approaches can include
Note: To date, no large multiexon
For an introduction to multigene panels click
When the diagnosis of Caffey disease is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Caffey Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date, no large intragenic deletions/duplications have been reported in individuals with Caffey disease.
One individual with clinical and radiographic features of Caffey disease did not have an identified
• Note: To date, no large multiexon
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of Caffey disease, molecular genetic testing approaches can include
Note: To date, no large multiexon
For an introduction to multigene panels click
• Note: To date, no large multiexon
• For an introduction to multigene panels click
## Option 2
When the diagnosis of Caffey disease is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Caffey Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date, no large intragenic deletions/duplications have been reported in individuals with Caffey disease.
One individual with clinical and radiographic features of Caffey disease did not have an identified
## Clinical Characteristics
Caffey disease is characterized by massive subperiosteal new bone formation (hyperostosis) usually involving the diaphyses of the long bones, as well as the ribs, mandible, scapulae, and clavicles [
Hyperostosis can also involve the ribs, mandible, scapulae, and clavicles. The hyperostosis resolves before age two years [
Tumoral calcinosis (1 individual); thought to be due to constant remodeling after repeated inflammatory events [
Anemia (1 individual) [
Thrombocytosis (1 individual) [
There are no known genotype-phenotype correlations.
Reduced penetrance based on family history or molecular genetic testing has been reported [
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
"Prenatal lethal forms of hyperostosis," also referred to as "prenatal Caffey disease" or "Caffey dysplasia" [
The number of clinical reports of Caffey disease described to date is no more than a few hundred; however, given the spontaneous resolution of this condition in early childhood, it is likely underdiagnosed.
• Tumoral calcinosis (1 individual); thought to be due to constant remodeling after repeated inflammatory events [
• Anemia (1 individual) [
• Thrombocytosis (1 individual) [
## Clinical Description
Caffey disease is characterized by massive subperiosteal new bone formation (hyperostosis) usually involving the diaphyses of the long bones, as well as the ribs, mandible, scapulae, and clavicles [
Hyperostosis can also involve the ribs, mandible, scapulae, and clavicles. The hyperostosis resolves before age two years [
Tumoral calcinosis (1 individual); thought to be due to constant remodeling after repeated inflammatory events [
Anemia (1 individual) [
Thrombocytosis (1 individual) [
• Tumoral calcinosis (1 individual); thought to be due to constant remodeling after repeated inflammatory events [
• Anemia (1 individual) [
• Thrombocytosis (1 individual) [
## Genotype-Phenotype Correlations
There are no known genotype-phenotype correlations.
## Penetrance
Reduced penetrance based on family history or molecular genetic testing has been reported [
## Nomenclature
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
"Prenatal lethal forms of hyperostosis," also referred to as "prenatal Caffey disease" or "Caffey dysplasia" [
## Prevalence
The number of clinical reports of Caffey disease described to date is no more than a few hundred; however, given the spontaneous resolution of this condition in early childhood, it is likely underdiagnosed.
## Genetically Related (Allelic) Disorders
Other phenotypes known to be associated with germline pathogenic variants in
EDS = Ehlers-Danlos syndrome; OI = osteogenesis imperfecta
## Differential Diagnosis
Other genetic and acquired conditions may manifest as joint swelling and hyperostosis and thus need to be distinguished from Caffey disease.
Genes of Interest in the Differential Diagnosis of Caffey Disease
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
## Management
No clinical practice guidelines for Caffey disease have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.
To establish the extent of disease and needs in an individual diagnosed with Caffey disease, the evaluations summarized in
Caffey Disease: Recommended Evaluations Following Initial Diagnosis
Assess for pain & extremity swelling.
Radiographs of long bones, ribs, scapulae, clavicles, & mandible to assess extent of disease & stage of hyperostosis
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Caffey Disease: Treatment of Manifestations
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Caffey Disease: Recommended Surveillance
DXA = dual-energy x-ray absorptiometry
See
Search
• Assess for pain & extremity swelling.
• Radiographs of long bones, ribs, scapulae, clavicles, & mandible to assess extent of disease & stage of hyperostosis
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Caffey disease, the evaluations summarized in
Caffey Disease: Recommended Evaluations Following Initial Diagnosis
Assess for pain & extremity swelling.
Radiographs of long bones, ribs, scapulae, clavicles, & mandible to assess extent of disease & stage of hyperostosis
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Assess for pain & extremity swelling.
• Radiographs of long bones, ribs, scapulae, clavicles, & mandible to assess extent of disease & stage of hyperostosis
## Treatment of Manifestations
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Caffey Disease: Treatment of Manifestations
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Caffey Disease: Recommended Surveillance
DXA = dual-energy x-ray absorptiometry
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Caffey disease is inherited in an autosomal dominant manner.
Some individuals diagnosed with Caffey disease have a parent who had Caffey disease in childhood.
An individual diagnosed with Caffey disease may have the disorder as the result of a
If the proband appears to be the only family member with Caffey disease (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include molecular genetic testing (if a molecular diagnosis has been established in the proband) and a detailed medical history focusing on features of hyperostosis in infancy and current bone health.
If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
The family history of some individuals diagnosed with Caffey disease may appear to be negative because of failure to recognize or remember the occurrence of the disorder in family members or because of reduced penetrance in a parent. Therefore, an apparently negative family history cannot be confirmed unless a molecular diagnosis has been established in the proband and molecular genetic testing has established that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband had Caffey disease in childhood and/or is known to have a Caffey disease-related pathogenic variant, the risk to the sibs is 50%.
If the proband has a known Caffey disease-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism [
If the genetic status of the parents has not been established but neither parent is known to have had Caffey disease in childhood, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for Caffey disease because of the possibility of reduced penetrance in a parent or parental germline mosaicism.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who were affected as children.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Some individuals diagnosed with Caffey disease have a parent who had Caffey disease in childhood.
• An individual diagnosed with Caffey disease may have the disorder as the result of a
• If the proband appears to be the only family member with Caffey disease (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include molecular genetic testing (if a molecular diagnosis has been established in the proband) and a detailed medical history focusing on features of hyperostosis in infancy and current bone health.
• If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The family history of some individuals diagnosed with Caffey disease may appear to be negative because of failure to recognize or remember the occurrence of the disorder in family members or because of reduced penetrance in a parent. Therefore, an apparently negative family history cannot be confirmed unless a molecular diagnosis has been established in the proband and molecular genetic testing has established that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a parent of the proband had Caffey disease in childhood and/or is known to have a Caffey disease-related pathogenic variant, the risk to the sibs is 50%.
• If the proband has a known Caffey disease-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism [
• If the genetic status of the parents has not been established but neither parent is known to have had Caffey disease in childhood, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for Caffey disease because of the possibility of reduced penetrance in a parent or parental germline mosaicism.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who were affected as children.
## Mode of Inheritance
Caffey disease is inherited in an autosomal dominant manner.
## Risk to Family Members
Some individuals diagnosed with Caffey disease have a parent who had Caffey disease in childhood.
An individual diagnosed with Caffey disease may have the disorder as the result of a
If the proband appears to be the only family member with Caffey disease (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include molecular genetic testing (if a molecular diagnosis has been established in the proband) and a detailed medical history focusing on features of hyperostosis in infancy and current bone health.
If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
The family history of some individuals diagnosed with Caffey disease may appear to be negative because of failure to recognize or remember the occurrence of the disorder in family members or because of reduced penetrance in a parent. Therefore, an apparently negative family history cannot be confirmed unless a molecular diagnosis has been established in the proband and molecular genetic testing has established that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband had Caffey disease in childhood and/or is known to have a Caffey disease-related pathogenic variant, the risk to the sibs is 50%.
If the proband has a known Caffey disease-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism [
If the genetic status of the parents has not been established but neither parent is known to have had Caffey disease in childhood, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for Caffey disease because of the possibility of reduced penetrance in a parent or parental germline mosaicism.
• Some individuals diagnosed with Caffey disease have a parent who had Caffey disease in childhood.
• An individual diagnosed with Caffey disease may have the disorder as the result of a
• If the proband appears to be the only family member with Caffey disease (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include molecular genetic testing (if a molecular diagnosis has been established in the proband) and a detailed medical history focusing on features of hyperostosis in infancy and current bone health.
• If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The family history of some individuals diagnosed with Caffey disease may appear to be negative because of failure to recognize or remember the occurrence of the disorder in family members or because of reduced penetrance in a parent. Therefore, an apparently negative family history cannot be confirmed unless a molecular diagnosis has been established in the proband and molecular genetic testing has established that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a parent of the proband had Caffey disease in childhood and/or is known to have a Caffey disease-related pathogenic variant, the risk to the sibs is 50%.
• If the proband has a known Caffey disease-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism [
• If the genetic status of the parents has not been established but neither parent is known to have had Caffey disease in childhood, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for Caffey disease because of the possibility of reduced penetrance in a parent or parental germline mosaicism.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who were affected as children.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who were affected as children.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
Caffey Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Caffey Disease (
Both
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions.
## Molecular Pathogenesis
Both
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions.
## Chapter Notes
The authors would like to acknowledge the patients and families who allowed the use of photographs in this review.
23 May 2024 (sw) Comprehensive update posted live
13 June 2019 (ha) Comprehensive update posted live
2 August 2012 (me) Review posted live
17 February 2012 (ag) Original submission
• 23 May 2024 (sw) Comprehensive update posted live
• 13 June 2019 (ha) Comprehensive update posted live
• 2 August 2012 (me) Review posted live
• 17 February 2012 (ag) Original submission
## Author History
## Revision History
23 May 2024 (sw) Comprehensive update posted live
13 June 2019 (ha) Comprehensive update posted live
2 August 2012 (me) Review posted live
17 February 2012 (ag) Original submission
• 23 May 2024 (sw) Comprehensive update posted live
• 13 June 2019 (ha) Comprehensive update posted live
• 2 August 2012 (me) Review posted live
• 17 February 2012 (ag) Original submission
## References
## Literature Cited
Skeletal survey in a female age five weeks with
Note widespread involvement with (a) symmetric bilateral periosteal reaction involving the mandible and clavicles; and asymmetric involvement of (b) the humerus, proximal shaft of the radius, and distal shaft of the ulna; and of (c, d) the tibia and fibula.
Arrows point to significant subperiosteal thickening and bowing. Asymmetric reactions of the iliac bones, femora, tibiae, and left fibula were also noted (not shown). Symptoms resolved within a month of onset.
Clinical photograph and radiograph of male age two months with
Arrows denote the area of swelling on clinical examination and the subperiosteal reaction of the right tibia observed on lower extremity radiograph. Skeletal survey at presentation also revealed bilateral involvement of the clavicles, radii, and ulnae. Clinical symptoms resolved within a month of onset and periosteal changes remodelled over a period of one year.
|
[] |
2/8/2012
|
23/5/2024
|
29/11/2012
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cah
|
cah
|
[
"21-OHD CAH",
"Virilizing Adrenal Hyperplasia",
"Virilizing Adrenal Hyperplasia",
"21-OHD CAH",
"Classic Simple Virilizing 21-OHD CAH",
"Classic Salt-Wasting 21-OHD CAH",
"Non-Classic 21-OHD CAH",
"Steroid 21-hydroxylase",
"CYP21A2",
"21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia"
] |
21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia
|
Saroj Nimkarn, Prasanna K Gangishetti, Mabel Yau, Maria I New
|
Summary 21-hydroxylase deficiency (21-OHD) is the most common cause of congenital adrenal hyperplasia (CAH), a family of autosomal recessive disorders involving impaired synthesis of cortisol from cholesterol by the adrenal cortex. In 21-OHD CAH, excessive adrenal androgen biosynthesis results in virilization in all individuals and salt wasting in some individuals. A classic form with severe enzyme deficiency and prenatal onset of virilization is distinguished from a non-classic form with mild enzyme deficiency and postnatal onset. The classic form is further divided into the simple virilizing form (~25% of affected individuals) and the salt-wasting form, in which aldosterone production is inadequate (≥75% of individuals). Newborns with salt-wasting 21-OHD CAH are at risk for life-threatening salt-wasting crises. Individuals with the non-classic form of 21-OHD CAH present postnatally with signs of hyperandrogenism; females with the non-classic form are not virilized at birth. The diagnosis of classic 21-OHD CAH is established in newborns with characteristic clinical features, elevated serum 17-OHP, and elevated adrenal androgens. The diagnosis of non-classic 21-OHD is established by comparison of baseline serum 17-OHP and ACTH-stimulated serum 17-OHP or early morning elevated 17-OHP. Identification of biallelic pathogenic variants in Efficacy of glucocorticoid and mineralocorticoid replacement therapy every three to four months while children are actively growing, and less often thereafter; For testicular adrenal rest tumors in males every three to five years after onset of puberty; Weight, bone mineral density, fertility, cardiovascular and metabolic risks in adults. 21-OHD CAH is inherited in an autosomal recessive manner. Most parents are heterozygous for a pathogenic variant. Approximately 1% of pathogenic variants are
|
Classic simple virilizing 21-OHD CAH
Classic salt-wasting 21-OHD CAH
Non-classic 21-OHD CAH
For synonyms and outdated names see
• Classic simple virilizing 21-OHD CAH
• Classic salt-wasting 21-OHD CAH
• Non-classic 21-OHD CAH
## Diagnosis
21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH)
Females who are virilized at birth, or who become virilized postnatally, or who have precocious puberty or adrenarche. Virilization affects maturation, growth (leading to tall stature), and sex hormone-sensitive areas (external genitalia, skin, and hair) (leading to secondary sexual characteristics).
Males with masculinization in childhood (i.e., premature adrenarche)
Any infant with a salt-losing crisis in the first four weeks of life. Individuals with untreated or poorly controlled salt wasting may have a decreased serum concentration of sodium, chloride, and total carbon dioxide (CO
An infant with elevated 17-OHP concentration detected as positive newborn screening
Note: Females with 21-OHD CAH have a normal 46,XX karyotype; males with 21-OHD CAH have a normal 46,XY karyotype.
Newborn screening for 21-OHD CAH serves two purposes:
To identify infants, especially males, with the classic form of 21-OHD CAH who are at risk for life-threatening salt-wasting crises
To expedite the diagnosis of females with ambiguous genitalia
Note: Newborn screening rarely detects individuals with the non-classic form of 21-OHD CAH [
As with newborn screening for other disorders, the concentration of 17-OHP is measured on a filter paper blood spot sample obtained by the heel-stick technique.
The majority of screening programs use a single screening test without retesting of samples with questionable 17-OHP concentrations. See
To improve efficacy of screening, some screening programs reevaluate samples with borderline first-tier test results with a second-tier test and some implement repeat screening in this situation [
Note: (1) Results on blood samples taken in the first 24 hours of life are elevated in all infants and may give false-positive results. (2) False-positive results may also be observed in low birth-weight infants or premature infants. Therefore, birth weight- or gestational age-adjusted normative data is used to determine if a test result is screen positive. (3) False-negative results may be observed in neonates receiving dexamethasone for management of unrelated problems.
Note: In individuals with the salt-wasting form of 21-OHD CAH, the serum concentration of aldosterone is inappropriately low compared to the level of plasma renin activity (PRA) elevation. A reduced ratio of aldosterone to PRA indicates impaired aldosterone synthesis and can differentiate those individuals with the salt-wasting form of CAH from those with the simple virilizing form of CAH after the newborn period [
Note: Normal ranges of 17-OHP for sex and pubertal status vary by laboratory, reflecting the methods used. In adult females, normal ranges depend on the phase of the menstrual cycle.
Diagnosis of 21-OHD CAH after Infancy Based on 17 OHP Levels
Modified from
Randomly measured 17-OHP can be normal in the non-classic form.
Note: A large-scale gene conversion (see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
The majority of individuals from heterogeneous populations with 21-OHD CAH are compound heterozygotes [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Approximately 20% of mutated alleles are deleted for a 30-kb gene segment that encompasses the 3' end of the
• Females who are virilized at birth, or who become virilized postnatally, or who have precocious puberty or adrenarche. Virilization affects maturation, growth (leading to tall stature), and sex hormone-sensitive areas (external genitalia, skin, and hair) (leading to secondary sexual characteristics).
• Males with masculinization in childhood (i.e., premature adrenarche)
• Any infant with a salt-losing crisis in the first four weeks of life. Individuals with untreated or poorly controlled salt wasting may have a decreased serum concentration of sodium, chloride, and total carbon dioxide (CO
• An infant with elevated 17-OHP concentration detected as positive newborn screening
• To identify infants, especially males, with the classic form of 21-OHD CAH who are at risk for life-threatening salt-wasting crises
• To expedite the diagnosis of females with ambiguous genitalia
• The majority of screening programs use a single screening test without retesting of samples with questionable 17-OHP concentrations. See
• To improve efficacy of screening, some screening programs reevaluate samples with borderline first-tier test results with a second-tier test and some implement repeat screening in this situation [
• Note: In individuals with the salt-wasting form of 21-OHD CAH, the serum concentration of aldosterone is inappropriately low compared to the level of plasma renin activity (PRA) elevation. A reduced ratio of aldosterone to PRA indicates impaired aldosterone synthesis and can differentiate those individuals with the salt-wasting form of CAH from those with the simple virilizing form of CAH after the newborn period [
• Note: Normal ranges of 17-OHP for sex and pubertal status vary by laboratory, reflecting the methods used. In adult females, normal ranges depend on the phase of the menstrual cycle.
• Note: A large-scale gene conversion (see
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH)
Females who are virilized at birth, or who become virilized postnatally, or who have precocious puberty or adrenarche. Virilization affects maturation, growth (leading to tall stature), and sex hormone-sensitive areas (external genitalia, skin, and hair) (leading to secondary sexual characteristics).
Males with masculinization in childhood (i.e., premature adrenarche)
Any infant with a salt-losing crisis in the first four weeks of life. Individuals with untreated or poorly controlled salt wasting may have a decreased serum concentration of sodium, chloride, and total carbon dioxide (CO
An infant with elevated 17-OHP concentration detected as positive newborn screening
Note: Females with 21-OHD CAH have a normal 46,XX karyotype; males with 21-OHD CAH have a normal 46,XY karyotype.
Newborn screening for 21-OHD CAH serves two purposes:
To identify infants, especially males, with the classic form of 21-OHD CAH who are at risk for life-threatening salt-wasting crises
To expedite the diagnosis of females with ambiguous genitalia
Note: Newborn screening rarely detects individuals with the non-classic form of 21-OHD CAH [
As with newborn screening for other disorders, the concentration of 17-OHP is measured on a filter paper blood spot sample obtained by the heel-stick technique.
The majority of screening programs use a single screening test without retesting of samples with questionable 17-OHP concentrations. See
To improve efficacy of screening, some screening programs reevaluate samples with borderline first-tier test results with a second-tier test and some implement repeat screening in this situation [
Note: (1) Results on blood samples taken in the first 24 hours of life are elevated in all infants and may give false-positive results. (2) False-positive results may also be observed in low birth-weight infants or premature infants. Therefore, birth weight- or gestational age-adjusted normative data is used to determine if a test result is screen positive. (3) False-negative results may be observed in neonates receiving dexamethasone for management of unrelated problems.
• Females who are virilized at birth, or who become virilized postnatally, or who have precocious puberty or adrenarche. Virilization affects maturation, growth (leading to tall stature), and sex hormone-sensitive areas (external genitalia, skin, and hair) (leading to secondary sexual characteristics).
• Males with masculinization in childhood (i.e., premature adrenarche)
• Any infant with a salt-losing crisis in the first four weeks of life. Individuals with untreated or poorly controlled salt wasting may have a decreased serum concentration of sodium, chloride, and total carbon dioxide (CO
• An infant with elevated 17-OHP concentration detected as positive newborn screening
• To identify infants, especially males, with the classic form of 21-OHD CAH who are at risk for life-threatening salt-wasting crises
• To expedite the diagnosis of females with ambiguous genitalia
• The majority of screening programs use a single screening test without retesting of samples with questionable 17-OHP concentrations. See
• To improve efficacy of screening, some screening programs reevaluate samples with borderline first-tier test results with a second-tier test and some implement repeat screening in this situation [
## Newborn Screening
Newborn screening for 21-OHD CAH serves two purposes:
To identify infants, especially males, with the classic form of 21-OHD CAH who are at risk for life-threatening salt-wasting crises
To expedite the diagnosis of females with ambiguous genitalia
Note: Newborn screening rarely detects individuals with the non-classic form of 21-OHD CAH [
As with newborn screening for other disorders, the concentration of 17-OHP is measured on a filter paper blood spot sample obtained by the heel-stick technique.
The majority of screening programs use a single screening test without retesting of samples with questionable 17-OHP concentrations. See
To improve efficacy of screening, some screening programs reevaluate samples with borderline first-tier test results with a second-tier test and some implement repeat screening in this situation [
Note: (1) Results on blood samples taken in the first 24 hours of life are elevated in all infants and may give false-positive results. (2) False-positive results may also be observed in low birth-weight infants or premature infants. Therefore, birth weight- or gestational age-adjusted normative data is used to determine if a test result is screen positive. (3) False-negative results may be observed in neonates receiving dexamethasone for management of unrelated problems.
• To identify infants, especially males, with the classic form of 21-OHD CAH who are at risk for life-threatening salt-wasting crises
• To expedite the diagnosis of females with ambiguous genitalia
• The majority of screening programs use a single screening test without retesting of samples with questionable 17-OHP concentrations. See
• To improve efficacy of screening, some screening programs reevaluate samples with borderline first-tier test results with a second-tier test and some implement repeat screening in this situation [
## Establishing the Diagnosis
Note: In individuals with the salt-wasting form of 21-OHD CAH, the serum concentration of aldosterone is inappropriately low compared to the level of plasma renin activity (PRA) elevation. A reduced ratio of aldosterone to PRA indicates impaired aldosterone synthesis and can differentiate those individuals with the salt-wasting form of CAH from those with the simple virilizing form of CAH after the newborn period [
Note: Normal ranges of 17-OHP for sex and pubertal status vary by laboratory, reflecting the methods used. In adult females, normal ranges depend on the phase of the menstrual cycle.
Diagnosis of 21-OHD CAH after Infancy Based on 17 OHP Levels
Modified from
Randomly measured 17-OHP can be normal in the non-classic form.
Note: A large-scale gene conversion (see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
The majority of individuals from heterogeneous populations with 21-OHD CAH are compound heterozygotes [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Approximately 20% of mutated alleles are deleted for a 30-kb gene segment that encompasses the 3' end of the
• Note: In individuals with the salt-wasting form of 21-OHD CAH, the serum concentration of aldosterone is inappropriately low compared to the level of plasma renin activity (PRA) elevation. A reduced ratio of aldosterone to PRA indicates impaired aldosterone synthesis and can differentiate those individuals with the salt-wasting form of CAH from those with the simple virilizing form of CAH after the newborn period [
• Note: Normal ranges of 17-OHP for sex and pubertal status vary by laboratory, reflecting the methods used. In adult females, normal ranges depend on the phase of the menstrual cycle.
• Note: A large-scale gene conversion (see
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH) occurs in a classic form and a non-classic form (
In classic 21-OHD CAH prenatal exposure to potent androgens such as testosterone and Δ
Individuals with the non-classic form of 21-OHD CAH have only moderate enzyme deficiency and present postnatally with signs of hyperandrogenism; females with the non-classic form are not virilized at birth.
Clinical Features in Individuals with Classic and Non-Classic 21-OHD CAH
After birth, both females and males with classic simple virilizing 21-OHD CAH who do not receive glucocorticoid replacement therapy develop signs of androgen excess including precocious development of pubic and axillary hair, acne, rapid linear growth, and advanced bone age. Untreated males have progressive penile enlargement and small testes. Untreated females have clitoral enlargement, hirsutism, male pattern baldness, menstrual abnormalities, and reduced fertility.
The initial growth in the young child with untreated 21-OHD CAH is rapid; however, potential height is reduced and short adult stature results from premature epiphyseal fusion. Even if treatment with cortisol replacement therapy begins at an early age and secretion of excess adrenal androgens is controlled, individuals with 21-OHD CAH do not generally achieve the expected adult height. Bone age may be advanced compared to chronologic age.
It should be noted that in some previously untreated children, the start of glucocorticoid replacement therapy triggers true precocious puberty. This central precocious puberty may occur when glucocorticoid treatment releases the hypothalamic pituitary axis from inhibition by estrogens derived from excess adrenal androgen secretion.
In males, the main cause of subfertility is the presence of testicular adrenal rest tumors, which are thought to originate from aberrant adrenal tissue. In addition, hypogonadotropic hypogonadism may result from suppression of LH secretion by the pituitary by excessive adrenal androgens and their aromatization products [
Affected males who are not detected in a newborn screening program are at high risk for a salt-wasting adrenal crisis because their normal male genitalia do not alert medical professionals to their condition; they are often discharged from the hospital after birth without diagnosis and experience a salt-wasting crisis at home. Conversely, the ambiguous genitalia of females with the salt-wasting form usually prompts early diagnosis and treatment.
Although an overt salt-wasting crisis classifies the child as a salt waster, some degree of aldosterone deficiency, determined by the adrenal capacity to produce aldosterone in response to renin stimulation, was found in all forms of 21-OHD CAH [
Non-classic 21-OHD CAH may present at any time postnatally, with symptoms of androgen excess including acne, premature development of pubic hair, accelerated growth, advanced bone age, and as in classic 21-OHD CAH, reduced adult stature as a result of premature epiphyseal fusion [
The rates of bisexual and homosexual orientation, which were increased in women with all forms of 21-OHD CAH, were found to correlate with the degree of prenatal androgenization. Bisexual/homosexual orientation was correlated with global measures of masculinization of nonsexual behavior and predicted independently by the degree of both prenatal androgenization and masculinization of childhood behavior [
In contrast, males with 21-OHD CAH do not show a general alteration in childhood play behavior, core gender identity, or sexual orientation [
The lack of steroid product impairs the negative feedback control of adrenocorticotropin (ACTH) secretion from the pituitary, leading to chronic stimulation of the adrenal cortex by ACTH, resulting in adrenal hyperplasia.
A study by
Alleles can be grouped as severe or mild, based on residual enzyme activity (
Salt-wasting 21-OHD CAH usually has the most severe pathogenic variants (e.g., homozygous deletions).
Non-classic 21-OHD CAH usually has one mild allele or both mild alleles.
In the context of prenatal diagnosis, it is important to distinguish classic and non-classic genotypes in order to determine the need to offer prenatal treatment.
In families in which the proband is a virilized female, predicting the risk of genital virilization in subsequent affected female fetuses is feasible.
In families in which the proband is a male, predicting the risk of genital virilization in subsequent affected female fetuses based on genotype is less reliable.
Note: The single-nucleotide variants
Among affected individuals who were compound heterozygotes for the pathogenic single-nucleotide variant
In a small number (<3%) of affected individuals with the p.Val282Leu or p.Pro31Leu pathogenic variant and a severe variant, the classic phenotype was observed when a non-classic phenotype was expected.
In a very small percentage of affected individuals with the
Grouping of Common
From
Minimal residual activity
Terms used in the past for 21-OHD CAH include adrenogenital syndrome (AG syndrome) and congenital adrenocortical hyperplasia.
The non-classic form of 21-OHD CAH was previously referred to as the "attenuated" or "late-onset" form.
The salt-wasting form of 21-OHD CAH has also been called "salt-losing CAH."
Prevalence in specific populations:
1:300 in Yup'ik Eskimos of Alaska
1:5,000 in Saudi Arabia
1:10,000-1:16,000 in Europe and North America
1:21,000 in Japan
1:23,000 in New Zealand
• Salt-wasting 21-OHD CAH usually has the most severe pathogenic variants (e.g., homozygous deletions).
• Non-classic 21-OHD CAH usually has one mild allele or both mild alleles.
• In families in which the proband is a virilized female, predicting the risk of genital virilization in subsequent affected female fetuses is feasible.
• In families in which the proband is a male, predicting the risk of genital virilization in subsequent affected female fetuses based on genotype is less reliable.
• In a small number (<3%) of affected individuals with the p.Val282Leu or p.Pro31Leu pathogenic variant and a severe variant, the classic phenotype was observed when a non-classic phenotype was expected.
• In a very small percentage of affected individuals with the
• 1:300 in Yup'ik Eskimos of Alaska
• 1:5,000 in Saudi Arabia
• 1:10,000-1:16,000 in Europe and North America
• 1:21,000 in Japan
• 1:23,000 in New Zealand
## Clinical Description
21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH) occurs in a classic form and a non-classic form (
In classic 21-OHD CAH prenatal exposure to potent androgens such as testosterone and Δ
Individuals with the non-classic form of 21-OHD CAH have only moderate enzyme deficiency and present postnatally with signs of hyperandrogenism; females with the non-classic form are not virilized at birth.
Clinical Features in Individuals with Classic and Non-Classic 21-OHD CAH
After birth, both females and males with classic simple virilizing 21-OHD CAH who do not receive glucocorticoid replacement therapy develop signs of androgen excess including precocious development of pubic and axillary hair, acne, rapid linear growth, and advanced bone age. Untreated males have progressive penile enlargement and small testes. Untreated females have clitoral enlargement, hirsutism, male pattern baldness, menstrual abnormalities, and reduced fertility.
The initial growth in the young child with untreated 21-OHD CAH is rapid; however, potential height is reduced and short adult stature results from premature epiphyseal fusion. Even if treatment with cortisol replacement therapy begins at an early age and secretion of excess adrenal androgens is controlled, individuals with 21-OHD CAH do not generally achieve the expected adult height. Bone age may be advanced compared to chronologic age.
It should be noted that in some previously untreated children, the start of glucocorticoid replacement therapy triggers true precocious puberty. This central precocious puberty may occur when glucocorticoid treatment releases the hypothalamic pituitary axis from inhibition by estrogens derived from excess adrenal androgen secretion.
In males, the main cause of subfertility is the presence of testicular adrenal rest tumors, which are thought to originate from aberrant adrenal tissue. In addition, hypogonadotropic hypogonadism may result from suppression of LH secretion by the pituitary by excessive adrenal androgens and their aromatization products [
Affected males who are not detected in a newborn screening program are at high risk for a salt-wasting adrenal crisis because their normal male genitalia do not alert medical professionals to their condition; they are often discharged from the hospital after birth without diagnosis and experience a salt-wasting crisis at home. Conversely, the ambiguous genitalia of females with the salt-wasting form usually prompts early diagnosis and treatment.
Although an overt salt-wasting crisis classifies the child as a salt waster, some degree of aldosterone deficiency, determined by the adrenal capacity to produce aldosterone in response to renin stimulation, was found in all forms of 21-OHD CAH [
Non-classic 21-OHD CAH may present at any time postnatally, with symptoms of androgen excess including acne, premature development of pubic hair, accelerated growth, advanced bone age, and as in classic 21-OHD CAH, reduced adult stature as a result of premature epiphyseal fusion [
The rates of bisexual and homosexual orientation, which were increased in women with all forms of 21-OHD CAH, were found to correlate with the degree of prenatal androgenization. Bisexual/homosexual orientation was correlated with global measures of masculinization of nonsexual behavior and predicted independently by the degree of both prenatal androgenization and masculinization of childhood behavior [
In contrast, males with 21-OHD CAH do not show a general alteration in childhood play behavior, core gender identity, or sexual orientation [
The lack of steroid product impairs the negative feedback control of adrenocorticotropin (ACTH) secretion from the pituitary, leading to chronic stimulation of the adrenal cortex by ACTH, resulting in adrenal hyperplasia.
## Classic Simple Virilizing 21-OHD CAH
After birth, both females and males with classic simple virilizing 21-OHD CAH who do not receive glucocorticoid replacement therapy develop signs of androgen excess including precocious development of pubic and axillary hair, acne, rapid linear growth, and advanced bone age. Untreated males have progressive penile enlargement and small testes. Untreated females have clitoral enlargement, hirsutism, male pattern baldness, menstrual abnormalities, and reduced fertility.
The initial growth in the young child with untreated 21-OHD CAH is rapid; however, potential height is reduced and short adult stature results from premature epiphyseal fusion. Even if treatment with cortisol replacement therapy begins at an early age and secretion of excess adrenal androgens is controlled, individuals with 21-OHD CAH do not generally achieve the expected adult height. Bone age may be advanced compared to chronologic age.
It should be noted that in some previously untreated children, the start of glucocorticoid replacement therapy triggers true precocious puberty. This central precocious puberty may occur when glucocorticoid treatment releases the hypothalamic pituitary axis from inhibition by estrogens derived from excess adrenal androgen secretion.
In males, the main cause of subfertility is the presence of testicular adrenal rest tumors, which are thought to originate from aberrant adrenal tissue. In addition, hypogonadotropic hypogonadism may result from suppression of LH secretion by the pituitary by excessive adrenal androgens and their aromatization products [
Affected males who are not detected in a newborn screening program are at high risk for a salt-wasting adrenal crisis because their normal male genitalia do not alert medical professionals to their condition; they are often discharged from the hospital after birth without diagnosis and experience a salt-wasting crisis at home. Conversely, the ambiguous genitalia of females with the salt-wasting form usually prompts early diagnosis and treatment.
Although an overt salt-wasting crisis classifies the child as a salt waster, some degree of aldosterone deficiency, determined by the adrenal capacity to produce aldosterone in response to renin stimulation, was found in all forms of 21-OHD CAH [
## Non-Classic 21-OHD CAH
Non-classic 21-OHD CAH may present at any time postnatally, with symptoms of androgen excess including acne, premature development of pubic hair, accelerated growth, advanced bone age, and as in classic 21-OHD CAH, reduced adult stature as a result of premature epiphyseal fusion [
The rates of bisexual and homosexual orientation, which were increased in women with all forms of 21-OHD CAH, were found to correlate with the degree of prenatal androgenization. Bisexual/homosexual orientation was correlated with global measures of masculinization of nonsexual behavior and predicted independently by the degree of both prenatal androgenization and masculinization of childhood behavior [
In contrast, males with 21-OHD CAH do not show a general alteration in childhood play behavior, core gender identity, or sexual orientation [
The lack of steroid product impairs the negative feedback control of adrenocorticotropin (ACTH) secretion from the pituitary, leading to chronic stimulation of the adrenal cortex by ACTH, resulting in adrenal hyperplasia.
## Genotype-Phenotype Correlations
A study by
Alleles can be grouped as severe or mild, based on residual enzyme activity (
Salt-wasting 21-OHD CAH usually has the most severe pathogenic variants (e.g., homozygous deletions).
Non-classic 21-OHD CAH usually has one mild allele or both mild alleles.
In the context of prenatal diagnosis, it is important to distinguish classic and non-classic genotypes in order to determine the need to offer prenatal treatment.
In families in which the proband is a virilized female, predicting the risk of genital virilization in subsequent affected female fetuses is feasible.
In families in which the proband is a male, predicting the risk of genital virilization in subsequent affected female fetuses based on genotype is less reliable.
Note: The single-nucleotide variants
Among affected individuals who were compound heterozygotes for the pathogenic single-nucleotide variant
In a small number (<3%) of affected individuals with the p.Val282Leu or p.Pro31Leu pathogenic variant and a severe variant, the classic phenotype was observed when a non-classic phenotype was expected.
In a very small percentage of affected individuals with the
Grouping of Common
From
Minimal residual activity
• Salt-wasting 21-OHD CAH usually has the most severe pathogenic variants (e.g., homozygous deletions).
• Non-classic 21-OHD CAH usually has one mild allele or both mild alleles.
• In families in which the proband is a virilized female, predicting the risk of genital virilization in subsequent affected female fetuses is feasible.
• In families in which the proband is a male, predicting the risk of genital virilization in subsequent affected female fetuses based on genotype is less reliable.
• In a small number (<3%) of affected individuals with the p.Val282Leu or p.Pro31Leu pathogenic variant and a severe variant, the classic phenotype was observed when a non-classic phenotype was expected.
• In a very small percentage of affected individuals with the
## Nomenclature
Terms used in the past for 21-OHD CAH include adrenogenital syndrome (AG syndrome) and congenital adrenocortical hyperplasia.
The non-classic form of 21-OHD CAH was previously referred to as the "attenuated" or "late-onset" form.
The salt-wasting form of 21-OHD CAH has also been called "salt-losing CAH."
## Prevalence
Prevalence in specific populations:
1:300 in Yup'ik Eskimos of Alaska
1:5,000 in Saudi Arabia
1:10,000-1:16,000 in Europe and North America
1:21,000 in Japan
1:23,000 in New Zealand
• 1:300 in Yup'ik Eskimos of Alaska
• 1:5,000 in Saudi Arabia
• 1:10,000-1:16,000 in Europe and North America
• 1:21,000 in Japan
• 1:23,000 in New Zealand
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The production of cortisol in the
Enzyme Deficiencies Resulting in CAH
Unknown because of rarity of disease
Males undervirilized at birth
Associated with salt wasting
Associated with hypertension
Females virilized at birth or later
The phenotypic spectrum of cytochrome P450 oxidoreductase deficiency ranges from isolated steroid abnormalities to classic Antley-Bixler syndrome (ABS). Individuals with POR deficiency have cortisol deficiency, ranging from clinically insignificant to life threatening. Newborn males have ambiguous genitalia, including small penis and undescended testes; newborn females have vaginal atresia, fused labia minora, hypoplastic labia majora, and/or large clitoris. Craniofacial features of ABS, at the most severe end of the POR spectrum, can include craniosynostosis, choanal stenosis or atresia, stenotic external auditory canals, and hydrocephalus. Skeletal anomalies can include radiohumeral synostosis, neonatal fractures, congenital bowing of the long bones, camptodactyly, joint contractures, arachnodactyly, and clubfeet. Inheritance is autosomal recessive.
## Management
To establish the extent of disease and needs in an individual diagnosed with 21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH), the following evaluations are recommended:
Plasma renin activity (PRA)
Serum electrolytes
Baseline 17-OHP, Δ
ACTH stimulation test to compare stimulated concentration of 17-OHP to the baseline level
Careful physical examination of the external genitalia and its orifices
Vaginogram to assess the anatomy of urethra and vagina
Bone maturation assessment by bone age
Serum concentration of adrenal androgens (unconjugated dehydroepiandrosterone [DHEA], Δ
Consultation with a clinical geneticist and/or genetic counselor is recommended for those individuals with a new diagnosis of 21-OHD CAH.
Clinical practice guidelines for the treatment of individuals with congenital adrenal hyperplasia due to 21-hydroxylase deficiency have been published [
It is imperative to make the diagnosis of 21-OHD CAH as quickly as possible in order to initiate therapy and arrest the effects of cortisol deficiency and mineralocorticoid deficiency, if present.
A multidisciplinary team of specialists in pediatric endocrinology, pediatric urology/surgery, clinical genetics, and psychology is essential for the diagnosis and management of the individual with ambiguous genitalia [
Hydrocortisone in tablet form is the treatment of choice in growing children. The use of oral hydrocortisone suspension is discouraged. Treatment for CAH principally involves glucocorticoid replacement therapy, usually in the form of hydrocortisone (10-15 mg/m
Note: Overtreatment with glucocorticosteroids can result in cushingoid features and should be avoided. It often occurs when serum concentration of 17-OHP is reduced to the physiologic range for age. An acceptable range for serum concentration of 17-OHP in the treated individual is higher (100-1,000 ng/dL) than normal, provided androgens are maintained in an appropriate range for sex and pubertal status.
During periods of stress (e.g., surgery, febrile illness, shock, major trauma), all individuals with classic 21-OHD CAH require increased amounts of glucocorticoids. Typically, two to three times the normal dose is administered orally or by intramuscular injection when oral intake is not tolerated.
Affected individuals should carry medical information regarding emergency steroid dosing.
Individuals with classic 21-OHD CAH require lifelong administration of glucocorticoids. After linear growth is complete, more potent glucocorticoids (e.g., prednisone and dexamethasone) that tend to suppress growth in childhood can be used.
All individuals with the classic form should be treated with both 9α-fludrohydrocortisone and sodium chloride supplement in the newborn period and early infancy [
Sodium chloride supplementation may not be necessary after infancy; the amount of mineralocorticoid required daily may likewise decrease with age.
"Surgery should only be considered in cases of severe virilization (Prader III-V) and be performed in conjunction, when appropriate, with repair of the common urogenital sinus. Because orgasmic function and erectile sensation may be disturbed by clitoral surgery, the surgical procedure should be anatomically based to preserve erectile function and the innervation of the clitoris. Emphasis is on functional outcome rather than a strictly cosmetic appearance. It is generally felt that surgery that is performed for cosmetic reasons in the first year of life relieves parental distress and improves attachment between the child and the parents; the systematic evidence for this belief is lacking."
The Endocrine Society clinical practice guidelines [
"[C]litoral and perineal reconstruction [should] be considered in infancy and performed by an experienced surgeon in a center with similarly experienced pediatric endocrinologists, mental health professionals, and social work services."
Although there are no randomized controlled studies of either the best age or the best methods for feminizing surgery, the recommended procedures are neurovascular-sparing clitoroplasty and vaginoplasty using total or partial urogenital mobilization.
When necessary, vaginoplasty is usually performed in late adolescence because routine vaginal dilation is required to maintain a patent vagina.
Affected individuals were significantly shorter and had a higher body mass index.
Women with classic CAH had increased diastolic blood pressure.
Metabolic abnormalities were common among studied individuals, and included obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised.
Transition of pediatric individuals to medical care in the adult setting is an important step to ensure optimal lifelong treatment, aiming to achieve good health with a normal life expectancy and quality of life [
Only small series of adults undergoing adrenalectomy have been reported (see review in
Individuals with non-classic 21-OHD CAH do not always require treatment. Many are asymptomatic throughout their lives, or symptoms may develop during puberty, after puberty, or post partum.
The hyperandrogenic symptoms that require treatment include advanced bone age, early pubic hair, precocious puberty, tall stature, and early arrest of growth in children; infertility, cystic acne, and short stature in both adult males and females; hirsutism, frontal balding, polycystic ovaries, and irregular menstrual periods in females; and testicular adrenal rest tissue in males [
In previously treated individuals, an option of discontinuing therapy when symptoms resolve should be offered [
Traditionally, individuals with non-classic 21-OHD CAH have been treated with lower amounts of glucocorticoid than those required for individuals with classic 21-OHD CAH.
See
The following evaluations should be performed every three to four months when children are actively growing. Evaluation may be less often thereafter. The frequency of evaluation should vary depending on individual needs [
Early-morning serum concentrations of 17-OHP, Δ
Linear growth, weight gain, pubertal development, and clinical signs of cortisol and androgen excess
Bone age to assess osseous maturation (at 6- to 12-month intervals)
Blood pressure
Early morning plasma renin activity or direct renin assay in a controlled position (usually upright)
Fecundity and fertility
Weight
Lipid profile
Blood pressure
Bone mineral density
Physical stress such as febrile illness, gastroenteritis with dehydration, surgery accompanied by general anesthesia, and major trauma can precipitate an adrenal crisis in individuals with classic CAH. Increased doses of glucocorticoids are recommended in these situations.
If prenatal testing for 21-OHD CAH has not been performed, it is appropriate to evaluate newborn sibs of a proband in order to facilitate early diagnosis and treatment.
Serum 17-OHP concentration should be measured in addition to newborn screening.
Molecular genetic testing is indicated if the pathogenic variants in the family are known.
See
Search
• Plasma renin activity (PRA)
• Serum electrolytes
• Baseline 17-OHP, Δ
• ACTH stimulation test to compare stimulated concentration of 17-OHP to the baseline level
• Careful physical examination of the external genitalia and its orifices
• Vaginogram to assess the anatomy of urethra and vagina
• Bone maturation assessment by bone age
• Serum concentration of adrenal androgens (unconjugated dehydroepiandrosterone [DHEA], Δ
• Hydrocortisone in tablet form is the treatment of choice in growing children. The use of oral hydrocortisone suspension is discouraged. Treatment for CAH principally involves glucocorticoid replacement therapy, usually in the form of hydrocortisone (10-15 mg/m
• Note: Overtreatment with glucocorticosteroids can result in cushingoid features and should be avoided. It often occurs when serum concentration of 17-OHP is reduced to the physiologic range for age. An acceptable range for serum concentration of 17-OHP in the treated individual is higher (100-1,000 ng/dL) than normal, provided androgens are maintained in an appropriate range for sex and pubertal status.
• During periods of stress (e.g., surgery, febrile illness, shock, major trauma), all individuals with classic 21-OHD CAH require increased amounts of glucocorticoids. Typically, two to three times the normal dose is administered orally or by intramuscular injection when oral intake is not tolerated.
• Affected individuals should carry medical information regarding emergency steroid dosing.
• Individuals with classic 21-OHD CAH require lifelong administration of glucocorticoids. After linear growth is complete, more potent glucocorticoids (e.g., prednisone and dexamethasone) that tend to suppress growth in childhood can be used.
• All individuals with the classic form should be treated with both 9α-fludrohydrocortisone and sodium chloride supplement in the newborn period and early infancy [
• Sodium chloride supplementation may not be necessary after infancy; the amount of mineralocorticoid required daily may likewise decrease with age.
• Although there are no randomized controlled studies of either the best age or the best methods for feminizing surgery, the recommended procedures are neurovascular-sparing clitoroplasty and vaginoplasty using total or partial urogenital mobilization.
• When necessary, vaginoplasty is usually performed in late adolescence because routine vaginal dilation is required to maintain a patent vagina.
• Affected individuals were significantly shorter and had a higher body mass index.
• Women with classic CAH had increased diastolic blood pressure.
• Metabolic abnormalities were common among studied individuals, and included obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised.
• The hyperandrogenic symptoms that require treatment include advanced bone age, early pubic hair, precocious puberty, tall stature, and early arrest of growth in children; infertility, cystic acne, and short stature in both adult males and females; hirsutism, frontal balding, polycystic ovaries, and irregular menstrual periods in females; and testicular adrenal rest tissue in males [
• In previously treated individuals, an option of discontinuing therapy when symptoms resolve should be offered [
• Early-morning serum concentrations of 17-OHP, Δ
• Linear growth, weight gain, pubertal development, and clinical signs of cortisol and androgen excess
• Bone age to assess osseous maturation (at 6- to 12-month intervals)
• Blood pressure
• Early morning plasma renin activity or direct renin assay in a controlled position (usually upright)
• Fecundity and fertility
• Weight
• Lipid profile
• Blood pressure
• Bone mineral density
• Serum 17-OHP concentration should be measured in addition to newborn screening.
• Molecular genetic testing is indicated if the pathogenic variants in the family are known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with 21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH), the following evaluations are recommended:
Plasma renin activity (PRA)
Serum electrolytes
Baseline 17-OHP, Δ
ACTH stimulation test to compare stimulated concentration of 17-OHP to the baseline level
Careful physical examination of the external genitalia and its orifices
Vaginogram to assess the anatomy of urethra and vagina
Bone maturation assessment by bone age
Serum concentration of adrenal androgens (unconjugated dehydroepiandrosterone [DHEA], Δ
Consultation with a clinical geneticist and/or genetic counselor is recommended for those individuals with a new diagnosis of 21-OHD CAH.
• Plasma renin activity (PRA)
• Serum electrolytes
• Baseline 17-OHP, Δ
• ACTH stimulation test to compare stimulated concentration of 17-OHP to the baseline level
• Careful physical examination of the external genitalia and its orifices
• Vaginogram to assess the anatomy of urethra and vagina
• Bone maturation assessment by bone age
• Serum concentration of adrenal androgens (unconjugated dehydroepiandrosterone [DHEA], Δ
## Treatment of Manifestations
Clinical practice guidelines for the treatment of individuals with congenital adrenal hyperplasia due to 21-hydroxylase deficiency have been published [
It is imperative to make the diagnosis of 21-OHD CAH as quickly as possible in order to initiate therapy and arrest the effects of cortisol deficiency and mineralocorticoid deficiency, if present.
A multidisciplinary team of specialists in pediatric endocrinology, pediatric urology/surgery, clinical genetics, and psychology is essential for the diagnosis and management of the individual with ambiguous genitalia [
Hydrocortisone in tablet form is the treatment of choice in growing children. The use of oral hydrocortisone suspension is discouraged. Treatment for CAH principally involves glucocorticoid replacement therapy, usually in the form of hydrocortisone (10-15 mg/m
Note: Overtreatment with glucocorticosteroids can result in cushingoid features and should be avoided. It often occurs when serum concentration of 17-OHP is reduced to the physiologic range for age. An acceptable range for serum concentration of 17-OHP in the treated individual is higher (100-1,000 ng/dL) than normal, provided androgens are maintained in an appropriate range for sex and pubertal status.
During periods of stress (e.g., surgery, febrile illness, shock, major trauma), all individuals with classic 21-OHD CAH require increased amounts of glucocorticoids. Typically, two to three times the normal dose is administered orally or by intramuscular injection when oral intake is not tolerated.
Affected individuals should carry medical information regarding emergency steroid dosing.
Individuals with classic 21-OHD CAH require lifelong administration of glucocorticoids. After linear growth is complete, more potent glucocorticoids (e.g., prednisone and dexamethasone) that tend to suppress growth in childhood can be used.
All individuals with the classic form should be treated with both 9α-fludrohydrocortisone and sodium chloride supplement in the newborn period and early infancy [
Sodium chloride supplementation may not be necessary after infancy; the amount of mineralocorticoid required daily may likewise decrease with age.
"Surgery should only be considered in cases of severe virilization (Prader III-V) and be performed in conjunction, when appropriate, with repair of the common urogenital sinus. Because orgasmic function and erectile sensation may be disturbed by clitoral surgery, the surgical procedure should be anatomically based to preserve erectile function and the innervation of the clitoris. Emphasis is on functional outcome rather than a strictly cosmetic appearance. It is generally felt that surgery that is performed for cosmetic reasons in the first year of life relieves parental distress and improves attachment between the child and the parents; the systematic evidence for this belief is lacking."
The Endocrine Society clinical practice guidelines [
"[C]litoral and perineal reconstruction [should] be considered in infancy and performed by an experienced surgeon in a center with similarly experienced pediatric endocrinologists, mental health professionals, and social work services."
Although there are no randomized controlled studies of either the best age or the best methods for feminizing surgery, the recommended procedures are neurovascular-sparing clitoroplasty and vaginoplasty using total or partial urogenital mobilization.
When necessary, vaginoplasty is usually performed in late adolescence because routine vaginal dilation is required to maintain a patent vagina.
Affected individuals were significantly shorter and had a higher body mass index.
Women with classic CAH had increased diastolic blood pressure.
Metabolic abnormalities were common among studied individuals, and included obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised.
Transition of pediatric individuals to medical care in the adult setting is an important step to ensure optimal lifelong treatment, aiming to achieve good health with a normal life expectancy and quality of life [
Only small series of adults undergoing adrenalectomy have been reported (see review in
Individuals with non-classic 21-OHD CAH do not always require treatment. Many are asymptomatic throughout their lives, or symptoms may develop during puberty, after puberty, or post partum.
The hyperandrogenic symptoms that require treatment include advanced bone age, early pubic hair, precocious puberty, tall stature, and early arrest of growth in children; infertility, cystic acne, and short stature in both adult males and females; hirsutism, frontal balding, polycystic ovaries, and irregular menstrual periods in females; and testicular adrenal rest tissue in males [
In previously treated individuals, an option of discontinuing therapy when symptoms resolve should be offered [
Traditionally, individuals with non-classic 21-OHD CAH have been treated with lower amounts of glucocorticoid than those required for individuals with classic 21-OHD CAH.
• Hydrocortisone in tablet form is the treatment of choice in growing children. The use of oral hydrocortisone suspension is discouraged. Treatment for CAH principally involves glucocorticoid replacement therapy, usually in the form of hydrocortisone (10-15 mg/m
• Note: Overtreatment with glucocorticosteroids can result in cushingoid features and should be avoided. It often occurs when serum concentration of 17-OHP is reduced to the physiologic range for age. An acceptable range for serum concentration of 17-OHP in the treated individual is higher (100-1,000 ng/dL) than normal, provided androgens are maintained in an appropriate range for sex and pubertal status.
• During periods of stress (e.g., surgery, febrile illness, shock, major trauma), all individuals with classic 21-OHD CAH require increased amounts of glucocorticoids. Typically, two to three times the normal dose is administered orally or by intramuscular injection when oral intake is not tolerated.
• Affected individuals should carry medical information regarding emergency steroid dosing.
• Individuals with classic 21-OHD CAH require lifelong administration of glucocorticoids. After linear growth is complete, more potent glucocorticoids (e.g., prednisone and dexamethasone) that tend to suppress growth in childhood can be used.
• All individuals with the classic form should be treated with both 9α-fludrohydrocortisone and sodium chloride supplement in the newborn period and early infancy [
• Sodium chloride supplementation may not be necessary after infancy; the amount of mineralocorticoid required daily may likewise decrease with age.
• Although there are no randomized controlled studies of either the best age or the best methods for feminizing surgery, the recommended procedures are neurovascular-sparing clitoroplasty and vaginoplasty using total or partial urogenital mobilization.
• When necessary, vaginoplasty is usually performed in late adolescence because routine vaginal dilation is required to maintain a patent vagina.
• Affected individuals were significantly shorter and had a higher body mass index.
• Women with classic CAH had increased diastolic blood pressure.
• Metabolic abnormalities were common among studied individuals, and included obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised.
• The hyperandrogenic symptoms that require treatment include advanced bone age, early pubic hair, precocious puberty, tall stature, and early arrest of growth in children; infertility, cystic acne, and short stature in both adult males and females; hirsutism, frontal balding, polycystic ovaries, and irregular menstrual periods in females; and testicular adrenal rest tissue in males [
• In previously treated individuals, an option of discontinuing therapy when symptoms resolve should be offered [
## Classic 21-OHD CAH
Hydrocortisone in tablet form is the treatment of choice in growing children. The use of oral hydrocortisone suspension is discouraged. Treatment for CAH principally involves glucocorticoid replacement therapy, usually in the form of hydrocortisone (10-15 mg/m
Note: Overtreatment with glucocorticosteroids can result in cushingoid features and should be avoided. It often occurs when serum concentration of 17-OHP is reduced to the physiologic range for age. An acceptable range for serum concentration of 17-OHP in the treated individual is higher (100-1,000 ng/dL) than normal, provided androgens are maintained in an appropriate range for sex and pubertal status.
During periods of stress (e.g., surgery, febrile illness, shock, major trauma), all individuals with classic 21-OHD CAH require increased amounts of glucocorticoids. Typically, two to three times the normal dose is administered orally or by intramuscular injection when oral intake is not tolerated.
Affected individuals should carry medical information regarding emergency steroid dosing.
Individuals with classic 21-OHD CAH require lifelong administration of glucocorticoids. After linear growth is complete, more potent glucocorticoids (e.g., prednisone and dexamethasone) that tend to suppress growth in childhood can be used.
All individuals with the classic form should be treated with both 9α-fludrohydrocortisone and sodium chloride supplement in the newborn period and early infancy [
Sodium chloride supplementation may not be necessary after infancy; the amount of mineralocorticoid required daily may likewise decrease with age.
"Surgery should only be considered in cases of severe virilization (Prader III-V) and be performed in conjunction, when appropriate, with repair of the common urogenital sinus. Because orgasmic function and erectile sensation may be disturbed by clitoral surgery, the surgical procedure should be anatomically based to preserve erectile function and the innervation of the clitoris. Emphasis is on functional outcome rather than a strictly cosmetic appearance. It is generally felt that surgery that is performed for cosmetic reasons in the first year of life relieves parental distress and improves attachment between the child and the parents; the systematic evidence for this belief is lacking."
The Endocrine Society clinical practice guidelines [
"[C]litoral and perineal reconstruction [should] be considered in infancy and performed by an experienced surgeon in a center with similarly experienced pediatric endocrinologists, mental health professionals, and social work services."
Although there are no randomized controlled studies of either the best age or the best methods for feminizing surgery, the recommended procedures are neurovascular-sparing clitoroplasty and vaginoplasty using total or partial urogenital mobilization.
When necessary, vaginoplasty is usually performed in late adolescence because routine vaginal dilation is required to maintain a patent vagina.
Affected individuals were significantly shorter and had a higher body mass index.
Women with classic CAH had increased diastolic blood pressure.
Metabolic abnormalities were common among studied individuals, and included obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised.
Transition of pediatric individuals to medical care in the adult setting is an important step to ensure optimal lifelong treatment, aiming to achieve good health with a normal life expectancy and quality of life [
Only small series of adults undergoing adrenalectomy have been reported (see review in
• Hydrocortisone in tablet form is the treatment of choice in growing children. The use of oral hydrocortisone suspension is discouraged. Treatment for CAH principally involves glucocorticoid replacement therapy, usually in the form of hydrocortisone (10-15 mg/m
• Note: Overtreatment with glucocorticosteroids can result in cushingoid features and should be avoided. It often occurs when serum concentration of 17-OHP is reduced to the physiologic range for age. An acceptable range for serum concentration of 17-OHP in the treated individual is higher (100-1,000 ng/dL) than normal, provided androgens are maintained in an appropriate range for sex and pubertal status.
• During periods of stress (e.g., surgery, febrile illness, shock, major trauma), all individuals with classic 21-OHD CAH require increased amounts of glucocorticoids. Typically, two to three times the normal dose is administered orally or by intramuscular injection when oral intake is not tolerated.
• Affected individuals should carry medical information regarding emergency steroid dosing.
• Individuals with classic 21-OHD CAH require lifelong administration of glucocorticoids. After linear growth is complete, more potent glucocorticoids (e.g., prednisone and dexamethasone) that tend to suppress growth in childhood can be used.
• All individuals with the classic form should be treated with both 9α-fludrohydrocortisone and sodium chloride supplement in the newborn period and early infancy [
• Sodium chloride supplementation may not be necessary after infancy; the amount of mineralocorticoid required daily may likewise decrease with age.
• Although there are no randomized controlled studies of either the best age or the best methods for feminizing surgery, the recommended procedures are neurovascular-sparing clitoroplasty and vaginoplasty using total or partial urogenital mobilization.
• When necessary, vaginoplasty is usually performed in late adolescence because routine vaginal dilation is required to maintain a patent vagina.
• Affected individuals were significantly shorter and had a higher body mass index.
• Women with classic CAH had increased diastolic blood pressure.
• Metabolic abnormalities were common among studied individuals, and included obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised.
## Non-Classic 21-OHD CAH
Individuals with non-classic 21-OHD CAH do not always require treatment. Many are asymptomatic throughout their lives, or symptoms may develop during puberty, after puberty, or post partum.
The hyperandrogenic symptoms that require treatment include advanced bone age, early pubic hair, precocious puberty, tall stature, and early arrest of growth in children; infertility, cystic acne, and short stature in both adult males and females; hirsutism, frontal balding, polycystic ovaries, and irregular menstrual periods in females; and testicular adrenal rest tissue in males [
In previously treated individuals, an option of discontinuing therapy when symptoms resolve should be offered [
Traditionally, individuals with non-classic 21-OHD CAH have been treated with lower amounts of glucocorticoid than those required for individuals with classic 21-OHD CAH.
• The hyperandrogenic symptoms that require treatment include advanced bone age, early pubic hair, precocious puberty, tall stature, and early arrest of growth in children; infertility, cystic acne, and short stature in both adult males and females; hirsutism, frontal balding, polycystic ovaries, and irregular menstrual periods in females; and testicular adrenal rest tissue in males [
• In previously treated individuals, an option of discontinuing therapy when symptoms resolve should be offered [
## Prevention of Primary Manifestations
See
## Prevention of Secondary Complications
## Surveillance
The following evaluations should be performed every three to four months when children are actively growing. Evaluation may be less often thereafter. The frequency of evaluation should vary depending on individual needs [
Early-morning serum concentrations of 17-OHP, Δ
Linear growth, weight gain, pubertal development, and clinical signs of cortisol and androgen excess
Bone age to assess osseous maturation (at 6- to 12-month intervals)
Blood pressure
Early morning plasma renin activity or direct renin assay in a controlled position (usually upright)
Fecundity and fertility
Weight
Lipid profile
Blood pressure
Bone mineral density
• Early-morning serum concentrations of 17-OHP, Δ
• Linear growth, weight gain, pubertal development, and clinical signs of cortisol and androgen excess
• Bone age to assess osseous maturation (at 6- to 12-month intervals)
• Blood pressure
• Early morning plasma renin activity or direct renin assay in a controlled position (usually upright)
• Fecundity and fertility
• Weight
• Lipid profile
• Blood pressure
• Bone mineral density
## Agents/Circumstances to Avoid
Physical stress such as febrile illness, gastroenteritis with dehydration, surgery accompanied by general anesthesia, and major trauma can precipitate an adrenal crisis in individuals with classic CAH. Increased doses of glucocorticoids are recommended in these situations.
## Evaluation of Relatives at Risk
If prenatal testing for 21-OHD CAH has not been performed, it is appropriate to evaluate newborn sibs of a proband in order to facilitate early diagnosis and treatment.
Serum 17-OHP concentration should be measured in addition to newborn screening.
Molecular genetic testing is indicated if the pathogenic variants in the family are known.
See
• Serum 17-OHP concentration should be measured in addition to newborn screening.
• Molecular genetic testing is indicated if the pathogenic variants in the family are known.
## Pregnancy Management
## Therapies Under Investigation
Search
## Genetic Counseling
21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH) is inherited in an autosomal recessive manner.
Most parents are heterozygotes (i.e., carriers of one
Heterozygotes are asymptomatic but may have slightly elevated 17-OHP levels when stimulated with ACTH, as compared to individuals with two normal alleles (see
Approximately 1% of
In some instances, a parent who was previously not known to be affected may be found to have the non-classic form of 21-OHD CAH. It is appropriate to evaluate both parents of a proband with molecular genetic testing and hormonal profiling to determine if either has non-classic 21-OHD CAH.
At conception, if the parents of a proband are both heterozygotes, each sib has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
If one parent of a proband is heterozygous and the other has 21-OHD CAH, each sib has a 50% chance of inheriting both pathogenic variants and being affected and a 50% chance of inheriting one pathogenic variant and being a carrier.
Heterozygotes are asymptomatic but may have slightly elevated 17-OHP levels when stimulated with ACTH, as compared to individuals with two normal alleles (see
An affected individual transmits one pathogenic variant to each child.
Given the high carrier rate for 21-OHD CAH, it is appropriate to offer molecular genetic testing of
If the reproductive partner is found not to be a carrier, the child is at significantly decreased risk of having 21-OHD CAH.
If the reproductive partner is found to be heterozygous for a known pathogenic variant, the risk to each child of being affected is 50%. The ability to predict the phenotype based on genotype is clinically useful most of the time, but still imperfect (see
Note: Another potential cause of misdiagnosis is
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Noninvasive prenatal diagnostic methods for earlier diagnosis of affected female fetuses have been developed and may eliminate the unnecessary prenatal treatment of males and unaffected females [
If ambiguous external genitalia are noted on routine ultrasound examination, a fetal karyotype, FISH for
The prenatal diagnosis of 21-OHD CAH can be valuable in the medical management of the newborn and in preparation of the family for the related medical and social issues of 21-OHD CAH.
• Most parents are heterozygotes (i.e., carriers of one
• Heterozygotes are asymptomatic but may have slightly elevated 17-OHP levels when stimulated with ACTH, as compared to individuals with two normal alleles (see
• Approximately 1% of
• In some instances, a parent who was previously not known to be affected may be found to have the non-classic form of 21-OHD CAH. It is appropriate to evaluate both parents of a proband with molecular genetic testing and hormonal profiling to determine if either has non-classic 21-OHD CAH.
• At conception, if the parents of a proband are both heterozygotes, each sib has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• If one parent of a proband is heterozygous and the other has 21-OHD CAH, each sib has a 50% chance of inheriting both pathogenic variants and being affected and a 50% chance of inheriting one pathogenic variant and being a carrier.
• Heterozygotes are asymptomatic but may have slightly elevated 17-OHP levels when stimulated with ACTH, as compared to individuals with two normal alleles (see
• An affected individual transmits one pathogenic variant to each child.
• Given the high carrier rate for 21-OHD CAH, it is appropriate to offer molecular genetic testing of
• If the reproductive partner is found not to be a carrier, the child is at significantly decreased risk of having 21-OHD CAH.
• If the reproductive partner is found to be heterozygous for a known pathogenic variant, the risk to each child of being affected is 50%. The ability to predict the phenotype based on genotype is clinically useful most of the time, but still imperfect (see
• If the reproductive partner is found not to be a carrier, the child is at significantly decreased risk of having 21-OHD CAH.
• If the reproductive partner is found to be heterozygous for a known pathogenic variant, the risk to each child of being affected is 50%. The ability to predict the phenotype based on genotype is clinically useful most of the time, but still imperfect (see
• If the reproductive partner is found not to be a carrier, the child is at significantly decreased risk of having 21-OHD CAH.
• If the reproductive partner is found to be heterozygous for a known pathogenic variant, the risk to each child of being affected is 50%. The ability to predict the phenotype based on genotype is clinically useful most of the time, but still imperfect (see
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH) is inherited in an autosomal recessive manner.
## Risk to Family Members
Most parents are heterozygotes (i.e., carriers of one
Heterozygotes are asymptomatic but may have slightly elevated 17-OHP levels when stimulated with ACTH, as compared to individuals with two normal alleles (see
Approximately 1% of
In some instances, a parent who was previously not known to be affected may be found to have the non-classic form of 21-OHD CAH. It is appropriate to evaluate both parents of a proband with molecular genetic testing and hormonal profiling to determine if either has non-classic 21-OHD CAH.
At conception, if the parents of a proband are both heterozygotes, each sib has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
If one parent of a proband is heterozygous and the other has 21-OHD CAH, each sib has a 50% chance of inheriting both pathogenic variants and being affected and a 50% chance of inheriting one pathogenic variant and being a carrier.
Heterozygotes are asymptomatic but may have slightly elevated 17-OHP levels when stimulated with ACTH, as compared to individuals with two normal alleles (see
An affected individual transmits one pathogenic variant to each child.
Given the high carrier rate for 21-OHD CAH, it is appropriate to offer molecular genetic testing of
If the reproductive partner is found not to be a carrier, the child is at significantly decreased risk of having 21-OHD CAH.
If the reproductive partner is found to be heterozygous for a known pathogenic variant, the risk to each child of being affected is 50%. The ability to predict the phenotype based on genotype is clinically useful most of the time, but still imperfect (see
• Most parents are heterozygotes (i.e., carriers of one
• Heterozygotes are asymptomatic but may have slightly elevated 17-OHP levels when stimulated with ACTH, as compared to individuals with two normal alleles (see
• Approximately 1% of
• In some instances, a parent who was previously not known to be affected may be found to have the non-classic form of 21-OHD CAH. It is appropriate to evaluate both parents of a proband with molecular genetic testing and hormonal profiling to determine if either has non-classic 21-OHD CAH.
• At conception, if the parents of a proband are both heterozygotes, each sib has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• If one parent of a proband is heterozygous and the other has 21-OHD CAH, each sib has a 50% chance of inheriting both pathogenic variants and being affected and a 50% chance of inheriting one pathogenic variant and being a carrier.
• Heterozygotes are asymptomatic but may have slightly elevated 17-OHP levels when stimulated with ACTH, as compared to individuals with two normal alleles (see
• An affected individual transmits one pathogenic variant to each child.
• Given the high carrier rate for 21-OHD CAH, it is appropriate to offer molecular genetic testing of
• If the reproductive partner is found not to be a carrier, the child is at significantly decreased risk of having 21-OHD CAH.
• If the reproductive partner is found to be heterozygous for a known pathogenic variant, the risk to each child of being affected is 50%. The ability to predict the phenotype based on genotype is clinically useful most of the time, but still imperfect (see
• If the reproductive partner is found not to be a carrier, the child is at significantly decreased risk of having 21-OHD CAH.
• If the reproductive partner is found to be heterozygous for a known pathogenic variant, the risk to each child of being affected is 50%. The ability to predict the phenotype based on genotype is clinically useful most of the time, but still imperfect (see
• If the reproductive partner is found not to be a carrier, the child is at significantly decreased risk of having 21-OHD CAH.
• If the reproductive partner is found to be heterozygous for a known pathogenic variant, the risk to each child of being affected is 50%. The ability to predict the phenotype based on genotype is clinically useful most of the time, but still imperfect (see
## Carrier (Heterozygote) Detection
Note: Another potential cause of misdiagnosis is
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Noninvasive prenatal diagnostic methods for earlier diagnosis of affected female fetuses have been developed and may eliminate the unnecessary prenatal treatment of males and unaffected females [
If ambiguous external genitalia are noted on routine ultrasound examination, a fetal karyotype, FISH for
The prenatal diagnosis of 21-OHD CAH can be valuable in the medical management of the newborn and in preparation of the family for the related medical and social issues of 21-OHD CAH.
## Resources
2414 Morris Avenue
Suite 110
Union NJ 07093
Health Resources & Services Administration
•
• 2414 Morris Avenue
• Suite 110
• Union NJ 07093
•
•
•
•
•
•
• Health Resources & Services Administration
•
## Molecular Genetics
21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia (
Small-scale gene conversions account for some of the common pathogenic variants, such as a combination of p.Pro31Leu, c.293-13A or C>G, and p.Gly111ValfsTer21 on the same allele, detected by allele-specific PCR method.
Large-scale gene conversions also occur, some of which may require additional testing (see
Approximately 20%-30% of mutated alleles are the result of meiotic recombination between repeated sequences that result in a 30-kb deletion that encompasses the 3' end of the
Another common pathogenic variant is c.293-13A>G or c.293-13C>G, occurring with a frequency of 20%-30%, leading to aberrant splicing and truncated small or unusual protein.
Nine pathogenic variants in the nonfunctional pseudogene inactivate the functional gene when transferred from
More than 100 pathogenic variants, including single-nucleotide variants, small deletions, small insertions, and complex rearrangements of the gene, have been described to date. (For more information, see
Selected
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• Small-scale gene conversions account for some of the common pathogenic variants, such as a combination of p.Pro31Leu, c.293-13A or C>G, and p.Gly111ValfsTer21 on the same allele, detected by allele-specific PCR method.
• Large-scale gene conversions also occur, some of which may require additional testing (see
• Approximately 20%-30% of mutated alleles are the result of meiotic recombination between repeated sequences that result in a 30-kb deletion that encompasses the 3' end of the
• Another common pathogenic variant is c.293-13A>G or c.293-13C>G, occurring with a frequency of 20%-30%, leading to aberrant splicing and truncated small or unusual protein.
## References
Joint LWPES/ESPE CAH Working Group. Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Available
Lee PA, Houk CP, Ahmed SF, Hughes IA. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Pediatrics. 2006;118:e488-500.
Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC; Endocrine Society. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:4133-60.
• Joint LWPES/ESPE CAH Working Group. Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Available
• Lee PA, Houk CP, Ahmed SF, Hughes IA. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Pediatrics. 2006;118:e488-500.
• Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC; Endocrine Society. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:4133-60.
## Published Guidelines / Consensus Statements
Joint LWPES/ESPE CAH Working Group. Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Available
Lee PA, Houk CP, Ahmed SF, Hughes IA. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Pediatrics. 2006;118:e488-500.
Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC; Endocrine Society. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:4133-60.
• Joint LWPES/ESPE CAH Working Group. Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Available
• Lee PA, Houk CP, Ahmed SF, Hughes IA. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Pediatrics. 2006;118:e488-500.
• Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC; Endocrine Society. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:4133-60.
## Literature Cited
## Chapter Notes
Brian Betensky, Weill Medical College of Cornell University (2004-2006)Prasanna K Gangishetti, MBBS (2016-present)Maria I New, MD (2001-present)Saroj Nimkarn, MD (2006-present)Andrea Putnam, MS; New York Weill Cornell Center (2001-2004)Mabel Yau, MD (2016-present)
4 February 2016 (sw) Comprehensive update posted live
29 August 2013 (me) Comprehensive update posted live
24 August 2010 (cd) Revision: edits to Management and Genetic Counseling
15 September 2009 (me) Comprehensive update posted live
7 September 2006 (me) Comprehensive update posted live
15 April 2004 (me) Comprehensive update posted live
26 February 2002 (me) Review posted live
15 June 2001 (mn) Original submission
• 4 February 2016 (sw) Comprehensive update posted live
• 29 August 2013 (me) Comprehensive update posted live
• 24 August 2010 (cd) Revision: edits to Management and Genetic Counseling
• 15 September 2009 (me) Comprehensive update posted live
• 7 September 2006 (me) Comprehensive update posted live
• 15 April 2004 (me) Comprehensive update posted live
• 26 February 2002 (me) Review posted live
• 15 June 2001 (mn) Original submission
## Author History
Brian Betensky, Weill Medical College of Cornell University (2004-2006)Prasanna K Gangishetti, MBBS (2016-present)Maria I New, MD (2001-present)Saroj Nimkarn, MD (2006-present)Andrea Putnam, MS; New York Weill Cornell Center (2001-2004)Mabel Yau, MD (2016-present)
## Revision History
4 February 2016 (sw) Comprehensive update posted live
29 August 2013 (me) Comprehensive update posted live
24 August 2010 (cd) Revision: edits to Management and Genetic Counseling
15 September 2009 (me) Comprehensive update posted live
7 September 2006 (me) Comprehensive update posted live
15 April 2004 (me) Comprehensive update posted live
26 February 2002 (me) Review posted live
15 June 2001 (mn) Original submission
• 4 February 2016 (sw) Comprehensive update posted live
• 29 August 2013 (me) Comprehensive update posted live
• 24 August 2010 (cd) Revision: edits to Management and Genetic Counseling
• 15 September 2009 (me) Comprehensive update posted live
• 7 September 2006 (me) Comprehensive update posted live
• 15 April 2004 (me) Comprehensive update posted live
• 26 February 2002 (me) Review posted live
• 15 June 2001 (mn) Original submission
17-OHP nomogram for the diagnosis of steroid 21-hydroxylase deficiency (60-minute Cortrosyn™ stimulation test). The data for this nomogram were collected between 1982 and 1991 at the Department of Pediatrics, the New York Hospital-Cornell Medical Center, New York.
|
[] |
26/2/2002
|
4/2/2016
|
24/8/2010
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
campo-dysp
|
campo-dysp
|
[
"Camptomelic Dysplasia",
"SOX9-Related Campomelic Dysplasia",
"Camptomelic Dysplasia",
"SOX9-Related Campomelic Dysplasia",
"Acampomelic Campomelic Dysplasia",
"Transcription factor SOX-9",
"SOX9",
"Campomelic Dysplasia"
] |
Campomelic Dysplasia
|
Sheila Unger, Gerd Scherer, Andrea Superti-Furga
|
Summary Campomelic dysplasia (CD) is a skeletal dysplasia characterized by distinctive facies, Pierre Robin sequence with cleft palate, shortening and bowing of long bones, and clubfeet. Other findings include laryngotracheomalacia with respiratory compromise and ambiguous genitalia or normal female external genitalia in most individuals with a 46,XY karyotype. Many affected infants die in the neonatal period; additional findings identified in long-term survivors include short stature, cervical spine instability with cord compression, progressive scoliosis, and hearing impairment. The diagnosis of CD is usually based on clinical and radiographic findings. Identification of a heterozygous pathogenic variant in CD is inherited in an autosomal dominant manner. To date, most probands have CD as the result of a
|
Acampomelic campomelic dysplasia
Campomelic dysplasia
For synonyms and outdated names see
• Acampomelic campomelic dysplasia
• Campomelic dysplasia
## Diagnosis
No consensus clinical diagnostic criteria for campomelic dysplasia (CD) have been published. The diagnosis of CD (derived from the Greek for "bent limb") can usually be clearly established based on clinical and radiographic findings. Although no single clinical feature is obligatory, the radiographic features are consistent and are the most reliable diagnostic clues.
CD
Relatively large head
Pierre Robin sequence with cleft palate
Midface hypoplasia
Laryngotracheomalacia
Respiratory distress
Eleven pairs of ribs
Ambiguous genitalia or normal female external genitalia in an individual with a 46,XY karyotype
Dislocatable hips
Short bowed limbs (lower limbs more frequently than upper limbs)
Pretibial skin dimples (Bowing of the lower leg is often associated with a skin dimple over the apex of curve.)
Clubfeet
Note: Bowing of the limbs, the feature that gave the disorder its name, is neither specific nor an obligatory finding. When the limbs are not bowed, the term "acampomelic campomelic dysplasia" is used. Bowing of the limbs is present in many other skeletal dysplasias (e.g.,
Cervical spine anomalies (variable, often kyphosis) (
Scapular hypoplasia (
Hypoplastic thoracic vertebral pedicles (
Eleven pairs of ribs
Scoliosis or kyphoscoliosis
Vertically oriented narrow iliac wings (
Bowed femora and/or tibiae (occasionally upper limb) (
The clinical diagnosis of CD
The molecular diagnosis of CD
A heterozygous pathogenic (or likely pathogenic) variant involving
A heterozygous interstitial deletion or reciprocal translocation of 17q24.3-q25.1 involving
Note: In rare instances, the translocation may be familial; thus, parental karyotypes should be analyzed when an abnormality is found in the proband.
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by skeletal dysplasia,
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance –
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Campomelic Dysplasia
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., the family described by
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Deletions of
There are multiple reports of individuals with campomelic dysplasia (including the acampomelic form) due to apparently balanced translocations in the vicinity of the
• Relatively large head
• Pierre Robin sequence with cleft palate
• Midface hypoplasia
• Laryngotracheomalacia
• Respiratory distress
• Eleven pairs of ribs
• Ambiguous genitalia or normal female external genitalia in an individual with a 46,XY karyotype
• Dislocatable hips
• Short bowed limbs (lower limbs more frequently than upper limbs)
• Pretibial skin dimples (Bowing of the lower leg is often associated with a skin dimple over the apex of curve.)
• Clubfeet
• Cervical spine anomalies (variable, often kyphosis) (
• Scapular hypoplasia (
• Hypoplastic thoracic vertebral pedicles (
• Eleven pairs of ribs
• Scoliosis or kyphoscoliosis
• Vertically oriented narrow iliac wings (
• Bowed femora and/or tibiae (occasionally upper limb) (
• A heterozygous pathogenic (or likely pathogenic) variant involving
• A heterozygous interstitial deletion or reciprocal translocation of 17q24.3-q25.1 involving
• Note: In rare instances, the translocation may be familial; thus, parental karyotypes should be analyzed when an abnormality is found in the proband.
## Suggestive Findings
CD
Relatively large head
Pierre Robin sequence with cleft palate
Midface hypoplasia
Laryngotracheomalacia
Respiratory distress
Eleven pairs of ribs
Ambiguous genitalia or normal female external genitalia in an individual with a 46,XY karyotype
Dislocatable hips
Short bowed limbs (lower limbs more frequently than upper limbs)
Pretibial skin dimples (Bowing of the lower leg is often associated with a skin dimple over the apex of curve.)
Clubfeet
Note: Bowing of the limbs, the feature that gave the disorder its name, is neither specific nor an obligatory finding. When the limbs are not bowed, the term "acampomelic campomelic dysplasia" is used. Bowing of the limbs is present in many other skeletal dysplasias (e.g.,
Cervical spine anomalies (variable, often kyphosis) (
Scapular hypoplasia (
Hypoplastic thoracic vertebral pedicles (
Eleven pairs of ribs
Scoliosis or kyphoscoliosis
Vertically oriented narrow iliac wings (
Bowed femora and/or tibiae (occasionally upper limb) (
• Relatively large head
• Pierre Robin sequence with cleft palate
• Midface hypoplasia
• Laryngotracheomalacia
• Respiratory distress
• Eleven pairs of ribs
• Ambiguous genitalia or normal female external genitalia in an individual with a 46,XY karyotype
• Dislocatable hips
• Short bowed limbs (lower limbs more frequently than upper limbs)
• Pretibial skin dimples (Bowing of the lower leg is often associated with a skin dimple over the apex of curve.)
• Clubfeet
• Cervical spine anomalies (variable, often kyphosis) (
• Scapular hypoplasia (
• Hypoplastic thoracic vertebral pedicles (
• Eleven pairs of ribs
• Scoliosis or kyphoscoliosis
• Vertically oriented narrow iliac wings (
• Bowed femora and/or tibiae (occasionally upper limb) (
## Establishing the Diagnosis
The clinical diagnosis of CD
The molecular diagnosis of CD
A heterozygous pathogenic (or likely pathogenic) variant involving
A heterozygous interstitial deletion or reciprocal translocation of 17q24.3-q25.1 involving
Note: In rare instances, the translocation may be familial; thus, parental karyotypes should be analyzed when an abnormality is found in the proband.
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by skeletal dysplasia,
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance –
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Campomelic Dysplasia
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., the family described by
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Deletions of
There are multiple reports of individuals with campomelic dysplasia (including the acampomelic form) due to apparently balanced translocations in the vicinity of the
• A heterozygous pathogenic (or likely pathogenic) variant involving
• A heterozygous interstitial deletion or reciprocal translocation of 17q24.3-q25.1 involving
• Note: In rare instances, the translocation may be familial; thus, parental karyotypes should be analyzed when an abnormality is found in the proband.
## Option 1
For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by skeletal dysplasia,
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance –
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Campomelic Dysplasia
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., the family described by
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Deletions of
There are multiple reports of individuals with campomelic dysplasia (including the acampomelic form) due to apparently balanced translocations in the vicinity of the
## Clinical Characteristics
To date, approximately 100 individuals (fetuses included) with a pathogenic variant in
Campomelic dysplasia (CD) is sometimes identified on prenatal ultrasound examination but may escape detection until after birth if the limbs are not bowed.
Many newborns with CD die shortly after birth secondary to respiratory insufficiency. In comparison with other lethal skeletal dysplasias, the cause of death in CD is not related to thoracic cage hypoplasia but rather to airway instability (tracheobronchomalacia) or cervical spine instability. Nonetheless, a number of infants with CD have survived the neonatal period [
The facies in CD resembles the type 2 collagen disorders (e.g.,
Approximately 75% of individuals with CD who have a 46,XY karyotype have either ambiguous external genitalia or normal female external genitalia. The internal genitalia are variable, often with a mixture of müllerian and wolffian duct structures.
Given the relatively small number of survivors described in the literature, it is difficult to generalize about the natural history. The following have been observed:
Intellect is normal.
Height is variably affected. Some newborns have significant short stature whereas others are within the normal range.
When present, scoliosis is usually progressive, contributes to the short stature, and may result in neurologic signs and symptoms.
Vertebral hypoplasia or malformation, particularly of the cervical spine, may lead to neurologic signs of cord compression unless surgically stabilized and may be the cause of death among those who initially survive the newborn period.
Hearing impairment/loss in some can be significant enough to require hearing aids.
A variety of congenital heart defects have been reported in a minority of cases.
Histologic pancreatic abnormalities have been described in three newborns who died at term from CD; however, pancreatic dysfunction has not been seen in survivors with CD [
Clear-cut genotype-phenotype correlations are not readily apparent in CD [
In two individuals with very distal translocation breakpoints (at 899 kb and 932 kb), the skeletal findings were so mild that they were transmitted through several generations [
Misregulation of
Pathogenic variants in the
Breakpoints at long distance from
The name "campomelic dysplasia," first proposed by Maroteaux in 1971, is derived from the Greek for "bent limb." Other terms used in the past to refer to campomelic dysplasia include campomelic dwarfism, campomelic syndrome, and camptomelic dwarfism.
Although the name "campomelic dysplasia" is well established, it can lead to confusion, as not every child with CD has bowed limbs (ACD) and, conversely, most children with bowed limbs do not have CD but another of the frequent genetic disorders of bone, including
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
No reliable data exist regarding the prevalence of CD. The authors estimate it to be in the range of 1:40,000 to 1:80,000.
• Intellect is normal.
• Height is variably affected. Some newborns have significant short stature whereas others are within the normal range.
• When present, scoliosis is usually progressive, contributes to the short stature, and may result in neurologic signs and symptoms.
• Vertebral hypoplasia or malformation, particularly of the cervical spine, may lead to neurologic signs of cord compression unless surgically stabilized and may be the cause of death among those who initially survive the newborn period.
• Hearing impairment/loss in some can be significant enough to require hearing aids.
• A variety of congenital heart defects have been reported in a minority of cases.
• Histologic pancreatic abnormalities have been described in three newborns who died at term from CD; however, pancreatic dysfunction has not been seen in survivors with CD [
• In two individuals with very distal translocation breakpoints (at 899 kb and 932 kb), the skeletal findings were so mild that they were transmitted through several generations [
• Misregulation of
## Clinical Description
To date, approximately 100 individuals (fetuses included) with a pathogenic variant in
Campomelic dysplasia (CD) is sometimes identified on prenatal ultrasound examination but may escape detection until after birth if the limbs are not bowed.
Many newborns with CD die shortly after birth secondary to respiratory insufficiency. In comparison with other lethal skeletal dysplasias, the cause of death in CD is not related to thoracic cage hypoplasia but rather to airway instability (tracheobronchomalacia) or cervical spine instability. Nonetheless, a number of infants with CD have survived the neonatal period [
The facies in CD resembles the type 2 collagen disorders (e.g.,
Approximately 75% of individuals with CD who have a 46,XY karyotype have either ambiguous external genitalia or normal female external genitalia. The internal genitalia are variable, often with a mixture of müllerian and wolffian duct structures.
Given the relatively small number of survivors described in the literature, it is difficult to generalize about the natural history. The following have been observed:
Intellect is normal.
Height is variably affected. Some newborns have significant short stature whereas others are within the normal range.
When present, scoliosis is usually progressive, contributes to the short stature, and may result in neurologic signs and symptoms.
Vertebral hypoplasia or malformation, particularly of the cervical spine, may lead to neurologic signs of cord compression unless surgically stabilized and may be the cause of death among those who initially survive the newborn period.
Hearing impairment/loss in some can be significant enough to require hearing aids.
A variety of congenital heart defects have been reported in a minority of cases.
Histologic pancreatic abnormalities have been described in three newborns who died at term from CD; however, pancreatic dysfunction has not been seen in survivors with CD [
• Intellect is normal.
• Height is variably affected. Some newborns have significant short stature whereas others are within the normal range.
• When present, scoliosis is usually progressive, contributes to the short stature, and may result in neurologic signs and symptoms.
• Vertebral hypoplasia or malformation, particularly of the cervical spine, may lead to neurologic signs of cord compression unless surgically stabilized and may be the cause of death among those who initially survive the newborn period.
• Hearing impairment/loss in some can be significant enough to require hearing aids.
• A variety of congenital heart defects have been reported in a minority of cases.
• Histologic pancreatic abnormalities have been described in three newborns who died at term from CD; however, pancreatic dysfunction has not been seen in survivors with CD [
## Genotype-Phenotype Correlations
Clear-cut genotype-phenotype correlations are not readily apparent in CD [
In two individuals with very distal translocation breakpoints (at 899 kb and 932 kb), the skeletal findings were so mild that they were transmitted through several generations [
Misregulation of
• In two individuals with very distal translocation breakpoints (at 899 kb and 932 kb), the skeletal findings were so mild that they were transmitted through several generations [
• Misregulation of
## Penetrance
Pathogenic variants in the
Breakpoints at long distance from
## Nomenclature
The name "campomelic dysplasia," first proposed by Maroteaux in 1971, is derived from the Greek for "bent limb." Other terms used in the past to refer to campomelic dysplasia include campomelic dwarfism, campomelic syndrome, and camptomelic dwarfism.
Although the name "campomelic dysplasia" is well established, it can lead to confusion, as not every child with CD has bowed limbs (ACD) and, conversely, most children with bowed limbs do not have CD but another of the frequent genetic disorders of bone, including
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
## Prevalence
No reliable data exist regarding the prevalence of CD. The authors estimate it to be in the range of 1:40,000 to 1:80,000.
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Disorders with Prenatal Limb Bowing in the Differential Diagnosis of Campomelic Dysplasia
AD = autosomal dominant; AR = autosomal recessive; CD = campomelic dysplasia; MOI = mode of inheritance; US = ultrasound
Perinatal and most infantile cases of hypophosphatasia are inherited in an autosomal recessive manner.
After birth, the differential diagnosis is mainly
## Differential Diagnosis in the Prenatal Period
Disorders with Prenatal Limb Bowing in the Differential Diagnosis of Campomelic Dysplasia
AD = autosomal dominant; AR = autosomal recessive; CD = campomelic dysplasia; MOI = mode of inheritance; US = ultrasound
Perinatal and most infantile cases of hypophosphatasia are inherited in an autosomal recessive manner.
## Differential Diagnosis After Birth
After birth, the differential diagnosis is mainly
## Management
To establish the extent of disease and needs in an individual diagnosed with campomelic dysplasia (CD), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Campomelic Dysplasia
CD = campomelic dysplasia
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with Campomelic Dysplasia
Recommended Surveillance for Individuals with Campomelic Dysplasia
There are no known circumstances to avoid. However, in long-term survivors with cervical spine malformations, it seems reasonable to limit activities that cause extreme flexion or extension (e.g., somersaults).
See
Search
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with campomelic dysplasia (CD), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Campomelic Dysplasia
CD = campomelic dysplasia
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Campomelic Dysplasia
## Prevention of Secondary Complications
## Surveillance
Recommended Surveillance for Individuals with Campomelic Dysplasia
## Agents/Circumstances to Avoid
There are no known circumstances to avoid. However, in long-term survivors with cervical spine malformations, it seems reasonable to limit activities that cause extreme flexion or extension (e.g., somersaults).
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Campomelic dysplasia (CD) is an autosomal dominant disorder typically caused by a
To date, most probands with campomelic dysplasia (CD) have the disorder as the result of a
A few adults have been diagnosed with CD following the birth of an affected child [
Genetic testing capable of detecting the
If the
Somatic and germline mosaicism in mildly affected parents of affected sibs has been reported in two families [
Somatic and/or germline mosaicism for a
If a parent of the proband is heterozygous for a
If the proband has a known
If a proband has a chromosome rearrangement, the recurrence risk to sibs depends on the chromosome findings in the parents:
If neither parent has a chromosome rearrangement, the risk to sibs is negligible.
If a parent has a balanced chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
Each child of an individual with a non-mosaic
The risk to offspring of an individual with a chromosome rearrangement involving
Because CD typically occurs as a
If a parent has a balanced chromosome rearrangement, the parent's family members are at risk and can be offered chromosome analysis.
Once a
Similarly, prenatal testing for a pregnancy at increased risk for a familial chromosome rearrangement is possible by chromosome analysis of fetal cells obtained by amniocentesis or chorionic villus sampling.
• To date, most probands with campomelic dysplasia (CD) have the disorder as the result of a
• A few adults have been diagnosed with CD following the birth of an affected child [
• Genetic testing capable of detecting the
• If the
• Somatic and germline mosaicism in mildly affected parents of affected sibs has been reported in two families [
• Somatic and/or germline mosaicism for a
• Somatic and germline mosaicism in mildly affected parents of affected sibs has been reported in two families [
• Somatic and/or germline mosaicism for a
• Somatic and germline mosaicism in mildly affected parents of affected sibs has been reported in two families [
• Somatic and/or germline mosaicism for a
• If a parent of the proband is heterozygous for a
• If the proband has a known
• If a proband has a chromosome rearrangement, the recurrence risk to sibs depends on the chromosome findings in the parents:
• If neither parent has a chromosome rearrangement, the risk to sibs is negligible.
• If a parent has a balanced chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
• If neither parent has a chromosome rearrangement, the risk to sibs is negligible.
• If a parent has a balanced chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
• If neither parent has a chromosome rearrangement, the risk to sibs is negligible.
• If a parent has a balanced chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
• Each child of an individual with a non-mosaic
• The risk to offspring of an individual with a chromosome rearrangement involving
• Because CD typically occurs as a
• If a parent has a balanced chromosome rearrangement, the parent's family members are at risk and can be offered chromosome analysis.
• Once a
• Similarly, prenatal testing for a pregnancy at increased risk for a familial chromosome rearrangement is possible by chromosome analysis of fetal cells obtained by amniocentesis or chorionic villus sampling.
## Mode of Inheritance
Campomelic dysplasia (CD) is an autosomal dominant disorder typically caused by a
## Risk to Family Members
To date, most probands with campomelic dysplasia (CD) have the disorder as the result of a
A few adults have been diagnosed with CD following the birth of an affected child [
Genetic testing capable of detecting the
If the
Somatic and germline mosaicism in mildly affected parents of affected sibs has been reported in two families [
Somatic and/or germline mosaicism for a
If a parent of the proband is heterozygous for a
If the proband has a known
If a proband has a chromosome rearrangement, the recurrence risk to sibs depends on the chromosome findings in the parents:
If neither parent has a chromosome rearrangement, the risk to sibs is negligible.
If a parent has a balanced chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
Each child of an individual with a non-mosaic
The risk to offspring of an individual with a chromosome rearrangement involving
Because CD typically occurs as a
If a parent has a balanced chromosome rearrangement, the parent's family members are at risk and can be offered chromosome analysis.
• To date, most probands with campomelic dysplasia (CD) have the disorder as the result of a
• A few adults have been diagnosed with CD following the birth of an affected child [
• Genetic testing capable of detecting the
• If the
• Somatic and germline mosaicism in mildly affected parents of affected sibs has been reported in two families [
• Somatic and/or germline mosaicism for a
• Somatic and germline mosaicism in mildly affected parents of affected sibs has been reported in two families [
• Somatic and/or germline mosaicism for a
• Somatic and germline mosaicism in mildly affected parents of affected sibs has been reported in two families [
• Somatic and/or germline mosaicism for a
• If a parent of the proband is heterozygous for a
• If the proband has a known
• If a proband has a chromosome rearrangement, the recurrence risk to sibs depends on the chromosome findings in the parents:
• If neither parent has a chromosome rearrangement, the risk to sibs is negligible.
• If a parent has a balanced chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
• If neither parent has a chromosome rearrangement, the risk to sibs is negligible.
• If a parent has a balanced chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
• If neither parent has a chromosome rearrangement, the risk to sibs is negligible.
• If a parent has a balanced chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
• Each child of an individual with a non-mosaic
• The risk to offspring of an individual with a chromosome rearrangement involving
• Because CD typically occurs as a
• If a parent has a balanced chromosome rearrangement, the parent's family members are at risk and can be offered chromosome analysis.
## Related Genetic Counseling Issues
## Prenatal Testing and Preimplantation Genetic Testing
Once a
Similarly, prenatal testing for a pregnancy at increased risk for a familial chromosome rearrangement is possible by chromosome analysis of fetal cells obtained by amniocentesis or chorionic villus sampling.
• Once a
• Similarly, prenatal testing for a pregnancy at increased risk for a familial chromosome rearrangement is possible by chromosome analysis of fetal cells obtained by amniocentesis or chorionic villus sampling.
## Resources
University Hospital Freiberg, Centre for Pediatrics and Adolescent Medicine
Mathildenstrasse 1
Freiburg 79106
Germany
•
•
•
•
•
•
•
• University Hospital Freiberg, Centre for Pediatrics and Adolescent Medicine
• Mathildenstrasse 1
• Freiburg 79106
• Germany
•
•
## Molecular Genetics
Campomelic Dysplasia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Campomelic Dysplasia (
Pathogenic variants within the
SOX9 is a proven key regulator at various steps of chondrocyte differentiation, regulating expression of the collagen genes
Regulation of
Studies in mice provide evidence that the murine ortholog of human
Thus, the wide spectrum of pathologic symptoms seen in CD, including the skeletal defects, XY sex reversal, pancreatic defects (size reduction of islets of Langerhans and reduced insulin secretion), heart defects, and sensorineural and conductive hearing impairment, can be attributed directly to impaired ability of the pleiotropic developmental regulator SOX9 to activate target genes during organogenesis.
• Regulation of
• Studies in mice provide evidence that the murine ortholog of human
## Molecular Pathogenesis
Pathogenic variants within the
SOX9 is a proven key regulator at various steps of chondrocyte differentiation, regulating expression of the collagen genes
Regulation of
Studies in mice provide evidence that the murine ortholog of human
Thus, the wide spectrum of pathologic symptoms seen in CD, including the skeletal defects, XY sex reversal, pancreatic defects (size reduction of islets of Langerhans and reduced insulin secretion), heart defects, and sensorineural and conductive hearing impairment, can be attributed directly to impaired ability of the pleiotropic developmental regulator SOX9 to activate target genes during organogenesis.
• Regulation of
• Studies in mice provide evidence that the murine ortholog of human
## Chapter Notes
6 April 2023 (sw) Revision: "
18 March 2021 (sw) Comprehensive update posted live
9 May 2013 (me) Comprehensive update posted live
31 July 2008 (cg) Review posted live
14 May 2008 (su) Original submission
• 6 April 2023 (sw) Revision: "
• 18 March 2021 (sw) Comprehensive update posted live
• 9 May 2013 (me) Comprehensive update posted live
• 31 July 2008 (cg) Review posted live
• 14 May 2008 (su) Original submission
## Author Notes
## Revision History
6 April 2023 (sw) Revision: "
18 March 2021 (sw) Comprehensive update posted live
9 May 2013 (me) Comprehensive update posted live
31 July 2008 (cg) Review posted live
14 May 2008 (su) Original submission
• 6 April 2023 (sw) Revision: "
• 18 March 2021 (sw) Comprehensive update posted live
• 9 May 2013 (me) Comprehensive update posted live
• 31 July 2008 (cg) Review posted live
• 14 May 2008 (su) Original submission
## References
## Literature Cited
Cervical spine changes (i.e., abnormal AP curvature and anterior dislocation of C2 on C3) (arrow) in a boy age 11 months with classic campomelic dysplasia
Molecularly confirmed "acampomelic" campomelic dysplasia
A. Tracheostomy tube is in place and the scapulae are markedly hypoplastic (arrows).
B. Vertically oriented narrow iliac wings
C. Straight femora and tibiae
Classic radiographic features of campomelic dysplasia in a 24-week fetus. Note cervical spine abnormalities, hypoplastic thoracic vertebral pedicles, scapular hypoplasia, narrow iliac wings, bowing of the femora and the tibiae, and clubfeet.
|
[
"H Akiyama, V Lefebvre. Unraveling the transcriptional regulatory machinery in chondrogenesis.. J Bone Miner Metab 2011;29:390-5",
"S Benko, JA Fantes, J Amiel, DJ Kleinjan, S Thomas, J Ramsay, N Jamshidi, A Essafi, S Heaney, CT Gordon, D McBride, C Golzio, M Fisher, P Perry, V Abadie, C Ayuso, M Holder-Espinasse, N Kilpatrick, MM Lees, A Picard, IK Temple, P Thomas, MP Vazquez, M Vekemans, H Roest Crollius, ND Hastie, A Munnich, HC Etchevers, A Pelet, PG Farlie, DR Fitzpatrick, S Lyonnet. Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence.. Nat Genet 2009;41:359-64",
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"P Bernard, P Tang, S Liu, P Dewing, VR Harley, E Vilain. Dimerization of SOX9 is required for chondrogenesis, but not for sex determination.. Hum Mol Genet 2003;12:1755-65",
"B Bhagavath, LC Layman, R Ullmann, Y Shen, K Ha, K Rehman, S Looney, PG McDonough, HG Kim, BR Carr. Familial 46,XY sex reversal without campomelic dysplasia caused by a deletion upstream of the SOX9 gene.. Mol Cell Endocrinol 2014;393:1-7",
"FJ Cameron, RM Hageman, C Cooke-Yarborough, C Kwok, LL Goodwin, DO Sillence, AH Sinclair. A novel germ line mutation in SOX9 causes familial campomelic dysplasia and sex reversal.. Hum Mol Genet 1996;5:1625-30",
"M Castori, I Bottillo, S Morlino, C Barone, P Cascone, P Grammatico, L Laino. Variability in a three-generation family with Pierre Robin sequence, acampomelic campomelic dysplasia, and intellectual disability due to a novel ∼1 Mb deletion upstream of SOX9, and including KCNJ2 and KCNJ16.. Birth Defects Res A Clin Mol Teratol 2016;106:61-8",
"S Corbani, E Chouery, B Eid, N Jalkh, JA Ghoch, A Mégarbané. Mild campomelic dysplasia: report on a case and review.. Mol Syndromol 2011;1:163-8",
"JJ Cox, L Willatt, T Homfray, CG Woods. A SOX9 duplication and familial 46,XX developmental testicular disorder.. N Engl J Med 2011;364:91-3",
"F Csukasi, I Duran, W Zhang, JH Martin, M Barad, M Bamshad, MA Weis, D Eyre, D Krakow, DH Cohn. Dominant-negative SOX9 mutations in campomelic dysplasia.. Hum Mutat 2019;40:2344-52",
"AC Fonseca, A Bonaldi, DR Bertola, CA Kim, PA Otto, AM Vianna-Morgante. The clinical impact of chromosomal rearrangements with breakpoints upstream of the SOX9 gene: two novel de novo balanced translocations associated with acampomelic campomelic dysplasia.. BMC Med Genet 2013;14:50",
"M Fukami, T Tsuchiya, S Takada, A Kanbara, H Asahara, A Igarashi, Y Kamiyama, G Nishimura, T Ogata. Complex genomic rearrangement in the SOX9 5' region in a patient with Pierre Robin sequence and hypoplastic left scapula.. Am J Med Genet 2012;158A:1529-34",
"B Gentilin, F Forzano, MF Bedeschi, T Rizzuti, F Faravelli, C Izzi, M Lituania, C Rodriguez-Perez, MP Bondioni, G Savoldi, E Grosso, G Botta, E Viora, AM Baffico, F Lalatta. Phenotype of five cases of prenatally diagnosed campomelic dysplasia harboring novel mutations of the SOX9 gene.. Ultrasound Obstet Gynecol 2010;36:315-23",
"CT Gordon, TY Tan, S Benko, D Fitzpatrick, S Lyonnet, PG Farlie. Long-range regulation at the SOX9 locus in development and disease.. J Med Genet 2009;46:649-56",
"D Higeta, R Yamaguchi, T Takagi, G Nishimura, K Sameshima, K Saito, T Minegishi. Familial campomelic dysplasia due to maternal germinal mosaicism.. Congenit Anom (Kyoto) 2018;58:194-7",
"KL Hill-Harfe, L Kaplan, HJ Stalker, RT Zori, R Pop, G Scherer, MR Wallace. Fine mapping of chromosome 17 translocation breakpoints > or = 900 kb upstream of SOX9 in acampomelic campomelic dysplasia and a mild, familial skeletal dysplasia.. Am J Hum Genet 2005;76:663-71",
"SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97",
"LP Jakobsen, R Ullmann, SB Christensen, KE Jensen, K Molsted, KF Henriksen, C Hansen, MA Knudsen, LA Larsen, N Tommerup, Z Tumer. Pierre Robin sequence may be caused by dysregulation of SOX9 and KCNJ2.. J Med Genet 2007;44:381-6",
"S Jakubiczka, C Schröder, R Ullmann, M Volleth, S Ledig, E Gilberg, P Kroisel, P Wieacker. Translocation and deletion around SOX9 in a patient with acampomelic campomelic dysplasia and sex reversal.. Sex Dev 2010;4:143-9",
"G Kayhan, P Calis, D Karcaaltincaba, E Tug. Prenatal diagnosis of campomelic dysplasia due to SOX9 deletion.. J Obstet Gynaecol 2019;39:1175-6",
"C Lecointre, O Pichon, A Hamel, Y Heloury, L Michel-Calemard, Y Morel, A David, C Le Caignec. Familial acampomelic form of campomelic dysplasia caused by a 960 kb deletion upstream of SOX9.. Am J Med Genet 2009;149A:1183-9",
"M Leipoldt, M Erdel, GA Bien-Willner, M Smyk, M Theurl, S Yatsenko, JR Lupski, AH Lane, AL Shanske, P Stankiewicz, G Scherer. Two novel translocation breakpoints upstream of SOX9 define borders of the proximal and distal breakpoint cluster region in campomelic dysplasia.. Clin Genet 2007;71:67-75",
"S Mansour, AC Offiah, S McDowall, P Sim, J Tolmie, C Hall. The phenotype of survivors of campomelic dysplasia.. J Med Genet 2002;39:597-602",
"EP Mattos, MT Sanseverino, JA Magalhães, JC Leite, TM Félix, LA Todeschini, DP Cavalcanti, L Schüler-Faccini. Clinical and molecular characterization of a Brazilian cohort of campomelic dysplasia patients, and identification of seven new SOX9 mutations.. Genet Mol Biol 2015;38:14-20",
"J Meyer, P Sudbeck, M Held, T Wagner, ML Schmitz, FD Bricarelli, E Eggermont, U Friedrich, OA Haas, A Kobelt, JG Leroy, L van Maldergem, E Michel, B Mitulla, RA Pfeiffer, A Schinzel, H Schmidt, G Scherer. Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations.. Hum Mol Genet 1997;6:91-8",
"S Ninomiya, K Narahara, K Tsuji, Y Yokoyama, S Ito, Y Seino. Acampomelic campomelic syndrome and sex reversal associated with de novo t(12;17) translocation.. Am J Med Genet 1995;56:31-4",
"PN Olney, LS Kean, D Graham, LJ Elsas, KM May. Campomelic syndrome and deletion of SOX9.. Am J Med Genet 1999;84:20-4",
"D Pfeifer, R Kist, K Dewar, K Devon, ES Lander, B Birren, L Korniszewski, E Back, G Scherer. Campomelic dysplasia translocation breakpoints are scattered over 1 Mb proximal to SOX9: evidence for an extended control region.. Am J Hum Genet 1999;65:111-24",
"K Piper, SG Ball, JW Keeling, S Mansoor, DI Wilson, NA Hanley. Novel SOX9 expression during human pancreas development correlates to abnormalities in campomelic dysplasia.. Mech Dev 2002;116:223-6",
"R Pop, C Conz, KS Lindenberg, S Blesson, B Schmalenberger, S Briault, D Pfeifer, G Scherer. Screening of the 1 Mb SOX9 5' control region by array CGH identifies a large deletion in a case of campomelic dysplasia with XY sex reversal.. J Med Genet 2004;41",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"R Savarirayan, SP Robertson, A Bankier, JG Rogers. Variable expression of campomelic dysplasia in a father and his 46,XY daughter.. Pediatr Pathol Mol Med 2003;22:37-46",
"T Schramm, KP Gloning, S Minderer, C Daumer-Haas, K Hörtnagel, A Nerlich, B Tutschek. Prenatal sonographic diagnosis of skeletal dysplasias.. Ultrasound Obstet Gynecol 2009;34:160-70",
"M Smyk, E Obersztyn, B Nowakowska, E Bocian, SW Cheung, T Mazurczak, P Stankiewicz. Recurrent SOX9 deletion campomelic dysplasia due to somatic mosaicism in the father.. Am J Med Genet 2007;143A:866-70",
"E Sock, RA Pagon, K Keymolen, W Lissens, M Wegner, G Scherer. Loss of DNA-dependent dimerization of the transcription factor SOX9 as a cause for campomelic dysplasia.. Hum Mol Genet 2003;12:1439-47",
"A Staffler, M Hammel, M Wahlbuhl, C Bidlingmaier, AW Flemmer, P Pagel, T Nicolai, M Wegner, A Holzinger. Heterozygous SOX9 mutations allowing for residual DNA-binding and transcriptional activation lead to the acampomelic variant of campomelic dysplasia.. Hum Mutat 2010;31:E1436-44",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"S Thomas, R Winter, J Lonstein. The treatment of progressive kyphoscoliosis in Camptomelic dysplasia.. Spine 1997;22:1330-7",
"S Unger, CR Ferreira, GR Mortier, H Ali, DR Bertola, A Calder, DH Cohn, V Cormier-Daire, KM Girisha, C Hall, D Krakow, O Makitie, S Mundlos, G Nishimura, SP Robertson, R Savarirayan, D Sillence, M Simon, VR Sutton, ML Warman, A Superti-Furga. Nosology of genetic skeletal disorders: 2023 revision.. Am J Med Genet A. 2023;191:1164-209",
"GV Velagaleti, GA Bien-Willner, JK Northup, LH Lockhart, JC Hawkins, SM Jalal, M Withers, JR Lupski, P Stankiewicz. Position effects due to chromosome breakpoints that map approximately 900 Kb upstream and approximately 1.3 Mb downstream of SOX9 in two individuals with campomelic dysplasia.. Am J Hum Genet 2005;76:652-62",
"A Vetro, R Ciccone, R Giorda, MG Patricelli, ED Mina, A Forlino, O Zuffardi. XX males SRY negative: a confirmed cause of Infertility.. J Med Genet 2011;48:710-2",
"VP Vidal, MC Chaboissier, DG de Rooij, A Schedl. Sox9 induces testis development in XX transgenic mice.. Nat Genet 2001;28:216-17",
"AE von Bohlen, J Böhm, R Pop, DS Johnson, J Tolmie, R Stücker, D Morris-Rosendahl, G Scherer. A mutation creating an upstream initiation codon in the SOX9 5' UTR causes acampomelic campomelic dysplasia.. Mol Genet Genomic Med. 2017;5:261-8",
"T Wagner, J Wirth, J Meyer, B Zabel, M Held, J Zimmer, J Pasantes, FD Bricarelli, J Keutel, E Hustert, U Wolf, N Tommerup, W Schempp, G Scherer. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9.. Cell 1994;79:1111-20",
"LC Walters-Sen, DL Thrush, SE Hickey, S Hashimoto, S Reshmi, JM Gastier-Foster, RE Pyatt, C Astbury. Atypical breakpoint in a t(6;17) translocation case of acampomelic campomelic dysplasia.. Eur J Med Genet 2014;57:315-8",
"S White, T Ohnesorg, A Notini, K Roeszler, J Hewitt, H Daggag, C Smith, E Turbitt, S Gustin, J van den Bergen, D Miles, P Western, V Arboleda, V Schumacher, L Gordon, K Bell, H Bengtsson, T Speed, J Hutson, G Warne, V Harley, P Koopman, E Vilain, A Sinclair. Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis.. PLoS ONE 2011;6"
] |
31/7/2008
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18/3/2021
|
6/4/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
canavan
|
canavan
|
[
"ASPA Deficiency",
"Aspartoacylase Deficiency",
"Aspartoacylase Deficiency",
"ASPA Deficiency",
"Typical Canavan Disease",
"Atypical Canavan Disease",
"Aspartoacylase",
"ASPA",
"Canavan Disease"
] |
Canavan Disease
|
Amanda Nagy, Annette E Bley, Florian Eichler
|
Summary Canavan disease is a leukodystrophy characterized by neurodevelopmental delays, macrocephaly, and tone abnormalities. The phenotypic spectrum ranges from the more severe typical Canavan disease (85%-90% of individuals) to the less severe atypical Canavan disease (10%-15%). Typical Canavan disease is characterized by neurodevelopmental impairment evident by ages three to five months, followed by neurodegeneration and developmental regression. The clinical course of atypical Canavan disease is more variable, with neurodevelopmental delay usually becoming evident in the first years of life and frequently followed by developmental regression later in childhood or adolescence. All individuals with Canavan disease have reduced life expectancy, with the majority surviving to age ten years and the minority living to adulthood. The diagnosis of Canavan disease is established in a proband with suggestive findings either by biochemical testing or by molecular genetic testing. The biochemical diagnosis is established in an individual with suggestive clinical findings and elevated N-acetylaspartic acid (NAA) in urine (using gas chromatography-mass spectrometry) or in the brain by proton magnetic resonance spectroscopy. The molecular diagnosis is established in an individual with suggestive clinical findings and biallelic Canavan disease is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
Canavan Disease: Phenotypic Spectrum
For synonyms and outdated names see
## Diagnosis
No consensus clinical diagnostic criteria for Canavan disease have been published.
Canavan disease
The triad of hypotonia, head lag, and macrocephaly after age three to five months
Poor visual tracking and nystagmus
Difficulties with suck and swallow
Seizures
Developmental delays that become apparent in the first few months of life, with most not achieving developmental milestones beyond a six-month level
Developmental regression with onset in the first years of life
Brain CT or MRI performed in early infancy may be interpreted as normal [
Brain magnetic resonance spectroscopy to detect N-acetylaspartic acid has been reported as a method of diagnosing Canavan disease in infants, even those with normal serum and urine N-acetylaspartic acid levels [
Developmental delay with onset in the first years of life; may not experience regression
May be normocephalic or macrocephalic
Nystagmus and/or vision impairment
Ataxia or coordination difficulties
The diagnosis of Canavan disease
The
The
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Elevated NAA in urine using GC-MS is diagnostic of Canavan disease [
In typical Canavan disease urine NAA is significantly elevated, often >100-fold.
In atypical Canavan disease urine NAA is mildly elevated (~10-fold).
Note: (1) Although NAA concentration is also elevated in the blood and cerebrospinal fluid (CSF) of children with typical Canavan disease, elevated concentration of NAA in urine is sufficient for the diagnosis of typical Canavan disease in affected individuals [
Molecular genetic testing approaches can include a combination of
When the clinical and biochemical findings suggest the diagnosis of Canavan disease, molecular genetic testing approaches can include
Note: If an individual has a biochemical diagnosis of Canavan disease (see
For an introduction to multigene panels click
To date, the majority of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Canavan Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
• The triad of hypotonia, head lag, and macrocephaly after age three to five months
• Poor visual tracking and nystagmus
• Difficulties with suck and swallow
• Seizures
• Developmental delays that become apparent in the first few months of life, with most not achieving developmental milestones beyond a six-month level
• Developmental regression with onset in the first years of life
• Brain CT or MRI performed in early infancy may be interpreted as normal [
• Brain magnetic resonance spectroscopy to detect N-acetylaspartic acid has been reported as a method of diagnosing Canavan disease in infants, even those with normal serum and urine N-acetylaspartic acid levels [
• Developmental delay with onset in the first years of life; may not experience regression
• May be normocephalic or macrocephalic
• Nystagmus and/or vision impairment
• Ataxia or coordination difficulties
• In typical Canavan disease urine NAA is significantly elevated, often >100-fold.
• In atypical Canavan disease urine NAA is mildly elevated (~10-fold).
• Note: If an individual has a biochemical diagnosis of Canavan disease (see
• For an introduction to multigene panels click
## Suggestive Findings
Canavan disease
The triad of hypotonia, head lag, and macrocephaly after age three to five months
Poor visual tracking and nystagmus
Difficulties with suck and swallow
Seizures
Developmental delays that become apparent in the first few months of life, with most not achieving developmental milestones beyond a six-month level
Developmental regression with onset in the first years of life
Brain CT or MRI performed in early infancy may be interpreted as normal [
Brain magnetic resonance spectroscopy to detect N-acetylaspartic acid has been reported as a method of diagnosing Canavan disease in infants, even those with normal serum and urine N-acetylaspartic acid levels [
Developmental delay with onset in the first years of life; may not experience regression
May be normocephalic or macrocephalic
Nystagmus and/or vision impairment
Ataxia or coordination difficulties
• The triad of hypotonia, head lag, and macrocephaly after age three to five months
• Poor visual tracking and nystagmus
• Difficulties with suck and swallow
• Seizures
• Developmental delays that become apparent in the first few months of life, with most not achieving developmental milestones beyond a six-month level
• Developmental regression with onset in the first years of life
• Brain CT or MRI performed in early infancy may be interpreted as normal [
• Brain magnetic resonance spectroscopy to detect N-acetylaspartic acid has been reported as a method of diagnosing Canavan disease in infants, even those with normal serum and urine N-acetylaspartic acid levels [
• Developmental delay with onset in the first years of life; may not experience regression
• May be normocephalic or macrocephalic
• Nystagmus and/or vision impairment
• Ataxia or coordination difficulties
## Typical Canavan Disease
The triad of hypotonia, head lag, and macrocephaly after age three to five months
Poor visual tracking and nystagmus
Difficulties with suck and swallow
Seizures
Developmental delays that become apparent in the first few months of life, with most not achieving developmental milestones beyond a six-month level
Developmental regression with onset in the first years of life
Brain CT or MRI performed in early infancy may be interpreted as normal [
Brain magnetic resonance spectroscopy to detect N-acetylaspartic acid has been reported as a method of diagnosing Canavan disease in infants, even those with normal serum and urine N-acetylaspartic acid levels [
• The triad of hypotonia, head lag, and macrocephaly after age three to five months
• Poor visual tracking and nystagmus
• Difficulties with suck and swallow
• Seizures
• Developmental delays that become apparent in the first few months of life, with most not achieving developmental milestones beyond a six-month level
• Developmental regression with onset in the first years of life
• Brain CT or MRI performed in early infancy may be interpreted as normal [
• Brain magnetic resonance spectroscopy to detect N-acetylaspartic acid has been reported as a method of diagnosing Canavan disease in infants, even those with normal serum and urine N-acetylaspartic acid levels [
## Atypical Canavan Disease
Developmental delay with onset in the first years of life; may not experience regression
May be normocephalic or macrocephalic
Nystagmus and/or vision impairment
Ataxia or coordination difficulties
• Developmental delay with onset in the first years of life; may not experience regression
• May be normocephalic or macrocephalic
• Nystagmus and/or vision impairment
• Ataxia or coordination difficulties
## Establishing the Diagnosis
The diagnosis of Canavan disease
The
The
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Elevated NAA in urine using GC-MS is diagnostic of Canavan disease [
In typical Canavan disease urine NAA is significantly elevated, often >100-fold.
In atypical Canavan disease urine NAA is mildly elevated (~10-fold).
Note: (1) Although NAA concentration is also elevated in the blood and cerebrospinal fluid (CSF) of children with typical Canavan disease, elevated concentration of NAA in urine is sufficient for the diagnosis of typical Canavan disease in affected individuals [
Molecular genetic testing approaches can include a combination of
When the clinical and biochemical findings suggest the diagnosis of Canavan disease, molecular genetic testing approaches can include
Note: If an individual has a biochemical diagnosis of Canavan disease (see
For an introduction to multigene panels click
To date, the majority of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Canavan Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
• In typical Canavan disease urine NAA is significantly elevated, often >100-fold.
• In atypical Canavan disease urine NAA is mildly elevated (~10-fold).
• Note: If an individual has a biochemical diagnosis of Canavan disease (see
• For an introduction to multigene panels click
## Biochemical Diagnosis
Elevated NAA in urine using GC-MS is diagnostic of Canavan disease [
In typical Canavan disease urine NAA is significantly elevated, often >100-fold.
In atypical Canavan disease urine NAA is mildly elevated (~10-fold).
Note: (1) Although NAA concentration is also elevated in the blood and cerebrospinal fluid (CSF) of children with typical Canavan disease, elevated concentration of NAA in urine is sufficient for the diagnosis of typical Canavan disease in affected individuals [
• In typical Canavan disease urine NAA is significantly elevated, often >100-fold.
• In atypical Canavan disease urine NAA is mildly elevated (~10-fold).
## Molecular Genetic Diagnosis
Molecular genetic testing approaches can include a combination of
When the clinical and biochemical findings suggest the diagnosis of Canavan disease, molecular genetic testing approaches can include
Note: If an individual has a biochemical diagnosis of Canavan disease (see
For an introduction to multigene panels click
To date, the majority of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Canavan Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
• Note: If an individual has a biochemical diagnosis of Canavan disease (see
• For an introduction to multigene panels click
##
When the clinical and biochemical findings suggest the diagnosis of Canavan disease, molecular genetic testing approaches can include
Note: If an individual has a biochemical diagnosis of Canavan disease (see
For an introduction to multigene panels click
• Note: If an individual has a biochemical diagnosis of Canavan disease (see
• For an introduction to multigene panels click
##
To date, the majority of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Canavan Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
## Clinical Characteristics
Canavan disease is a leukodystrophy characterized by neurodevelopmental delays, macrocephaly, and tone abnormalities. The phenotypic spectrum ranges from the more severe typical Canavan disease (~85%-90% of individuals) to the less severe atypical Canavan disease (10%-15%) [
In typical Canavan disease, neurodevelopmental impairment becomes evident by ages three to five months and is followed by neurodegeneration and developmental regression.
In atypical Canavan disease, neurodevelopmental delay usually becomes evident in the first years of life, frequently followed by developmental regression later in childhood or adolescence; however, the clinical course is more variable than in typical Canavan disease.
Individuals with Canavan disease have a reduced life expectancy, with 73% surviving to age ten years and a minority of individuals living to adulthood, as reported in a cohort comprising individuals with typical and atypical Canavan disease [
More than half of affected children develop a social smile and laugh. The minority are able to reach for objects and use their hands purposefully.
Many children with atypical Canavan disease have normal head size, although macrocephaly is also seen.
In spite of developmental delay, most of these children participate in classroom settings and may benefit from an individualized education plan or other educational intervention [
Other findings in some individuals can include retinitis pigmentosa and seizures [
Ataxia, coordination difficulties, and gait disturbances are frequently reported in atypical Canavan disease [
Genotype-phenotype correlations have been proposed with the following classes of variants depending on the effect of these variants on residual aspartoacylase enzyme activity (see
The two common
The
Canavan disease has also been referred to as spongy degeneration of the brain (Van Bogaert and Bertrand type). Subcortical spongy degeneration is observed on neuropathology in typical Canavan disease; electron microscopy reveals swollen astrocytes and distorted mitochondria. See
Typical and atypical Canavan disease may also be referred to as infantile and juvenile Canavan disease, respectively.
Canavan disease occurs in all populations.
Due to the founder
Currently, most new diagnoses of Canavan disease are made in individuals with no known Ashkenazi Jewish ancestry [
## Clinical Description
Canavan disease is a leukodystrophy characterized by neurodevelopmental delays, macrocephaly, and tone abnormalities. The phenotypic spectrum ranges from the more severe typical Canavan disease (~85%-90% of individuals) to the less severe atypical Canavan disease (10%-15%) [
In typical Canavan disease, neurodevelopmental impairment becomes evident by ages three to five months and is followed by neurodegeneration and developmental regression.
In atypical Canavan disease, neurodevelopmental delay usually becomes evident in the first years of life, frequently followed by developmental regression later in childhood or adolescence; however, the clinical course is more variable than in typical Canavan disease.
Individuals with Canavan disease have a reduced life expectancy, with 73% surviving to age ten years and a minority of individuals living to adulthood, as reported in a cohort comprising individuals with typical and atypical Canavan disease [
More than half of affected children develop a social smile and laugh. The minority are able to reach for objects and use their hands purposefully.
Many children with atypical Canavan disease have normal head size, although macrocephaly is also seen.
In spite of developmental delay, most of these children participate in classroom settings and may benefit from an individualized education plan or other educational intervention [
Other findings in some individuals can include retinitis pigmentosa and seizures [
Ataxia, coordination difficulties, and gait disturbances are frequently reported in atypical Canavan disease [
## Typical Canavan Disease
More than half of affected children develop a social smile and laugh. The minority are able to reach for objects and use their hands purposefully.
## Atypical Canavan Disease
Many children with atypical Canavan disease have normal head size, although macrocephaly is also seen.
In spite of developmental delay, most of these children participate in classroom settings and may benefit from an individualized education plan or other educational intervention [
Other findings in some individuals can include retinitis pigmentosa and seizures [
Ataxia, coordination difficulties, and gait disturbances are frequently reported in atypical Canavan disease [
## Genotype-Phenotype Correlations
Genotype-phenotype correlations have been proposed with the following classes of variants depending on the effect of these variants on residual aspartoacylase enzyme activity (see
The two common
The
## Nomenclature
Canavan disease has also been referred to as spongy degeneration of the brain (Van Bogaert and Bertrand type). Subcortical spongy degeneration is observed on neuropathology in typical Canavan disease; electron microscopy reveals swollen astrocytes and distorted mitochondria. See
Typical and atypical Canavan disease may also be referred to as infantile and juvenile Canavan disease, respectively.
## Prevalence
Canavan disease occurs in all populations.
Due to the founder
Currently, most new diagnoses of Canavan disease are made in individuals with no known Ashkenazi Jewish ancestry [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genetic Neurodegenerative Disorders of Infancy in the Differential Diagnosis of Typical Canavan Disease
Spongy degeneration of brain
Profound developmental delay
Neonatal form manifests in 1st hrs/days of life w/progressive lethargy, hypotonia, & myoclonic jerks.
Apnea
Intractable seizures
Large head
Spasticity
Ataxia
Occasional seizures
Mild cognitive decline
Marked frontal predominance of white matter changes
Rostrocaudal progression of myelin loss on serial imaging studies
↑ startle response
Cherry-red spot of the macula of the retina
↑ startle response
Cherry-red spot of the macula of the retina
AD = autosomal dominant; AR = autosomal recessive; CSF = cerebrospinal fluid; Mat = maternal; MOI = mode of inheritance; XL = X-linked
In addition to being a neurodegenerative disorder of infancy
Biallelic pathogenic variants in
Classic megalencephalic leukoencephalopathy with subcortical cysts (MLC) is most commonly caused by biallelic pathogenic variants in
See
Atypical Canavan disease may be misdiagnosed as a mitochondrial disorder given the overlapping neuroimaging features of bilateral deep gray matter involvement (see
• Spongy degeneration of brain
• Profound developmental delay
• Neonatal form manifests in 1st hrs/days of life w/progressive lethargy, hypotonia, & myoclonic jerks.
• Apnea
• Intractable seizures
• Large head
• Spasticity
• Ataxia
• Occasional seizures
• Mild cognitive decline
• Marked frontal predominance of white matter changes
• Rostrocaudal progression of myelin loss on serial imaging studies
• ↑ startle response
• Cherry-red spot of the macula of the retina
• ↑ startle response
• Cherry-red spot of the macula of the retina
## Typical Canavan Disease
Genetic Neurodegenerative Disorders of Infancy in the Differential Diagnosis of Typical Canavan Disease
Spongy degeneration of brain
Profound developmental delay
Neonatal form manifests in 1st hrs/days of life w/progressive lethargy, hypotonia, & myoclonic jerks.
Apnea
Intractable seizures
Large head
Spasticity
Ataxia
Occasional seizures
Mild cognitive decline
Marked frontal predominance of white matter changes
Rostrocaudal progression of myelin loss on serial imaging studies
↑ startle response
Cherry-red spot of the macula of the retina
↑ startle response
Cherry-red spot of the macula of the retina
AD = autosomal dominant; AR = autosomal recessive; CSF = cerebrospinal fluid; Mat = maternal; MOI = mode of inheritance; XL = X-linked
In addition to being a neurodegenerative disorder of infancy
Biallelic pathogenic variants in
Classic megalencephalic leukoencephalopathy with subcortical cysts (MLC) is most commonly caused by biallelic pathogenic variants in
See
• Spongy degeneration of brain
• Profound developmental delay
• Neonatal form manifests in 1st hrs/days of life w/progressive lethargy, hypotonia, & myoclonic jerks.
• Apnea
• Intractable seizures
• Large head
• Spasticity
• Ataxia
• Occasional seizures
• Mild cognitive decline
• Marked frontal predominance of white matter changes
• Rostrocaudal progression of myelin loss on serial imaging studies
• ↑ startle response
• Cherry-red spot of the macula of the retina
• ↑ startle response
• Cherry-red spot of the macula of the retina
## Atypical Canavan Disease
Atypical Canavan disease may be misdiagnosed as a mitochondrial disorder given the overlapping neuroimaging features of bilateral deep gray matter involvement (see
## Management
No clinical practice guidelines for Canavan disease have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.
To establish the extent of disease and needs in an individual diagnosed with Canavan disease, the evaluations summarized in
Canavan Disease: Recommended Evaluations Following Initial Diagnosis
Consider EEG if seizures are a concern.
Measurement of head circumference
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention program
Atypical Canavan disease: eval for special education (IEP/504 plan)
Gross motor & fine motor skills
Contractures, hip development, & kyphoscoliosis
Mobility, ADL, & need for adaptive devices / positioning & mobility devices, disability parking placard
Need for PT (to retain/improve gross motor skills) &/or OT (to retain/improve fine motor skills)
Monitor growth trajectory (length & weight).
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support
Home nursing referral
ADL = activities of daily living; IEP = individualized education plan; NAA = N-acetylaspartic acid; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for Canavan disease.
Canavan Disease: Treatment of Manifestations
Many ASMs may be effective; none have been demonstrated specifically effective for this disorder.
Education of parents/caregivers
PT to minimize contractures & optimize abilities & seating posture
Consider need for durable medical equipment (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers) & disability parking placard.
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Low threshold for clinical feeding eval when showing clinical signs or symptoms of dysphagia
Radiographic swallowing study should be performed if there is diagnostic uncertainty &/or as recommended by speech-language pathologist to clarify tolerated consistencies.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services provide specially designed instruction and related services to children who qualify.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Canavan Disease: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
OT = occupational therapy; PT = physical therapy
See
A Phase I/II open label clinical trial to evaluate BBP-812, an AAV9-based gene therapy, is currently recruiting. See
A Phase I/II open label clinical trial to evaluate rAAV-Olig001-ASPA, an oligodendrocyte-specific AAV-based gene therapy, is active but not currently recruiting. See
Search
• Consider EEG if seizures are a concern.
• Measurement of head circumference
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention program
• Atypical Canavan disease: eval for special education (IEP/504 plan)
• Gross motor & fine motor skills
• Contractures, hip development, & kyphoscoliosis
• Mobility, ADL, & need for adaptive devices / positioning & mobility devices, disability parking placard
• Need for PT (to retain/improve gross motor skills) &/or OT (to retain/improve fine motor skills)
• Monitor growth trajectory (length & weight).
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support
• Home nursing referral
• Many ASMs may be effective; none have been demonstrated specifically effective for this disorder.
• Education of parents/caregivers
• PT to minimize contractures & optimize abilities & seating posture
• Consider need for durable medical equipment (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers) & disability parking placard.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Low threshold for clinical feeding eval when showing clinical signs or symptoms of dysphagia
• Radiographic swallowing study should be performed if there is diagnostic uncertainty &/or as recommended by speech-language pathologist to clarify tolerated consistencies.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services provide specially designed instruction and related services to children who qualify.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Canavan disease, the evaluations summarized in
Canavan Disease: Recommended Evaluations Following Initial Diagnosis
Consider EEG if seizures are a concern.
Measurement of head circumference
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention program
Atypical Canavan disease: eval for special education (IEP/504 plan)
Gross motor & fine motor skills
Contractures, hip development, & kyphoscoliosis
Mobility, ADL, & need for adaptive devices / positioning & mobility devices, disability parking placard
Need for PT (to retain/improve gross motor skills) &/or OT (to retain/improve fine motor skills)
Monitor growth trajectory (length & weight).
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support
Home nursing referral
ADL = activities of daily living; IEP = individualized education plan; NAA = N-acetylaspartic acid; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Consider EEG if seizures are a concern.
• Measurement of head circumference
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention program
• Atypical Canavan disease: eval for special education (IEP/504 plan)
• Gross motor & fine motor skills
• Contractures, hip development, & kyphoscoliosis
• Mobility, ADL, & need for adaptive devices / positioning & mobility devices, disability parking placard
• Need for PT (to retain/improve gross motor skills) &/or OT (to retain/improve fine motor skills)
• Monitor growth trajectory (length & weight).
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for Canavan disease.
Canavan Disease: Treatment of Manifestations
Many ASMs may be effective; none have been demonstrated specifically effective for this disorder.
Education of parents/caregivers
PT to minimize contractures & optimize abilities & seating posture
Consider need for durable medical equipment (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers) & disability parking placard.
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Low threshold for clinical feeding eval when showing clinical signs or symptoms of dysphagia
Radiographic swallowing study should be performed if there is diagnostic uncertainty &/or as recommended by speech-language pathologist to clarify tolerated consistencies.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services provide specially designed instruction and related services to children who qualify.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Many ASMs may be effective; none have been demonstrated specifically effective for this disorder.
• Education of parents/caregivers
• PT to minimize contractures & optimize abilities & seating posture
• Consider need for durable medical equipment (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers) & disability parking placard.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Low threshold for clinical feeding eval when showing clinical signs or symptoms of dysphagia
• Radiographic swallowing study should be performed if there is diagnostic uncertainty &/or as recommended by speech-language pathologist to clarify tolerated consistencies.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services provide specially designed instruction and related services to children who qualify.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services provide specially designed instruction and related services to children who qualify.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services provide specially designed instruction and related services to children who qualify.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Canavan Disease: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
OT = occupational therapy; PT = physical therapy
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
A Phase I/II open label clinical trial to evaluate BBP-812, an AAV9-based gene therapy, is currently recruiting. See
A Phase I/II open label clinical trial to evaluate rAAV-Olig001-ASPA, an oligodendrocyte-specific AAV-based gene therapy, is active but not currently recruiting. See
Search
## Genetic Counseling
Canavan disease is inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygous for an
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
The Canavan disease phenotype is consistent among affected family members.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Individuals with typical Canavan disease are not known to reproduce.
Individuals with atypical Canavan disease are not known to reproduce; however, most individuals reported to date were not yet of reproductive age.
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
Carrier detection using biochemical assay is not routinely possible because it relies on a complex enzyme assay in cultured skin fibroblasts and enzyme activity fluctuates with culture conditions.
The ACMG includes Canavan disease among those disorders for which carrier screening should be offered to all individuals who are pregnant or planning a pregnancy [
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Carrier testing should be offered for the reproductive partners of individuals known to be carriers of Canavan disease. Of note, targeted analysis for common
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for an
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• The Canavan disease phenotype is consistent among affected family members.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Individuals with typical Canavan disease are not known to reproduce.
• Individuals with atypical Canavan disease are not known to reproduce; however, most individuals reported to date were not yet of reproductive age.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• Carrier testing should be offered for the reproductive partners of individuals known to be carriers of Canavan disease. Of note, targeted analysis for common
## Mode of Inheritance
Canavan disease is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for an
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
The Canavan disease phenotype is consistent among affected family members.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Individuals with typical Canavan disease are not known to reproduce.
Individuals with atypical Canavan disease are not known to reproduce; however, most individuals reported to date were not yet of reproductive age.
• The parents of an affected child are presumed to be heterozygous for an
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• The Canavan disease phenotype is consistent among affected family members.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Individuals with typical Canavan disease are not known to reproduce.
• Individuals with atypical Canavan disease are not known to reproduce; however, most individuals reported to date were not yet of reproductive age.
## Carrier Detection
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
Carrier detection using biochemical assay is not routinely possible because it relies on a complex enzyme assay in cultured skin fibroblasts and enzyme activity fluctuates with culture conditions.
## Population Screening
The ACMG includes Canavan disease among those disorders for which carrier screening should be offered to all individuals who are pregnant or planning a pregnancy [
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Carrier testing should be offered for the reproductive partners of individuals known to be carriers of Canavan disease. Of note, targeted analysis for common
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• Carrier testing should be offered for the reproductive partners of individuals known to be carriers of Canavan disease. Of note, targeted analysis for common
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
•
•
•
•
•
## Molecular Genetics
Canavan Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Canavan Disease (
Note: If a novel
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Note: If a novel
Variants listed in the table have been provided by the authors.
## Chapter Notes
Dr Nagy (
We would like to recognize funding from the National Tay-Sachs & Allied Diseases Association (NTSAD) (
We also want to recognize funding for PeriNAA (Integrative Analysis of Peripheral N-acetylaspartate Metabolism) by the Federal Ministry of Education and Research (PV3782) that supports our Canavan disease research. We would also like to thank Freundeskreis UKE für Kinder mit Demenz eV, who support our Canavan disease research and the care for patients with Canavan disease.
Gita Bhatia, PhD; University of Texas Medical Branch (2009-2011) Annette E Bley, MD (2023-present) Lisvania Delgado, BS; University of Texas Medical Branch (2018-2023)Florian Eichler, MD (2023-present)Kimberlee Michals-Matalon, PhD, RD; University of Houston (2011-2023)Reuben Matalon, PhD; University of Texas Medical Branch (1999-2023) Amanda Nagy, MD (2023-present)
21 December 2023 (bp) Comprehensive update posted live
13 September 2018 (ha) Comprehensive update posted live
11 August 2011 (me) Comprehensive update posted live
1 October 2009 (me) Comprehensive update posted live
30 December 2005 (me) Comprehensive update posted live
7 November 2003 (me) Comprehensive update posted live
3 October 2001 (me) Comprehensive update posted live
16 September 1999 (pb) Review posted live
17 April 1999 (rm) Original submission
• 21 December 2023 (bp) Comprehensive update posted live
• 13 September 2018 (ha) Comprehensive update posted live
• 11 August 2011 (me) Comprehensive update posted live
• 1 October 2009 (me) Comprehensive update posted live
• 30 December 2005 (me) Comprehensive update posted live
• 7 November 2003 (me) Comprehensive update posted live
• 3 October 2001 (me) Comprehensive update posted live
• 16 September 1999 (pb) Review posted live
• 17 April 1999 (rm) Original submission
## Author Notes
Dr Nagy (
## Acknowledgments
We would like to recognize funding from the National Tay-Sachs & Allied Diseases Association (NTSAD) (
We also want to recognize funding for PeriNAA (Integrative Analysis of Peripheral N-acetylaspartate Metabolism) by the Federal Ministry of Education and Research (PV3782) that supports our Canavan disease research. We would also like to thank Freundeskreis UKE für Kinder mit Demenz eV, who support our Canavan disease research and the care for patients with Canavan disease.
## Author History
Gita Bhatia, PhD; University of Texas Medical Branch (2009-2011) Annette E Bley, MD (2023-present) Lisvania Delgado, BS; University of Texas Medical Branch (2018-2023)Florian Eichler, MD (2023-present)Kimberlee Michals-Matalon, PhD, RD; University of Houston (2011-2023)Reuben Matalon, PhD; University of Texas Medical Branch (1999-2023) Amanda Nagy, MD (2023-present)
## Revision History
21 December 2023 (bp) Comprehensive update posted live
13 September 2018 (ha) Comprehensive update posted live
11 August 2011 (me) Comprehensive update posted live
1 October 2009 (me) Comprehensive update posted live
30 December 2005 (me) Comprehensive update posted live
7 November 2003 (me) Comprehensive update posted live
3 October 2001 (me) Comprehensive update posted live
16 September 1999 (pb) Review posted live
17 April 1999 (rm) Original submission
• 21 December 2023 (bp) Comprehensive update posted live
• 13 September 2018 (ha) Comprehensive update posted live
• 11 August 2011 (me) Comprehensive update posted live
• 1 October 2009 (me) Comprehensive update posted live
• 30 December 2005 (me) Comprehensive update posted live
• 7 November 2003 (me) Comprehensive update posted live
• 3 October 2001 (me) Comprehensive update posted live
• 16 September 1999 (pb) Review posted live
• 17 April 1999 (rm) Original submission
## References
## Literature Cited
|
[] |
16/9/1999
|
21/12/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
cantu
|
cantu
|
[
"ATP-binding cassette sub-family C member 9",
"ATP-sensitive inward rectifier potassium channel 8",
"ABCC9",
"KCNJ8",
"Cantú Syndrome"
] |
Cantú Syndrome
|
Dorothy K Grange, Colin G Nichols, Gautam K Singh
|
Summary Cantú syndrome is characterized by congenital hypertrichosis; distinctive coarse facial features (including broad nasal bridge, wide mouth with full lips and macroglossia); enlarged heart with enhanced systolic function or pericardial effusion and in many, a large patent ductus arteriosus (PDA) requiring repair; and skeletal abnormalities (thickening of the calvaria, broad ribs, scoliosis, and flaring of the metaphyses). Other cardiovascular abnormalities may include dilated aortic root and ascending aorta with rare aortic aneurysm, tortuous vascularity involving brain and retinal vasculature, and pulmonary arteriovenous communications. Generalized edema (which may be present at birth) spontaneously resolves; peripheral edema of the lower extremities (and sometimes arms and hands) may develop at adolescence. Developmental delays are common, but intellect is typically normal; behavioral problems can include attention-deficit/hyperactivity disorder, autism spectrum disorder, obsessive-compulsive disorder, anxiety, and depression. The diagnosis of Cantú syndrome is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in Cantú syndrome is inherited in an autosomal dominant manner. Each child of an individual with Cantú syndrome has a 50% chance of inheriting the pathogenic variant and being affected. Prenatal and preimplantation genetic testing are possible if the pathogenic variant has been identified in an affected family member.
|
## Diagnosis
No formal diagnostic criteria for Cantú syndrome have been established.
Cantú syndrome
Congenital hypertrichosis: excess hair growth on scalp, forehead, face, back, and limbs (See
Craniofacial dysmorphic features: coarse facial features, epicanthal folds, broad nasal bridge, anteverted nares, long philtrum, macroglossia, wide mouth, and full lips (See
Enlarged heart with enhanced systolic function or pericardial effusion (See
Large patent ductus arteriosus (PDA) requiring repair
Characteristic skeletal abnormalities: thickening of the calvaria (see
The diagnosis of Cantú syndrome
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of Cantú syndrome, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
When the diagnosis of Cantú syndrome is unclear because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Note: All pathogenic variants reported to date are gain-of-function variants in
Molecular Genetic Testing Used in Cantú Syndrome
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
All pathogenic variants reported to date are gain-of-function variants in
A small number (<1%) of individuals with a clinical diagnosis of Cantú syndrome in whom no
• Congenital hypertrichosis: excess hair growth on scalp, forehead, face, back, and limbs (See
• Craniofacial dysmorphic features: coarse facial features, epicanthal folds, broad nasal bridge, anteverted nares, long philtrum, macroglossia, wide mouth, and full lips (See
• Enlarged heart with enhanced systolic function or pericardial effusion (See
• Large patent ductus arteriosus (PDA) requiring repair
• Characteristic skeletal abnormalities: thickening of the calvaria (see
## Suggestive Findings
Cantú syndrome
Congenital hypertrichosis: excess hair growth on scalp, forehead, face, back, and limbs (See
Craniofacial dysmorphic features: coarse facial features, epicanthal folds, broad nasal bridge, anteverted nares, long philtrum, macroglossia, wide mouth, and full lips (See
Enlarged heart with enhanced systolic function or pericardial effusion (See
Large patent ductus arteriosus (PDA) requiring repair
Characteristic skeletal abnormalities: thickening of the calvaria (see
• Congenital hypertrichosis: excess hair growth on scalp, forehead, face, back, and limbs (See
• Craniofacial dysmorphic features: coarse facial features, epicanthal folds, broad nasal bridge, anteverted nares, long philtrum, macroglossia, wide mouth, and full lips (See
• Enlarged heart with enhanced systolic function or pericardial effusion (See
• Large patent ductus arteriosus (PDA) requiring repair
• Characteristic skeletal abnormalities: thickening of the calvaria (see
## Establishing the Diagnosis
The diagnosis of Cantú syndrome
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of Cantú syndrome, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
When the diagnosis of Cantú syndrome is unclear because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Note: All pathogenic variants reported to date are gain-of-function variants in
Molecular Genetic Testing Used in Cantú Syndrome
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
All pathogenic variants reported to date are gain-of-function variants in
A small number (<1%) of individuals with a clinical diagnosis of Cantú syndrome in whom no
## Option 1
When the phenotypic findings suggest the diagnosis of Cantú syndrome, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
## Option 2
When the diagnosis of Cantú syndrome is unclear because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Note: All pathogenic variants reported to date are gain-of-function variants in
Molecular Genetic Testing Used in Cantú Syndrome
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
All pathogenic variants reported to date are gain-of-function variants in
A small number (<1%) of individuals with a clinical diagnosis of Cantú syndrome in whom no
## Clinical Characteristics
To date, approximately 150 individuals with a clinical diagnosis of Cantú syndrome have been identified; a pathogenic variant in
Cantú Syndrome: Frequency of Select Features
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OCD = obsessive-compulsive disorder; PDA = patent ductus arteriosus
Self-reported in many individuals
Many newborns have macrosomia (large birth weight and birth length) and macrocephaly.
Generalized edema at birth (observed on occasion) usually resolves spontaneously.
Macrocephaly, often present at birth, typically persists throughout life. Some individuals who do not have macrocephaly at birth have developed progressive macrocephaly in childhood.
Cardiac enlargement, with increased ventricular mass but normal chamber wall thickness and enlarged chambers of the heart, often present at birth. Despite the enlarged cardiac chambers, cardiac function is typically normal and ventricular contractility is increased on imaging studies [
Patent ductus arteriosus (PDA) in 58% (and described as extremely large in some), often requiring surgical closure in infancy or early childhood
Bicuspid aortic valve with and without stenosis
Pericardial effusion in about 25% of affected individuals. Small pericardial effusions may be asymptomatic; large fluid accumulations result in symptoms such as exercise intolerance and require intervention.
Dilated aortic root and ascending aorta are present in about two thirds of individuals. The natural history is poorly understood. However, development of an aortic aneurysm is rare. Aortic aneurysm requiring surgical intervention was reported in one individual with an
Umbilical hernia
Pyloric stenosis
Poor intestinal motility [
Ptosis
Craniosynostosis involving the sagittal and coronal sutures in one individual [
Increased frequency of infections, raising the possibility of immune dysfunction [
Growth hormone deficiency in a few individuals [
Panhypopituitarism [
The three individuals reported thus far with a pathogenic variant in
Brain MRI: cerebral atrophy and thin corpus callosum
Multiple tortuous venous collaterals and lack of flow in the inferior sagittal sinus
Systemic vasculature: dilated hepatic and celiac arteries, dilated and tortuous intrahepatic arteries and veins
Current information about genotype-phenotype correlation in Cantú syndrome is limited.
No significant genotype-phenotype correlations for
Penetrance for Cantú syndrome in familial cases reported thus far appears to be complete although with variable expression [
Cantú syndrome may also be referred to as hypertrichotic osteochondrodysplasia.
The prevalence of Cantú syndrome is unknown. To date, about 150 individuals have been reported with Cantú syndrome. Two previously reported conditions, acromegaloid facial appearance (AFA) syndrome and hypertrichosis with acromegaloid facial features (HAFF) syndrome, are now realized to be cases of Cantú syndrome with variable and sometimes milder phenotypic features. Cantú syndrome has been reported worldwide and in all ethnic groups.
• Cardiac enlargement, with increased ventricular mass but normal chamber wall thickness and enlarged chambers of the heart, often present at birth. Despite the enlarged cardiac chambers, cardiac function is typically normal and ventricular contractility is increased on imaging studies [
• Patent ductus arteriosus (PDA) in 58% (and described as extremely large in some), often requiring surgical closure in infancy or early childhood
• Bicuspid aortic valve with and without stenosis
• Pericardial effusion in about 25% of affected individuals. Small pericardial effusions may be asymptomatic; large fluid accumulations result in symptoms such as exercise intolerance and require intervention.
• Dilated aortic root and ascending aorta are present in about two thirds of individuals. The natural history is poorly understood. However, development of an aortic aneurysm is rare. Aortic aneurysm requiring surgical intervention was reported in one individual with an
• Umbilical hernia
• Pyloric stenosis
• Poor intestinal motility [
• Ptosis
• Craniosynostosis involving the sagittal and coronal sutures in one individual [
• Increased frequency of infections, raising the possibility of immune dysfunction [
• Growth hormone deficiency in a few individuals [
• Panhypopituitarism [
• Brain MRI: cerebral atrophy and thin corpus callosum
• Multiple tortuous venous collaterals and lack of flow in the inferior sagittal sinus
• Systemic vasculature: dilated hepatic and celiac arteries, dilated and tortuous intrahepatic arteries and veins
## Clinical Description
To date, approximately 150 individuals with a clinical diagnosis of Cantú syndrome have been identified; a pathogenic variant in
Cantú Syndrome: Frequency of Select Features
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OCD = obsessive-compulsive disorder; PDA = patent ductus arteriosus
Self-reported in many individuals
Many newborns have macrosomia (large birth weight and birth length) and macrocephaly.
Generalized edema at birth (observed on occasion) usually resolves spontaneously.
Macrocephaly, often present at birth, typically persists throughout life. Some individuals who do not have macrocephaly at birth have developed progressive macrocephaly in childhood.
Cardiac enlargement, with increased ventricular mass but normal chamber wall thickness and enlarged chambers of the heart, often present at birth. Despite the enlarged cardiac chambers, cardiac function is typically normal and ventricular contractility is increased on imaging studies [
Patent ductus arteriosus (PDA) in 58% (and described as extremely large in some), often requiring surgical closure in infancy or early childhood
Bicuspid aortic valve with and without stenosis
Pericardial effusion in about 25% of affected individuals. Small pericardial effusions may be asymptomatic; large fluid accumulations result in symptoms such as exercise intolerance and require intervention.
Dilated aortic root and ascending aorta are present in about two thirds of individuals. The natural history is poorly understood. However, development of an aortic aneurysm is rare. Aortic aneurysm requiring surgical intervention was reported in one individual with an
Umbilical hernia
Pyloric stenosis
Poor intestinal motility [
Ptosis
Craniosynostosis involving the sagittal and coronal sutures in one individual [
Increased frequency of infections, raising the possibility of immune dysfunction [
Growth hormone deficiency in a few individuals [
Panhypopituitarism [
The three individuals reported thus far with a pathogenic variant in
Brain MRI: cerebral atrophy and thin corpus callosum
Multiple tortuous venous collaterals and lack of flow in the inferior sagittal sinus
Systemic vasculature: dilated hepatic and celiac arteries, dilated and tortuous intrahepatic arteries and veins
• Cardiac enlargement, with increased ventricular mass but normal chamber wall thickness and enlarged chambers of the heart, often present at birth. Despite the enlarged cardiac chambers, cardiac function is typically normal and ventricular contractility is increased on imaging studies [
• Patent ductus arteriosus (PDA) in 58% (and described as extremely large in some), often requiring surgical closure in infancy or early childhood
• Bicuspid aortic valve with and without stenosis
• Pericardial effusion in about 25% of affected individuals. Small pericardial effusions may be asymptomatic; large fluid accumulations result in symptoms such as exercise intolerance and require intervention.
• Dilated aortic root and ascending aorta are present in about two thirds of individuals. The natural history is poorly understood. However, development of an aortic aneurysm is rare. Aortic aneurysm requiring surgical intervention was reported in one individual with an
• Umbilical hernia
• Pyloric stenosis
• Poor intestinal motility [
• Ptosis
• Craniosynostosis involving the sagittal and coronal sutures in one individual [
• Increased frequency of infections, raising the possibility of immune dysfunction [
• Growth hormone deficiency in a few individuals [
• Panhypopituitarism [
• Brain MRI: cerebral atrophy and thin corpus callosum
• Multiple tortuous venous collaterals and lack of flow in the inferior sagittal sinus
• Systemic vasculature: dilated hepatic and celiac arteries, dilated and tortuous intrahepatic arteries and veins
## Genotype-Phenotype Correlations
Current information about genotype-phenotype correlation in Cantú syndrome is limited.
No significant genotype-phenotype correlations for
## Penetrance
Penetrance for Cantú syndrome in familial cases reported thus far appears to be complete although with variable expression [
## Nomenclature
Cantú syndrome may also be referred to as hypertrichotic osteochondrodysplasia.
## Prevalence
The prevalence of Cantú syndrome is unknown. To date, about 150 individuals have been reported with Cantú syndrome. Two previously reported conditions, acromegaloid facial appearance (AFA) syndrome and hypertrichosis with acromegaloid facial features (HAFF) syndrome, are now realized to be cases of Cantú syndrome with variable and sometimes milder phenotypic features. Cantú syndrome has been reported worldwide and in all ethnic groups.
## Genetically Related (Allelic) Disorders
Other phenotypes associated with germline pathogenic variants in
Allelic Disorders
This diagnosis is in question because the reported persons did not meet the WHO definition of dilated cardiomyopathy [Author, personal observation].
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Cantú Syndrome
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; FHEIG syndrome = facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome; ID = intellectual disability; MOI = mode of inheritance; MPS = mucopolysaccharidosis; PDA = patent ductus arteriosus; XL = X-linked
Beckwith-Wiedemann syndrome (BWS) is caused by an epigenetic or genomic alteration leading to abnormal methylation at 11p15.5 or a heterozygous BWS-causing pathogenic variant in
The risk to the sibs of a child with BWS depends on the genetic basis for BWS in the proband.
Pathogenic variants in
Pathogenic variants in
Note: Both minoxidil and diazoxide can activate the same ATP-sensitive potassium (KATP) channels that are overactive in Cantú syndrome due to pathogenic variants in
## Other Conditions
Note: Both minoxidil and diazoxide can activate the same ATP-sensitive potassium (KATP) channels that are overactive in Cantú syndrome due to pathogenic variants in
## Management
To establish the extent of disease and needs in an individual diagnosed with Cantú syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Cantú Syndrome
Radiographic skeletal survey to assess for bone abnormalities
Eval for scoliosis
Community or
Social work involvement for parental support.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; MOI = mode of inheritance; MRA = magnetic resonance angiogram; MRV = magnetic resonance venography; OCD = obsessive-compulsive disorder
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment of Manifestations in Individuals with Cantú Syndrome
PDA = patent ductus arteriosus
The following information represents typical management recommendations for individuals with developmental delay in the United States; standard recommendations may vary from country to country.
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Recommended Surveillance for Individuals with Cantú Syndrome
Echocardiogram & EKG to monitor cardiac size & function & for evidence of pericardial effusion starting in infancy
Clinical eval & cardiac biomarkers such as BNP to monitor late development of high-output cardiac failure
Spine radiographs
Orthopedic eval if scoliosis is present
BNP = brain natriuretic peptide; EKG = electrocardiogram; MRA = magnetic resonance angiogram; MRV = magnetic resonance venography
Avoid the following:
Minoxidil
Diazoxide
Angiotensin-converting enzyme inhibitors
It is appropriate to clarify the genetic/clinical status of older and younger relatives of an affected individual in order to identify as early as possible those who should be evaluated and monitored for cardiac manifestations of Cantú syndrome, as well as peripheral edema and scoliosis (see
Evaluations can include:
Molecular genetic testing if the causative pathogenic variant in the family is known;
Complete physical examination to assess for the characteristic clinical features, as well as an echocardiogram, electrocardiogram, and skeletal survey, should be performed if the pathogenic variant in the family is not known. Additional studies such as brain MRI with magnetic resonance angiogram and magnetic resonance venography may be indicated.
See
Women affected by Cantú syndrome should be referred to a maternal-fetal medicine specialist for evaluation and management.
Search
• Radiographic skeletal survey to assess for bone abnormalities
• Eval for scoliosis
• Community or
• Social work involvement for parental support.
• Echocardiogram & EKG to monitor cardiac size & function & for evidence of pericardial effusion starting in infancy
• Clinical eval & cardiac biomarkers such as BNP to monitor late development of high-output cardiac failure
• Spine radiographs
• Orthopedic eval if scoliosis is present
• Minoxidil
• Diazoxide
• Angiotensin-converting enzyme inhibitors
• Molecular genetic testing if the causative pathogenic variant in the family is known;
• Complete physical examination to assess for the characteristic clinical features, as well as an echocardiogram, electrocardiogram, and skeletal survey, should be performed if the pathogenic variant in the family is not known. Additional studies such as brain MRI with magnetic resonance angiogram and magnetic resonance venography may be indicated.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Cantú syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Cantú Syndrome
Radiographic skeletal survey to assess for bone abnormalities
Eval for scoliosis
Community or
Social work involvement for parental support.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; MOI = mode of inheritance; MRA = magnetic resonance angiogram; MRV = magnetic resonance venography; OCD = obsessive-compulsive disorder
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Radiographic skeletal survey to assess for bone abnormalities
• Eval for scoliosis
• Community or
• Social work involvement for parental support.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Cantú Syndrome
PDA = patent ductus arteriosus
The following information represents typical management recommendations for individuals with developmental delay in the United States; standard recommendations may vary from country to country.
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
## Developmental Delay Management Issues
The following information represents typical management recommendations for individuals with developmental delay in the United States; standard recommendations may vary from country to country.
## Motor Delay
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
## Surveillance
Recommended Surveillance for Individuals with Cantú Syndrome
Echocardiogram & EKG to monitor cardiac size & function & for evidence of pericardial effusion starting in infancy
Clinical eval & cardiac biomarkers such as BNP to monitor late development of high-output cardiac failure
Spine radiographs
Orthopedic eval if scoliosis is present
BNP = brain natriuretic peptide; EKG = electrocardiogram; MRA = magnetic resonance angiogram; MRV = magnetic resonance venography
• Echocardiogram & EKG to monitor cardiac size & function & for evidence of pericardial effusion starting in infancy
• Clinical eval & cardiac biomarkers such as BNP to monitor late development of high-output cardiac failure
• Spine radiographs
• Orthopedic eval if scoliosis is present
## Agents/Circumstances to Avoid
Avoid the following:
Minoxidil
Diazoxide
Angiotensin-converting enzyme inhibitors
• Minoxidil
• Diazoxide
• Angiotensin-converting enzyme inhibitors
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic/clinical status of older and younger relatives of an affected individual in order to identify as early as possible those who should be evaluated and monitored for cardiac manifestations of Cantú syndrome, as well as peripheral edema and scoliosis (see
Evaluations can include:
Molecular genetic testing if the causative pathogenic variant in the family is known;
Complete physical examination to assess for the characteristic clinical features, as well as an echocardiogram, electrocardiogram, and skeletal survey, should be performed if the pathogenic variant in the family is not known. Additional studies such as brain MRI with magnetic resonance angiogram and magnetic resonance venography may be indicated.
See
• Molecular genetic testing if the causative pathogenic variant in the family is known;
• Complete physical examination to assess for the characteristic clinical features, as well as an echocardiogram, electrocardiogram, and skeletal survey, should be performed if the pathogenic variant in the family is not known. Additional studies such as brain MRI with magnetic resonance angiogram and magnetic resonance venography may be indicated.
## Pregnancy Management
Women affected by Cantú syndrome should be referred to a maternal-fetal medicine specialist for evaluation and management.
## Therapies Under Investigation
Search
## Genetic Counseling
Cantú syndrome is inherited in an autosomal dominant manner.
In one study, 22% of individuals diagnosed with Cantú syndrome had an affected parent [
Approximately 75% to 80% of individuals diagnosed with Cantú syndrome have the disorder as the result of a
If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the causative
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Parental germline (or somatic and germline) mosaicism has been reported [
* A parent with somatic and germline mosaicism for an
The family history of some individuals diagnosed with Cantú syndrome may appear to be negative because of failure to recognize the disorder in family members with a milder phenotype. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband is affected and/or has the
If the proband has a known Cantú syndrome-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [
If the parents are clinically unaffected but their genetic status is unknown, risk to sibs of a proband is presumed to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
In a fetus
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• In one study, 22% of individuals diagnosed with Cantú syndrome had an affected parent [
• Approximately 75% to 80% of individuals diagnosed with Cantú syndrome have the disorder as the result of a
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the causative
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Parental germline (or somatic and germline) mosaicism has been reported [
• * A parent with somatic and germline mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Parental germline (or somatic and germline) mosaicism has been reported [
• * A parent with somatic and germline mosaicism for an
• The family history of some individuals diagnosed with Cantú syndrome may appear to be negative because of failure to recognize the disorder in family members with a milder phenotype. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Parental germline (or somatic and germline) mosaicism has been reported [
• * A parent with somatic and germline mosaicism for an
• If a parent of the proband is affected and/or has the
• If the proband has a known Cantú syndrome-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [
• If the parents are clinically unaffected but their genetic status is unknown, risk to sibs of a proband is presumed to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Cantú syndrome is inherited in an autosomal dominant manner.
## Risk to Family Members
In one study, 22% of individuals diagnosed with Cantú syndrome had an affected parent [
Approximately 75% to 80% of individuals diagnosed with Cantú syndrome have the disorder as the result of a
If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the causative
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Parental germline (or somatic and germline) mosaicism has been reported [
* A parent with somatic and germline mosaicism for an
The family history of some individuals diagnosed with Cantú syndrome may appear to be negative because of failure to recognize the disorder in family members with a milder phenotype. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband is affected and/or has the
If the proband has a known Cantú syndrome-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [
If the parents are clinically unaffected but their genetic status is unknown, risk to sibs of a proband is presumed to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.
• In one study, 22% of individuals diagnosed with Cantú syndrome had an affected parent [
• Approximately 75% to 80% of individuals diagnosed with Cantú syndrome have the disorder as the result of a
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the causative
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Parental germline (or somatic and germline) mosaicism has been reported [
• * A parent with somatic and germline mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Parental germline (or somatic and germline) mosaicism has been reported [
• * A parent with somatic and germline mosaicism for an
• The family history of some individuals diagnosed with Cantú syndrome may appear to be negative because of failure to recognize the disorder in family members with a milder phenotype. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Parental germline (or somatic and germline) mosaicism has been reported [
• * A parent with somatic and germline mosaicism for an
• If a parent of the proband is affected and/or has the
• If the proband has a known Cantú syndrome-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [
• If the parents are clinically unaffected but their genetic status is unknown, risk to sibs of a proband is presumed to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
In a fetus
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
## Molecular Genetics
Cantú syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Cantú syndrome (
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
Dr Nichols's research is focused on the biology of ion channels, with emphasis on the molecular basis of potassium channel activity and the role of potassium channels in physiology and disease. Using various molecular biological and biophysical approaches, his laboratory is developing detailed understanding of the structural basis of channel activity, and animal models to understand the role of potassium channels in disease processes including diabetes, cardiovascular pathology and arrhythmias, and epilepsy.
1 October 2020 (ha) Comprehensive update posted live
2 October 2014 (me) Review posted live
2 October 2013 (dkg) Original submission
• 1 October 2020 (ha) Comprehensive update posted live
• 2 October 2014 (me) Review posted live
• 2 October 2013 (dkg) Original submission
## Author Notes
Dr Nichols's research is focused on the biology of ion channels, with emphasis on the molecular basis of potassium channel activity and the role of potassium channels in physiology and disease. Using various molecular biological and biophysical approaches, his laboratory is developing detailed understanding of the structural basis of channel activity, and animal models to understand the role of potassium channels in disease processes including diabetes, cardiovascular pathology and arrhythmias, and epilepsy.
## Revision History
1 October 2020 (ha) Comprehensive update posted live
2 October 2014 (me) Review posted live
2 October 2013 (dkg) Original submission
• 1 October 2020 (ha) Comprehensive update posted live
• 2 October 2014 (me) Review posted live
• 2 October 2013 (dkg) Original submission
## References
## Literature Cited
Woman age 40 years (A, D), girl age 16 years (B, E), and girl age 11 years (C, F) with Cantù syndrome
A, B, C. Facial appearance showing hirsutism of the forehead with low frontal hairline and coarse features
D, E. Lateral views showing excess hair on the cheeks
F. Hirsutism of the arms
From
Girl age 11 years (A, B) and girl age 16 years (C) with Cantù syndrome
A. Narrow thorax and pectus carinatum deformity
B, C. Hirsutism of the lower back (B) and forearms(C)
From
Woman age 40 years with Cantù syndrome
A. Chest x-ray showing marked cardiomegaly
B. Lateral skull x-ray showing thickened calvarium
C. Erlenmeyer flask deformity with metaphyseal flaring of the distal radius (arrow)
D. Metaphyseal flaring of the distal femur (arrow)
From
Girl age 16 years with Cantù syndrome
A. Chest x-ray showing cardiomegaly
B. Early metaphyseal flaring of the distal radius (arrow)
From
|
[
"C Antzelevitch, GX Yan. J wave syndromes.. Heart Rhythm 2010;7:549-58",
"M Bienengraeber, TM Olson, VA Selivanov, EC Kathmann, F O'Cochlain, F Gao, AB Karger, JD Ballew, DM Hodgson, LV Zingman, YP Pang, AE Alekseev, A Terzic. ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating.. Nat Genet 2004;36:382-7",
"CA Brownstein, MC Towne, LJ Luquette, DJ Harris, NS Marinakis, P Meinecke, K Kutsche, PM Campeau, TW Yu, DM Margulies, PB Agrawal, AH Beggs. Mutation of KCNJ8 in a patient with Cantú syndrome with unique vascular abnormalities - support for the role of K(ATP) channels in this condition.. Eur J Med Genet 2013;56:678-82",
"JM Cantú, D García-Cruz, J Sánchez-Corona, A Hernández, Z Nazará. A distinct osteochondrodysplasia with hypertrichosis-individualization of a probable autosomal recessive entity.. Hum Genet 1982;60:36-41",
"M Chihara, A Asahina, M. Itoh. A novel mutation in the KCNJ8 gene encoding the Kir6.1 subunit of an ATP-sensitive potassium channel in a Japanese patient with Cantú syndrome.. J Eur Acad Dermatol Venereol. 2020;34:e476-e478",
"PE Cooper, H Reutter, J Woelfle, H Engels, DK Grange, G van Haaften, BW van Bon, A Hoischen, CG Nichols. Cantú syndrome resulting from activating mutation in the KCNJ8 gene.. Hum Mutat. 2014;35:809-13",
"D García-Cruz, A Mampel, MI Echeverria, AL Vargas, G Castañeda-Cisneros, N Davalos-Rodriguez, B Patiño-Garcia, MO Garcia-Cruz, V Castañeda, EG Cardona, B Marin-Solis, JM Cantu, N Nuñez-Reveles, C Moran-Moguel, PK Thavanati, S Ramirez-Garcia, J Sanchez-Corona. Cantu syndrome and lymphoedema.. Clin Dysmorphol. 2011;20:32-7",
"DK Grange, SM Lorch, PL Cole, GK Singh. Cantú syndrome in a woman and her two daughters: further confirmation of autosomal dominant inheritance and review of the cardiac manifestations.. Am J Med Genet 2006;140:1673-80",
"DK Grange, HI Roessler, C McClenaghan, K Duran, K Shields, MS Remedi, NVAM Knoers, J-M Lee, EP Kirk, I Scurr, SF Smithson, GK Singh, MM van Haelst, CG Nichols, G van Haaften. Cantu syndrome: findings from 74 patients in the International Cantu Syndrome Registry.. Am J Med Genet C Semin Med Genet 2019;181:658-81",
"A Herrera, ME Vajravelu, S Givler, L Mitteer, CM Avitabile, K Lord, DD De León. Prevalence of adverse events in children with congenital hyperinsulinism treated with diazoxide.. J Clin Endocrinol Metab 2018;103:4365-72",
"Y Hiraki, S Miyatake, M Hayashidani, Y Nishimura, H Matsuura, M Kamada, T Kawagoe, K Yunoki, N Okamoto, H Yofune, M Nakashima, Y Tsurusaki, H Satisu, A Murakami, N Miyake, G Nishimura, N. Matsumoto. Aortic aneurysm and craniosynostosis in a family with Cantú syndrome.. Am J Med Genet A. 2014;164A:231-6",
"D Hu, H Barajas-Martínez, A Terzic, S Park, R Pfeiffer, E Burashnikov, Y Wu, M Borggrefe, C Veltmann, R Schimpf, JJ Cai, GB Nam, P Deshmukh, M Scheinman, M Preminger, J Steinberg, A López-Izquierdo, D Ponce-Balbuena, C Wolpert, M Haïssaguerre, JA Sánchez-Chapula, C Antzelevitch. ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene.. Int J Cardiol. 2014;171:431-42",
"D Kobayashi, AL Cook, DA Williams. Pulmonary hypertension secondary to partial pulmonary venous obstruction in a child with Cantú syndrome.. Pediatr Pulmonol 2010;45:727-9",
"B Lazalde, R Sanchez-Urbina, I Nuno-Arana, WE Bitar, M Ramirez-Duenas. Autosomal dominant inheritance in Cantú syndrome (congenital hypertrichosis, osteochondrodysplasia, and cardiomegaly).. Am J Med Genet 2000;94:421-7",
"CR Leon Guerrero, S Pathak, DK Grange, GK Singh, CG Nichols, JM Lee, KD Vo. Neurologic and neuroimaging manifestations of Cantu syndrome: a case series.. Neurology 2016;87:270-6",
"P Marques, R Spencer, PJ Morrison, IM Carr, MN Dang, DT Bonthron, S Hunter, M Korbonits. Cantu syndrome with coexisting familial pituitary adenoma.. Endocrine 2018;59:677-84",
"K Ohko, K Nakajima, H Nakajima, Y Hiraki, K Kubota, T Fukao, S Miyatake, N Matsumoto, S Sano. Skin and hair abnormalities of Cantu syndrome: a congenital hypertrichosis due to a genetic alteration mimicking the pharmacological effect of minoxidil.. J Dermatol 2020;47:306-10",
"TM Olson, AE Alekseev, C Moreau, XK Liu, LV Zingman, T Miki, S Seino, SJ Asirvatham, A Jahangir, A Terzic. KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation.. Nat Clin Pract Cardiovasc Med 2007;4:110-6",
"JY Park, SH Koo, YJ Jung, YJ Lim, ML Chung. A patient with Cantú syndrome associated with fatal bronchopulmonary dysplasia and pulmonary hypertension.. Am J Med Genet A 2014;164A:2118-20",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med 2015;17:405-24",
"SP Robertson, E Kirk, F Bernier, J Brereton, A Turner, A Bankier. Congenital hypertrichosis. Osteochondrodysplasia and cardiomegaly: Cantú syndrome.. Am J Med Genet 1999;85:395-402",
"I Scurr, L Wilson, M Lees, S Robertson, E Kirk, A Turner, J Morton, A Kidd, V Shashi, C Stanley, M Berry, AD Irvine, D Goudie, C Turner, C Brewer, S Smithson. Cantú syndrome: report of nine new cases and expansion of the clinical phenotype.. Am J Med Genet A 2011;155A:508-18",
"MF Smeland, C McClenaghan, HI Roessler, S Savelberg, GÅM Hansen, H Hjellnes, KA Arntzen, KI Müller, AR Dybesland, T Harter, M Sala-Rabanal, CH Emfinger, Y Huang, SS Singareddy, J Gunn, DF Wozniak, A Kovacs, M Massink, F Tessadori, SM Kamel, J Bakkers, MS Remedi, M Van Ghelue, CG Nichols, G van Haaften. ABCC9-related Intellectual disability myopathy syndrome is a K(ATP) channelopathy with loss-of-function mutations in ABCC9.. Nat Commun 2019;10:4457",
"NJ Theis, T Calvert, P McIntyre, SP Robertson, BJ Wheeler. Cantu syndrome and hypopituitarism: implications for endocrine monitoring.. Endocrinol Diabetes Metab Case Rep. 2019;2019:19-0103",
"KR Veeramah, TM Karafet, D Wolf, RA Samson, MF Hammer. The KCNJ8-S422L variant previously associated with J-wave syndromes is found at an increased frequency in Ashkenazi Jews.. Eur J Hum Genet 2014;22:94-8"
] |
2/10/2014
|
1/10/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
carasil
|
carasil
|
[
"CARASIL (Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)",
"CARASIL (Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)",
"Classic CARASIL",
"HTRA1 Cerebral Small Vessel Disease (HTRA1-CSVD)",
"Serine protease HTRA1",
"HTRA1",
"HTRA1 Disorder"
] |
Osamu Onodera, Hiroaki Nozaki, Toshio Fukutake
|
Summary Classic CARASIL is characterized by early-onset changes in the deep white matter of the brain observed on MRI, and associated neurologic findings. The most frequent initial symptom is gait disturbance from spasticity beginning between ages 20 and 40 years. Forty-four percent of affected individuals have stroke-like episodes before age 40 years. Mood changes (apathy and irritability), pseudobulbar palsy, and cognitive dysfunction begin between ages 20 and 50 years. The disease progresses slowly following the onset of neurologic symptoms. Scalp alopecia and acute mid- to lower-back pain (lumbago) before age 30 years are characteristic. The most frequent initial symptom in individuals with The diagnosis of Once the
|
Classic CARASIL
For synonym s and outdated names see
• Classic CARASIL
## Diagnosis
Clinical diagnostic criteria for
Slowly progressive dementia
Mood changes, such as apathy and irritability
Slowly progressive gait disturbance with spasticity in the lower extremities [
Note: Those with a heterozygous
Additional young adult-onset findings in those with biallelic pathogenic variants in
Spondylosis deformans. Acute mid- to lower-back pain (lumbago) associated with spondylosis and disk degeneration with osteophyte formation in the lumbar spine
Alopecia. Typically seen before age 30 years
Note: Alopecia is variable; affected individuals with biallelic
Early-onset leukoaraiosis (changes in deep white matter in the brain, observed on MRI or CT). Leukoaraiosis may precede neurologic symptoms [
Brain MRI resembling that of
Symmetrically distributed white matter hyperintensities located in the periventricular and deep white matter
Note: White matter changes may precede the onset of neurologic symptoms, including gait disturbance, mood change, and cognitive decline.
T
Relative preservation of U-fibers
Lacunar infarcts (linearly arranged groups of rounded and circumscribed lesions with signal intensity identical to that of cerebrospinal fluid) in the basal ganglia and subcortical white matter
Microbleeds in the cerebral cortex, basal ganglia, brain stem, and cerebellum
Note: It is not clear if the white matter changes in the anterior temporal poles and external capsule, which are characteristic signs in CADASIL, are also observed in early stages of CARASIL.
Autosomal recessive inheritance in those with classic CARASIL;
Autosomal dominant inheritance for those with a heterozygous
Note: Absence of a known family history of
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
When the phenotypic and imaging findings suggest the diagnosis of classic CARASIL, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of CARASIL or
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Slowly progressive dementia
• Mood changes, such as apathy and irritability
• Slowly progressive gait disturbance with spasticity in the lower extremities [
• Spondylosis deformans. Acute mid- to lower-back pain (lumbago) associated with spondylosis and disk degeneration with osteophyte formation in the lumbar spine
• Alopecia. Typically seen before age 30 years
• Note: Alopecia is variable; affected individuals with biallelic
• Early-onset leukoaraiosis (changes in deep white matter in the brain, observed on MRI or CT). Leukoaraiosis may precede neurologic symptoms [
• Brain MRI resembling that of
• Symmetrically distributed white matter hyperintensities located in the periventricular and deep white matter
• Note: White matter changes may precede the onset of neurologic symptoms, including gait disturbance, mood change, and cognitive decline.
• T
• Relative preservation of U-fibers
• Lacunar infarcts (linearly arranged groups of rounded and circumscribed lesions with signal intensity identical to that of cerebrospinal fluid) in the basal ganglia and subcortical white matter
• Microbleeds in the cerebral cortex, basal ganglia, brain stem, and cerebellum
• Note: It is not clear if the white matter changes in the anterior temporal poles and external capsule, which are characteristic signs in CADASIL, are also observed in early stages of CARASIL.
• Symmetrically distributed white matter hyperintensities located in the periventricular and deep white matter
• Note: White matter changes may precede the onset of neurologic symptoms, including gait disturbance, mood change, and cognitive decline.
• T
• Relative preservation of U-fibers
• Lacunar infarcts (linearly arranged groups of rounded and circumscribed lesions with signal intensity identical to that of cerebrospinal fluid) in the basal ganglia and subcortical white matter
• Microbleeds in the cerebral cortex, basal ganglia, brain stem, and cerebellum
• Note: It is not clear if the white matter changes in the anterior temporal poles and external capsule, which are characteristic signs in CADASIL, are also observed in early stages of CARASIL.
• Symmetrically distributed white matter hyperintensities located in the periventricular and deep white matter
• Note: White matter changes may precede the onset of neurologic symptoms, including gait disturbance, mood change, and cognitive decline.
• T
• Relative preservation of U-fibers
• Lacunar infarcts (linearly arranged groups of rounded and circumscribed lesions with signal intensity identical to that of cerebrospinal fluid) in the basal ganglia and subcortical white matter
• Microbleeds in the cerebral cortex, basal ganglia, brain stem, and cerebellum
• Note: It is not clear if the white matter changes in the anterior temporal poles and external capsule, which are characteristic signs in CADASIL, are also observed in early stages of CARASIL.
• Autosomal recessive inheritance in those with classic CARASIL;
• Autosomal dominant inheritance for those with a heterozygous
• For an introduction to multigene panels click
## Suggestive Findings
Slowly progressive dementia
Mood changes, such as apathy and irritability
Slowly progressive gait disturbance with spasticity in the lower extremities [
Note: Those with a heterozygous
Additional young adult-onset findings in those with biallelic pathogenic variants in
Spondylosis deformans. Acute mid- to lower-back pain (lumbago) associated with spondylosis and disk degeneration with osteophyte formation in the lumbar spine
Alopecia. Typically seen before age 30 years
Note: Alopecia is variable; affected individuals with biallelic
Early-onset leukoaraiosis (changes in deep white matter in the brain, observed on MRI or CT). Leukoaraiosis may precede neurologic symptoms [
Brain MRI resembling that of
Symmetrically distributed white matter hyperintensities located in the periventricular and deep white matter
Note: White matter changes may precede the onset of neurologic symptoms, including gait disturbance, mood change, and cognitive decline.
T
Relative preservation of U-fibers
Lacunar infarcts (linearly arranged groups of rounded and circumscribed lesions with signal intensity identical to that of cerebrospinal fluid) in the basal ganglia and subcortical white matter
Microbleeds in the cerebral cortex, basal ganglia, brain stem, and cerebellum
Note: It is not clear if the white matter changes in the anterior temporal poles and external capsule, which are characteristic signs in CADASIL, are also observed in early stages of CARASIL.
Autosomal recessive inheritance in those with classic CARASIL;
Autosomal dominant inheritance for those with a heterozygous
Note: Absence of a known family history of
• Slowly progressive dementia
• Mood changes, such as apathy and irritability
• Slowly progressive gait disturbance with spasticity in the lower extremities [
• Spondylosis deformans. Acute mid- to lower-back pain (lumbago) associated with spondylosis and disk degeneration with osteophyte formation in the lumbar spine
• Alopecia. Typically seen before age 30 years
• Note: Alopecia is variable; affected individuals with biallelic
• Early-onset leukoaraiosis (changes in deep white matter in the brain, observed on MRI or CT). Leukoaraiosis may precede neurologic symptoms [
• Brain MRI resembling that of
• Symmetrically distributed white matter hyperintensities located in the periventricular and deep white matter
• Note: White matter changes may precede the onset of neurologic symptoms, including gait disturbance, mood change, and cognitive decline.
• T
• Relative preservation of U-fibers
• Lacunar infarcts (linearly arranged groups of rounded and circumscribed lesions with signal intensity identical to that of cerebrospinal fluid) in the basal ganglia and subcortical white matter
• Microbleeds in the cerebral cortex, basal ganglia, brain stem, and cerebellum
• Note: It is not clear if the white matter changes in the anterior temporal poles and external capsule, which are characteristic signs in CADASIL, are also observed in early stages of CARASIL.
• Symmetrically distributed white matter hyperintensities located in the periventricular and deep white matter
• Note: White matter changes may precede the onset of neurologic symptoms, including gait disturbance, mood change, and cognitive decline.
• T
• Relative preservation of U-fibers
• Lacunar infarcts (linearly arranged groups of rounded and circumscribed lesions with signal intensity identical to that of cerebrospinal fluid) in the basal ganglia and subcortical white matter
• Microbleeds in the cerebral cortex, basal ganglia, brain stem, and cerebellum
• Note: It is not clear if the white matter changes in the anterior temporal poles and external capsule, which are characteristic signs in CADASIL, are also observed in early stages of CARASIL.
• Symmetrically distributed white matter hyperintensities located in the periventricular and deep white matter
• Note: White matter changes may precede the onset of neurologic symptoms, including gait disturbance, mood change, and cognitive decline.
• T
• Relative preservation of U-fibers
• Lacunar infarcts (linearly arranged groups of rounded and circumscribed lesions with signal intensity identical to that of cerebrospinal fluid) in the basal ganglia and subcortical white matter
• Microbleeds in the cerebral cortex, basal ganglia, brain stem, and cerebellum
• Note: It is not clear if the white matter changes in the anterior temporal poles and external capsule, which are characteristic signs in CADASIL, are also observed in early stages of CARASIL.
• Autosomal recessive inheritance in those with classic CARASIL;
• Autosomal dominant inheritance for those with a heterozygous
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
When the phenotypic and imaging findings suggest the diagnosis of classic CARASIL, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of CARASIL or
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• For an introduction to multigene panels click
## Option 1
When the phenotypic and imaging findings suggest the diagnosis of classic CARASIL, molecular genetic testing approaches can include
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the diagnosis of CARASIL or
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Clinical Characteristics
The most frequent initial symptom is slowly progressive gait disturbance from spasticity and pyramidal signs in the lower extremities beginning between ages 20 and 40 years.
Mood change (depression and irritability) and cognitive dysfunction begin between ages 20 and 50 years.
Pseudobulbar palsy also begins between ages 30 and 50 years.
Forty-four percent of affected individuals have a stroke-like episode (e.g., hemiparesis or hemisensory impairment) before age 40 years.
The disease progresses slowly following the onset of neurologic symptoms. In the advanced stage, emotional incontinence, abulia, and akinetic mutism develop.
Scalp alopecia is diffuse, not confined to the frontal or parietal regions.
There is no obvious body hair loss.
Note: Granular osmiophilic material within the vascular media close to smooth muscle cells, a pathologic hallmark for CADASIL, is never observed in CARASIL.
Slowly progressive gait disturbance (the most frequent initial symptom)
Mood change (depression and irritability) and cognitive dysfunction
A stroke-like episode (e.g., hemiparesis or hemisensory impairment) in 63% of affected individuals
Slow progression of the disease following the onset of neurologic symptoms
Spondylosis deformans is seen in about 36% of affected individuals.
Alopecia is seen in about 20% of affected individuals.
No strong genotype-phenotype correlations for
Those who have a heterozygous
Other names for
CARASIL, for those who have biallelic
Familial young adult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago without arterial hypertension
Nemoto disease
Maeda syndrome
CADASIL2 (
• The most frequent initial symptom is slowly progressive gait disturbance from spasticity and pyramidal signs in the lower extremities beginning between ages 20 and 40 years.
• Mood change (depression and irritability) and cognitive dysfunction begin between ages 20 and 50 years.
• Pseudobulbar palsy also begins between ages 30 and 50 years.
• Forty-four percent of affected individuals have a stroke-like episode (e.g., hemiparesis or hemisensory impairment) before age 40 years.
• The disease progresses slowly following the onset of neurologic symptoms. In the advanced stage, emotional incontinence, abulia, and akinetic mutism develop.
• Scalp alopecia is diffuse, not confined to the frontal or parietal regions.
• There is no obvious body hair loss.
• Slowly progressive gait disturbance (the most frequent initial symptom)
• Mood change (depression and irritability) and cognitive dysfunction
• A stroke-like episode (e.g., hemiparesis or hemisensory impairment) in 63% of affected individuals
• Slow progression of the disease following the onset of neurologic symptoms
• Spondylosis deformans is seen in about 36% of affected individuals.
• Alopecia is seen in about 20% of affected individuals.
• CARASIL, for those who have biallelic
• Familial young adult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago without arterial hypertension
• Nemoto disease
• Maeda syndrome
• CADASIL2 (
## Clinical Description
The most frequent initial symptom is slowly progressive gait disturbance from spasticity and pyramidal signs in the lower extremities beginning between ages 20 and 40 years.
Mood change (depression and irritability) and cognitive dysfunction begin between ages 20 and 50 years.
Pseudobulbar palsy also begins between ages 30 and 50 years.
Forty-four percent of affected individuals have a stroke-like episode (e.g., hemiparesis or hemisensory impairment) before age 40 years.
The disease progresses slowly following the onset of neurologic symptoms. In the advanced stage, emotional incontinence, abulia, and akinetic mutism develop.
Scalp alopecia is diffuse, not confined to the frontal or parietal regions.
There is no obvious body hair loss.
Note: Granular osmiophilic material within the vascular media close to smooth muscle cells, a pathologic hallmark for CADASIL, is never observed in CARASIL.
Slowly progressive gait disturbance (the most frequent initial symptom)
Mood change (depression and irritability) and cognitive dysfunction
A stroke-like episode (e.g., hemiparesis or hemisensory impairment) in 63% of affected individuals
Slow progression of the disease following the onset of neurologic symptoms
Spondylosis deformans is seen in about 36% of affected individuals.
Alopecia is seen in about 20% of affected individuals.
• The most frequent initial symptom is slowly progressive gait disturbance from spasticity and pyramidal signs in the lower extremities beginning between ages 20 and 40 years.
• Mood change (depression and irritability) and cognitive dysfunction begin between ages 20 and 50 years.
• Pseudobulbar palsy also begins between ages 30 and 50 years.
• Forty-four percent of affected individuals have a stroke-like episode (e.g., hemiparesis or hemisensory impairment) before age 40 years.
• The disease progresses slowly following the onset of neurologic symptoms. In the advanced stage, emotional incontinence, abulia, and akinetic mutism develop.
• Scalp alopecia is diffuse, not confined to the frontal or parietal regions.
• There is no obvious body hair loss.
• Slowly progressive gait disturbance (the most frequent initial symptom)
• Mood change (depression and irritability) and cognitive dysfunction
• A stroke-like episode (e.g., hemiparesis or hemisensory impairment) in 63% of affected individuals
• Slow progression of the disease following the onset of neurologic symptoms
• Spondylosis deformans is seen in about 36% of affected individuals.
• Alopecia is seen in about 20% of affected individuals.
The most frequent initial symptom is slowly progressive gait disturbance from spasticity and pyramidal signs in the lower extremities beginning between ages 20 and 40 years.
Mood change (depression and irritability) and cognitive dysfunction begin between ages 20 and 50 years.
Pseudobulbar palsy also begins between ages 30 and 50 years.
Forty-four percent of affected individuals have a stroke-like episode (e.g., hemiparesis or hemisensory impairment) before age 40 years.
The disease progresses slowly following the onset of neurologic symptoms. In the advanced stage, emotional incontinence, abulia, and akinetic mutism develop.
Scalp alopecia is diffuse, not confined to the frontal or parietal regions.
There is no obvious body hair loss.
Note: Granular osmiophilic material within the vascular media close to smooth muscle cells, a pathologic hallmark for CADASIL, is never observed in CARASIL.
• The most frequent initial symptom is slowly progressive gait disturbance from spasticity and pyramidal signs in the lower extremities beginning between ages 20 and 40 years.
• Mood change (depression and irritability) and cognitive dysfunction begin between ages 20 and 50 years.
• Pseudobulbar palsy also begins between ages 30 and 50 years.
• Forty-four percent of affected individuals have a stroke-like episode (e.g., hemiparesis or hemisensory impairment) before age 40 years.
• The disease progresses slowly following the onset of neurologic symptoms. In the advanced stage, emotional incontinence, abulia, and akinetic mutism develop.
• Scalp alopecia is diffuse, not confined to the frontal or parietal regions.
• There is no obvious body hair loss.
Slowly progressive gait disturbance (the most frequent initial symptom)
Mood change (depression and irritability) and cognitive dysfunction
A stroke-like episode (e.g., hemiparesis or hemisensory impairment) in 63% of affected individuals
Slow progression of the disease following the onset of neurologic symptoms
Spondylosis deformans is seen in about 36% of affected individuals.
Alopecia is seen in about 20% of affected individuals.
• Slowly progressive gait disturbance (the most frequent initial symptom)
• Mood change (depression and irritability) and cognitive dysfunction
• A stroke-like episode (e.g., hemiparesis or hemisensory impairment) in 63% of affected individuals
• Slow progression of the disease following the onset of neurologic symptoms
• Spondylosis deformans is seen in about 36% of affected individuals.
• Alopecia is seen in about 20% of affected individuals.
## Genotype-Phenotype Correlations
No strong genotype-phenotype correlations for
Those who have a heterozygous
## Nomenclature
Other names for
CARASIL, for those who have biallelic
Familial young adult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago without arterial hypertension
Nemoto disease
Maeda syndrome
CADASIL2 (
• CARASIL, for those who have biallelic
• Familial young adult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago without arterial hypertension
• Nemoto disease
• Maeda syndrome
• CADASIL2 (
## Prevalence
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Note: Classic CARASIL should be considered in any young person who has alopecia in conjunction with multiple white matter lesions on MRI.
Inherited Disorders with Adult-Onset Leukoaraiosis to Consider in the Differential Diagnosis of
Intracranial aneurysm
Renal abnormalities (hematuria, cystic kidney)
Muscle cramps
Retinal arteriolar tortuosity (retinal hemorrhages)
Periodic severe pain in extremities
Angiokeratoma
Renal insufficiency
Hypohidrosis
Left ventricular hypertrophy
Corneal opacities
Contrast-enhancing lesion mimicking tumor on brain MRI
Retinal artery abnormalities (macular capillary dropout, tortuous telangiectasia)
Progressive visual loss
Raynaud phenomenon
Migraine
Proteinuria & hematuria
AD = autosomal dominant; CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASAL = cathepsin A-related arteriopathy with strokes and leukoencephalopathy; HERNS = hereditary endotheliopathy with retinopathy, nephropathy, and stroke; MOI = mode of inheritance; XL = X-linked
Recommended laboratory investigations: skin biopsy evaluation for NOTCH3 protein expression and electron microscopy for granular osmiophilic material
Small vessel diseases (e.g., familial SVD, Portuguese-French type [
Swedish hereditary multi-infarct dementia [
Sporadic small vessel diseases including Binswanger disease and primary angiitis of the nervous system (Binswanger disease can be distinguished from CARASIL by the presence of hypertension.)
• Intracranial aneurysm
• Renal abnormalities (hematuria, cystic kidney)
• Muscle cramps
• Retinal arteriolar tortuosity (retinal hemorrhages)
• Periodic severe pain in extremities
• Angiokeratoma
• Renal insufficiency
• Hypohidrosis
• Left ventricular hypertrophy
• Corneal opacities
• Contrast-enhancing lesion mimicking tumor on brain MRI
• Retinal artery abnormalities (macular capillary dropout, tortuous telangiectasia)
• Progressive visual loss
• Raynaud phenomenon
• Migraine
• Proteinuria & hematuria
• Small vessel diseases (e.g., familial SVD, Portuguese-French type [
• Swedish hereditary multi-infarct dementia [
• Sporadic small vessel diseases including Binswanger disease and primary angiitis of the nervous system (Binswanger disease can be distinguished from CARASIL by the presence of hypertension.)
## Management
Consensus clinical management guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Supportive care in the form of practical help, emotional support, and counseling are appropriate for affected individuals and their families.
Treatment of Manifestations in Individuals with
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
The interval at which a person with
Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis, should be avoided.
It has been speculated that hypertension or smoking may influence the age of onset and frequency of stroke episodes in individuals with
See
Search
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
## Treatment of Manifestations
Supportive care in the form of practical help, emotional support, and counseling are appropriate for affected individuals and their families.
Treatment of Manifestations in Individuals with
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
## Surveillance
The interval at which a person with
## Agents/Circumstances to Avoid
Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis, should be avoided.
## Evaluation of Relatives at Risk
It has been speculated that hypertension or smoking may influence the age of onset and frequency of stroke episodes in individuals with
See
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of an individual with biallelic
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
It is not clear whether individuals who are heterozygous for an
If both parents are known to be heterozygous for an
It is not clear whether carriers (heterozygotes) are asymptomatic (see
Molecular genetic testing for at-risk family members requires prior identification of the
Most individuals diagnosed with autosomal dominant
Because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if a pathogenic variant occurred
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
The family history of some individuals diagnosed with
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known
If the parents have not been tested for the
See Management,
Predictive testing for at-risk relatives is possible once the
Potential consequences of such testing including (but not limited to) socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result – as well as the capabilities and limitations of predictive testing – should be discussed in the context of formal genetic counseling prior to testing.
For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of
The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being affected or of being heterozygous.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an individual with biallelic
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• It is not clear whether individuals who are heterozygous for an
• If both parents are known to be heterozygous for an
• It is not clear whether carriers (heterozygotes) are asymptomatic (see
• Most individuals diagnosed with autosomal dominant
• Because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if a pathogenic variant occurred
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• The family history of some individuals diagnosed with
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known
• If the parents have not been tested for the
• Predictive testing for at-risk relatives is possible once the
• Potential consequences of such testing including (but not limited to) socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result – as well as the capabilities and limitations of predictive testing – should be discussed in the context of formal genetic counseling prior to testing.
• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
• The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being affected or of being heterozygous.
## Mode of Inheritance
## Autosomal Recessive Inheritance
The parents of an individual with biallelic
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
It is not clear whether individuals who are heterozygous for an
If both parents are known to be heterozygous for an
It is not clear whether carriers (heterozygotes) are asymptomatic (see
Molecular genetic testing for at-risk family members requires prior identification of the
• The parents of an individual with biallelic
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• It is not clear whether individuals who are heterozygous for an
• If both parents are known to be heterozygous for an
• It is not clear whether carriers (heterozygotes) are asymptomatic (see
## Risk to Family Members
The parents of an individual with biallelic
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
It is not clear whether individuals who are heterozygous for an
If both parents are known to be heterozygous for an
It is not clear whether carriers (heterozygotes) are asymptomatic (see
• The parents of an individual with biallelic
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• It is not clear whether individuals who are heterozygous for an
• If both parents are known to be heterozygous for an
• It is not clear whether carriers (heterozygotes) are asymptomatic (see
## Heterozygote Detection
Molecular genetic testing for at-risk family members requires prior identification of the
## Autosomal Dominant Inheritance – Risk to Family Members
Most individuals diagnosed with autosomal dominant
Because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if a pathogenic variant occurred
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
The family history of some individuals diagnosed with
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known
If the parents have not been tested for the
• Most individuals diagnosed with autosomal dominant
• Because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if a pathogenic variant occurred
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• The family history of some individuals diagnosed with
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known
• If the parents have not been tested for the
## Related Genetic Counseling Issues
See Management,
Predictive testing for at-risk relatives is possible once the
Potential consequences of such testing including (but not limited to) socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result – as well as the capabilities and limitations of predictive testing – should be discussed in the context of formal genetic counseling prior to testing.
For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of
The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being affected or of being heterozygous.
• Predictive testing for at-risk relatives is possible once the
• Potential consequences of such testing including (but not limited to) socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result – as well as the capabilities and limitations of predictive testing – should be discussed in the context of formal genetic counseling prior to testing.
• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
• The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being affected or of being heterozygous.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
National Center
7272 Greenville Avenue
Dallas TX 75231
•
•
•
• National Center
• 7272 Greenville Avenue
• Dallas TX 75231
•
## Molecular Genetics
HTRA1 Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for HTRA1 Disorder (
In vitro functional expression studies with
## Molecular Pathogenesis
In vitro functional expression studies with
## Chapter Notes
7 November 2019 (ma) Comprehensive update posted live
11 September 2014 (me) Comprehensive update posted live
17 February 2011 (cd) Revision: prenatal testing available clinically
27 April 2010 (me) Review posted live
5 January 2010 (oo) Original submission
• 7 November 2019 (ma) Comprehensive update posted live
• 11 September 2014 (me) Comprehensive update posted live
• 17 February 2011 (cd) Revision: prenatal testing available clinically
• 27 April 2010 (me) Review posted live
• 5 January 2010 (oo) Original submission
## Revision History
7 November 2019 (ma) Comprehensive update posted live
11 September 2014 (me) Comprehensive update posted live
17 February 2011 (cd) Revision: prenatal testing available clinically
27 April 2010 (me) Review posted live
5 January 2010 (oo) Original submission
• 7 November 2019 (ma) Comprehensive update posted live
• 11 September 2014 (me) Comprehensive update posted live
• 17 February 2011 (cd) Revision: prenatal testing available clinically
• 27 April 2010 (me) Review posted live
• 5 January 2010 (oo) Original submission
## References
Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
## Published Guidelines / Consensus Statements
Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
## Literature Cited
|
[
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"S Bianchi, C Di Palma, GN Gallus, I Taglia, A Poggiani, F Rosini, A Rufa, DF Muresanu, A Cerase, MT Dotti, A Federico. Two novel HTRA1 mutations in a European CARASIL patient.. Neurology. 2014;82:898-900",
"M Bugiani, SH Kevelam, HS Bakels, Q Waisfisz, C Ceuterick-de Groote, HW Niessen, TE Abbink, SA Lesnik Oberstein, MS van der Knaap. Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL).. Neurology. 2016;87:1777-86",
"H Chabriat, A Joutel, M Dichgans, E Tournier-Lasserve, MG Bousser. CADASIL.. Lancet Neurol. 2009;8:643-53",
"Y Chen, Z He, S Meng, L Li, H Yang, X. Zhang. A novel mutation of the high-temperature requirement A serine peptidase 1 (HTRA1) gene in a Chinese family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).. J Int Med Res. 2013;41:1445-55",
"T Clausen, C Southan, M Ehrmann. The HtrA family of proteases: implications for protein composition and cell fate.. Mol Cell. 2002;10:443-55",
"S Favaretto, M Margoni, L Salviati, L Pianese, R Manara, C. Baracchini. A new Italian family with HTRA1 mutation associated with autosomal-dominant variant of CARASIL: are we pointing towards a disease spectrum?. J Neurol Sci. 2019;396:108-11",
"T Fukutake. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): from discovery to gene identification.. J Stroke Cerebrovasc Dis. 2011;20:85-93",
"T Fukutake, K Hirayama. Familial young-adult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago without arterial hypertension.. Eur Neurol 1995;35:69-79",
"K Hara, A Shiga, T Fukutake, H Nozaki, A Miyashita, A Yokoseki, H Kawata, A Koyama, K Arima, T Takahashi, M Ikeda, H Shiota, M Tamura, Y Shimoe, M Hirayama, T Arisato, S Yanagawa, A Tanaka, I Nakano, S Ikeda, Y Yoshida, T Yamamoto, T Ikeuchi, R Kuwano, M Nishizawa, S Tsuji, O Onodera. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.. N Engl J Med. 2009;360:1729-39",
"J Ito, H Nozaki, Y Toyoshima, T Abe, A Sato, H Hashidate, S Igarashi, O Onodera, H Takahashi, A Kakita. Histopathologic features of an autopsied patient with cerebral small vessel disease and a heterozygous HTRA1 mutation.. Neuropathology. 2018;38:428-32",
"S Ito, M Takao, T Fukutake, H Hatsuta, S Funabe, N Ito, Y Shimoe, T Niki, I Nakano, M Fukayama, S Murayama. Histopathologic analysis of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): a report of a new genetically confirmed case and comparison to 2 previous cases.. J Neuropathol Exp Neurol. 2016;75:1020-30",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"WC Low, M Junna, A Borjesson-Hanson, CM Morris, TH Moss, DL Stevens, D St Clair, T Mizuno, WW Zhang, K Mykkanen, J Wahlstrom, O Andersen, H Kalimo, M Viitanen, RN Kalaria. Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL.. Brain. 2007;130:357-67",
"M Mendioroz, I Fernández-Cadenas, A Del Río-Espinola, A Rovira, E Solé, MT Fernández-Figueras, V García-Patos, J Sastre-Garriga, S Domingues-Montanari, J Alvarez-Sabín, J Montaner. A missense HTRA1 mutation expands CARASIL syndrome to the Caucasian population.. Neurology. 2010;75:2033-5",
"Y Nishimoto, M Shibata, M Nihonmatsu, H Nozaki, A Shiga, A Shirata, K Yamane, A Kosakai, K Takahashi, M Nishizawa, O Onodera, N Suzuki. A novel mutation in the HTRA1 gene causes CARASIL without alopecia.. Neurology. 2011;76:1353-5",
"H Nozaki, T Kato, M Nihonmatsu, Y Saito, I Mizuta, T Noda, R Koike, K Miyazaki, M Kaito, S Ito, M Makino, A Koyama, A Shiga, M Uemura, Y Sekine, A Murakami, S Moritani, K Hara, A Yokoseki, R Kuwano, N Endo, T Momotsu, M Yoshida, M Nishizawa, T Mizuno, O Onodera. Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL.. Neurology. 2016;86:1964-74",
"H Nozaki, M Nishizawa, O Onodera. Features of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy.. Stroke. 2014;45:3447-53",
"H Nozaki, Y Sekine, T Fukutake, Y Nishimoto, Y Shimoe, A Shirata, S Yanagawa, M Hirayama, M Tamura, M Nishizawa, O Onodera. Characteristic features and progression of abnormalities on MRI for CARASIL.. Neurology. 2015;85:459-63",
"T Oide, H Nakayama, S Yanagawa, N Ito, S Ikeda, K Arima. Extensive loss of arterial medial smooth muscle cells and mural extracellular matrix in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).. Neuropathology. 2008;28:132-42",
"C Oka, R Tsujimoto, M Kajikawa, K Koshiba-Takeuchi, J Ina, M Yano, A Tsuchiya, Y Ueta, A Soma, H Kanda, M Matsumoto, M Kawaichi. HtrA1 serine protease inhibits signaling mediated by Tgfbeta family proteins.. Development. 2004;131:1041-53",
"R Okeda, S Murayama, M Sawabe, T Kuroiwa. Pathology of the cerebral artery in Binswanger's disease in the aged: observation by serial sections and morphometry of the cerebral arteries.. Neuropathology. 2004;24:21-9",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"S Singhal, S Bevan, T Barrick, P Rich, HS Markus. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype.. Brain. 2004;127:2031-8",
"L Truebestein, A Tennstaedt, T Mönig, T Krojer, F Canellas, M Kaiser, T Clausen, M Ehrmann. Nat Struct Mol Biol. 2011;18:386-8",
"M Uemura, H Nozaki, A Koyama, N Sakai, S Ando, M Kanazawa, T Kato, O Onodera. HTRA1 mutations identified in symptomatic carriers have the property of interfering the trimer-dependent activation cascade.. Front Neurol. 2019;10:693",
"E Verdura, D Hervé, E Scharrer, M Amador Mdel, L Guyant-Maréchal, A Philippi, A Corlobé, F Bergametti, S Gazal, C Prieto-Morin, N Beaufort, B Le Bail, I Viakhireva, M Dichgans, H Chabriat, C Haffner, E Tournier-Lasserve. Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease.. Brain. 2015;138:2347-58",
"S Verreault, A Joutel, F Riant, G Neves, M Rui Silva, J Maciazek, E Tournier-Lasserve, MG Bousser, H Chabriat. A novel hereditary small vessel disease of the brain.. Ann Neurol. 2006;59:353-7",
"S Yanagawa, N Ito, K Arima, S Ikeda. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy.. Neurology. 2002;58:817-20"
] |
27/4/2010
|
7/11/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
carney
|
carney
|
[
"Carney Syndrome",
"Carney Syndrome",
"cAMP-dependent protein kinase type I-alpha regulatory subunit",
"PRKAR1A",
"Carney Complex"
] |
Carney Complex
|
Constantine A Stratakis
|
Summary Carney complex (CNC) is characterized by skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, and schwannomas. Pale brown to black lentigines are the most common presenting feature of CNC and typically increase in number at puberty. Cardiac myxomas occur at a young age, may occur in any or all cardiac chambers, and can manifest as intracardiac obstruction of blood flow, embolic phenomenon, and/or heart failure. Other sites for myxomas include the skin, breast, oropharynx, and female genital tract. Primary pigmented nodular adrenocortical disease (PPNAD), which causes Cushing syndrome, is the most frequently observed endocrine tumor in CNC, occurring in approximately 25% of affected individuals. Large cell calcifying Sertoli cell tumors (LCCSCTs) are observed in one third of affected males within the first decade and in most adult males. Up to 75% of individuals with CNC have multiple thyroid nodules, most of which are nonfunctioning thyroid follicular adenomas. Clinically evident acromegaly from a growth hormone (GH)-producing adenoma is evident in approximately 10% of adults. Psammomatous melanotic schwannoma (PMS), a rare tumor of the nerve sheath, occurs in an estimated 10% of affected individuals. The median age of diagnosis is 20 years. The clinical diagnosis of CNC is established in a proband with two or more major diagnostic criteria. The molecular diagnosis can be established in a proband with suggestive findings and a heterozygous germline pathogenic variant in CNC is inherited in an autosomal dominant manner. Approximately 70% of individuals diagnosed with CNC have an affected parent; approximately 30% have a
|
## Diagnosis
Consensus clinical diagnostic criteria for Carney complex (CNC) have been published [
CNC
Spotty skin pigmentation with typical distribution (lips, conjunctiva and inner or outer canthi, vaginal and penile mucosa)
Myxoma * (cutaneous and mucosal)
Cardiac myxoma *
Breast myxomatosis * or fat-suppressed MRI findings suggestive of this diagnosis
Primary pigmented nodular adrenocortical disease (PPNAD) * or paradoxic positive response of urinary glucocorticosteroid excretion to dexamethasone administration during Liddle's test
Acromegaly as a result of growth hormone (GH)-producing adenoma *
Large cell calcifying Sertoli cell tumor (LCCSCT) * or characteristic calcification on testicular ultrasound
Thyroid carcinoma * or multiple, hypoechoic nodules on thyroid ultrasound in a child younger than age 18 years
Psammomatous melanotic schwannoma (PMS) *
Blue nevus, epithelioid blue nevus *
Breast ductal adenoma *
Osteochondromyxoma *
Note: Criteria denoted by * are based on histologic confirmation.
Intense freckling (without darkly pigmented spots or typical distribution)
Multiple blue nevi, common type
Café au lait macules or other "birthmarks"
Elevated insulin-like growth factor 1 (IGF-1) levels, abnormal glucose tolerance test (GTT), or paradoxic GH response to thyrotropin-releasing hormone (TRH) testing in the absence of clinical acromegaly
Cardiomyopathy (due to cardiac myxoma)
Multiple skin tags or other skin lesions; lipomas
Colonic polyps (usually in association with acromegaly)
Hyperprolactinemia (usually mild and almost always combined with clinical or subclinical acromegaly)
Single, benign thyroid nodule in a child younger than age 18 years; multiple thyroid nodules in an individual older than age 18 years (detected on ultrasound examination)
Family history of carcinoma, in particular of the thyroid, pancreas, and ovary; other multiple benign or malignant tumors; Cushing syndrome; acromegaly; or sudden death
The clinical diagnosis of CNC
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Carney Complex
NA = not applicable
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
In the largest study to date, 114 (62%) of 185 families studied had an identifiable
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
In a study of 36 unrelated individuals with CNC who were negative for
Approximately 20% of families with CNC have been linked to 2p16 [
Germline
One individual with CNC had a germline rearrangement resulting in four copies of
• Spotty skin pigmentation with typical distribution (lips, conjunctiva and inner or outer canthi, vaginal and penile mucosa)
• Myxoma * (cutaneous and mucosal)
• Cardiac myxoma *
• Breast myxomatosis * or fat-suppressed MRI findings suggestive of this diagnosis
• Primary pigmented nodular adrenocortical disease (PPNAD) * or paradoxic positive response of urinary glucocorticosteroid excretion to dexamethasone administration during Liddle's test
• Acromegaly as a result of growth hormone (GH)-producing adenoma *
• Large cell calcifying Sertoli cell tumor (LCCSCT) * or characteristic calcification on testicular ultrasound
• Thyroid carcinoma * or multiple, hypoechoic nodules on thyroid ultrasound in a child younger than age 18 years
• Psammomatous melanotic schwannoma (PMS) *
• Blue nevus, epithelioid blue nevus *
• Breast ductal adenoma *
• Osteochondromyxoma *
• Intense freckling (without darkly pigmented spots or typical distribution)
• Multiple blue nevi, common type
• Café au lait macules or other "birthmarks"
• Elevated insulin-like growth factor 1 (IGF-1) levels, abnormal glucose tolerance test (GTT), or paradoxic GH response to thyrotropin-releasing hormone (TRH) testing in the absence of clinical acromegaly
• Cardiomyopathy (due to cardiac myxoma)
• Multiple skin tags or other skin lesions; lipomas
• Colonic polyps (usually in association with acromegaly)
• Hyperprolactinemia (usually mild and almost always combined with clinical or subclinical acromegaly)
• Single, benign thyroid nodule in a child younger than age 18 years; multiple thyroid nodules in an individual older than age 18 years (detected on ultrasound examination)
• Family history of carcinoma, in particular of the thyroid, pancreas, and ovary; other multiple benign or malignant tumors; Cushing syndrome; acromegaly; or sudden death
• For an introduction to multigene panels click
## Suggestive Findings
CNC
Spotty skin pigmentation with typical distribution (lips, conjunctiva and inner or outer canthi, vaginal and penile mucosa)
Myxoma * (cutaneous and mucosal)
Cardiac myxoma *
Breast myxomatosis * or fat-suppressed MRI findings suggestive of this diagnosis
Primary pigmented nodular adrenocortical disease (PPNAD) * or paradoxic positive response of urinary glucocorticosteroid excretion to dexamethasone administration during Liddle's test
Acromegaly as a result of growth hormone (GH)-producing adenoma *
Large cell calcifying Sertoli cell tumor (LCCSCT) * or characteristic calcification on testicular ultrasound
Thyroid carcinoma * or multiple, hypoechoic nodules on thyroid ultrasound in a child younger than age 18 years
Psammomatous melanotic schwannoma (PMS) *
Blue nevus, epithelioid blue nevus *
Breast ductal adenoma *
Osteochondromyxoma *
Note: Criteria denoted by * are based on histologic confirmation.
Intense freckling (without darkly pigmented spots or typical distribution)
Multiple blue nevi, common type
Café au lait macules or other "birthmarks"
Elevated insulin-like growth factor 1 (IGF-1) levels, abnormal glucose tolerance test (GTT), or paradoxic GH response to thyrotropin-releasing hormone (TRH) testing in the absence of clinical acromegaly
Cardiomyopathy (due to cardiac myxoma)
Multiple skin tags or other skin lesions; lipomas
Colonic polyps (usually in association with acromegaly)
Hyperprolactinemia (usually mild and almost always combined with clinical or subclinical acromegaly)
Single, benign thyroid nodule in a child younger than age 18 years; multiple thyroid nodules in an individual older than age 18 years (detected on ultrasound examination)
Family history of carcinoma, in particular of the thyroid, pancreas, and ovary; other multiple benign or malignant tumors; Cushing syndrome; acromegaly; or sudden death
• Spotty skin pigmentation with typical distribution (lips, conjunctiva and inner or outer canthi, vaginal and penile mucosa)
• Myxoma * (cutaneous and mucosal)
• Cardiac myxoma *
• Breast myxomatosis * or fat-suppressed MRI findings suggestive of this diagnosis
• Primary pigmented nodular adrenocortical disease (PPNAD) * or paradoxic positive response of urinary glucocorticosteroid excretion to dexamethasone administration during Liddle's test
• Acromegaly as a result of growth hormone (GH)-producing adenoma *
• Large cell calcifying Sertoli cell tumor (LCCSCT) * or characteristic calcification on testicular ultrasound
• Thyroid carcinoma * or multiple, hypoechoic nodules on thyroid ultrasound in a child younger than age 18 years
• Psammomatous melanotic schwannoma (PMS) *
• Blue nevus, epithelioid blue nevus *
• Breast ductal adenoma *
• Osteochondromyxoma *
• Intense freckling (without darkly pigmented spots or typical distribution)
• Multiple blue nevi, common type
• Café au lait macules or other "birthmarks"
• Elevated insulin-like growth factor 1 (IGF-1) levels, abnormal glucose tolerance test (GTT), or paradoxic GH response to thyrotropin-releasing hormone (TRH) testing in the absence of clinical acromegaly
• Cardiomyopathy (due to cardiac myxoma)
• Multiple skin tags or other skin lesions; lipomas
• Colonic polyps (usually in association with acromegaly)
• Hyperprolactinemia (usually mild and almost always combined with clinical or subclinical acromegaly)
• Single, benign thyroid nodule in a child younger than age 18 years; multiple thyroid nodules in an individual older than age 18 years (detected on ultrasound examination)
• Family history of carcinoma, in particular of the thyroid, pancreas, and ovary; other multiple benign or malignant tumors; Cushing syndrome; acromegaly; or sudden death
## Establishing the Diagnosis
The clinical diagnosis of CNC
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Carney Complex
NA = not applicable
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
In the largest study to date, 114 (62%) of 185 families studied had an identifiable
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
In a study of 36 unrelated individuals with CNC who were negative for
Approximately 20% of families with CNC have been linked to 2p16 [
Germline
One individual with CNC had a germline rearrangement resulting in four copies of
• For an introduction to multigene panels click
## Clinical Characteristics
The Carney complex (CNC) of skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, and schwannomas may be evident at birth, although the median age of diagnosis is 20 years. To date, more than 750 individuals have been identified with a pathogenic variant in
Carney Complex: Frequency of Select Features
LCCSCT = large cell calcifying Sertoli cell tumor; GH = growth hormone; PMS = psammomatous melanotic schwannoma; PPNAD = primary pigmented nodular adrenocortical disease
Pale brown to black lentigines are the most common presenting feature of CNC and may be present at birth. Typically, they increase in number and appear anywhere on the body, including the face, the lips, and mucosa around puberty. These lentigines tend to fade after the fourth decade but may still be evident in the eighth decade.
Additional pigmentary abnormalities that develop over time are epithelioid-type blue nevi (small, bluish, domed papules with a smooth surface), combined nevi, café au lait macules, and depigmented lesions.
Cutaneous myxomas are papules or subcutaneous nodules that usually have a smooth surface and are white, flesh-colored, opalescent, or pink. They appear between birth and the fourth decade. Most individuals with CNC have multiple lesions. Myxomas occur on any part of the body except the hands and feet and typically affect the eyelids, external ear canal, and nipples.
Cardiac myxomas occur at a young age and may occur in any or all cardiac chambers. Cardiac myxomas present with symptoms related to intracardiac obstruction of blood flow, embolic phenomenon (into the systemic circulation), and/or heart failure. Myxomas that completely occlude a valvular orifice can cause sudden death.
Breast myxomas, often bilateral, occur in females after puberty. Both males and females may develop nipple myxomas at any age.
Other sites for myxomas include the oropharynx (tongue, hard palate, pharynx) and the female genital tract (uterus, cervix, vagina).
Osteochondromyxoma is a rare myxomatous tumor of the bone that affects nasal sinuses and long bones.
Clinical and genotypic data on more than 380 affected individuals are available from more than 20 years of study at the National Institutes of Health (Bethesda, MD) and the Hospital Côchin (Paris). Phenotype analysis in 353 individuals with 80 different
A
The "hot spot'' pathogenic variant
Individuals with CNC heterozygous for a
Those with isolated PPNAD (which was accompanied by lentiginosis in some individuals) diagnosed before age eight years were rarely heterozygous for a
Large
The overall penetrance of CNC in those with a
To date only two
Carney complex has also been designated by the following acronyms:
NAME (
LAMB (
More than 750 individuals with CNC are known to the author.
• Pale brown to black lentigines are the most common presenting feature of CNC and may be present at birth. Typically, they increase in number and appear anywhere on the body, including the face, the lips, and mucosa around puberty. These lentigines tend to fade after the fourth decade but may still be evident in the eighth decade.
• Additional pigmentary abnormalities that develop over time are epithelioid-type blue nevi (small, bluish, domed papules with a smooth surface), combined nevi, café au lait macules, and depigmented lesions.
• Cutaneous myxomas are papules or subcutaneous nodules that usually have a smooth surface and are white, flesh-colored, opalescent, or pink. They appear between birth and the fourth decade. Most individuals with CNC have multiple lesions. Myxomas occur on any part of the body except the hands and feet and typically affect the eyelids, external ear canal, and nipples.
• Cardiac myxomas occur at a young age and may occur in any or all cardiac chambers. Cardiac myxomas present with symptoms related to intracardiac obstruction of blood flow, embolic phenomenon (into the systemic circulation), and/or heart failure. Myxomas that completely occlude a valvular orifice can cause sudden death.
• Breast myxomas, often bilateral, occur in females after puberty. Both males and females may develop nipple myxomas at any age.
• Other sites for myxomas include the oropharynx (tongue, hard palate, pharynx) and the female genital tract (uterus, cervix, vagina).
• Osteochondromyxoma is a rare myxomatous tumor of the bone that affects nasal sinuses and long bones.
• A
• The "hot spot'' pathogenic variant
• Individuals with CNC heterozygous for a
• Those with isolated PPNAD (which was accompanied by lentiginosis in some individuals) diagnosed before age eight years were rarely heterozygous for a
• Large
• NAME (
• LAMB (
## Clinical Description
The Carney complex (CNC) of skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, and schwannomas may be evident at birth, although the median age of diagnosis is 20 years. To date, more than 750 individuals have been identified with a pathogenic variant in
Carney Complex: Frequency of Select Features
LCCSCT = large cell calcifying Sertoli cell tumor; GH = growth hormone; PMS = psammomatous melanotic schwannoma; PPNAD = primary pigmented nodular adrenocortical disease
Pale brown to black lentigines are the most common presenting feature of CNC and may be present at birth. Typically, they increase in number and appear anywhere on the body, including the face, the lips, and mucosa around puberty. These lentigines tend to fade after the fourth decade but may still be evident in the eighth decade.
Additional pigmentary abnormalities that develop over time are epithelioid-type blue nevi (small, bluish, domed papules with a smooth surface), combined nevi, café au lait macules, and depigmented lesions.
Cutaneous myxomas are papules or subcutaneous nodules that usually have a smooth surface and are white, flesh-colored, opalescent, or pink. They appear between birth and the fourth decade. Most individuals with CNC have multiple lesions. Myxomas occur on any part of the body except the hands and feet and typically affect the eyelids, external ear canal, and nipples.
Cardiac myxomas occur at a young age and may occur in any or all cardiac chambers. Cardiac myxomas present with symptoms related to intracardiac obstruction of blood flow, embolic phenomenon (into the systemic circulation), and/or heart failure. Myxomas that completely occlude a valvular orifice can cause sudden death.
Breast myxomas, often bilateral, occur in females after puberty. Both males and females may develop nipple myxomas at any age.
Other sites for myxomas include the oropharynx (tongue, hard palate, pharynx) and the female genital tract (uterus, cervix, vagina).
Osteochondromyxoma is a rare myxomatous tumor of the bone that affects nasal sinuses and long bones.
• Pale brown to black lentigines are the most common presenting feature of CNC and may be present at birth. Typically, they increase in number and appear anywhere on the body, including the face, the lips, and mucosa around puberty. These lentigines tend to fade after the fourth decade but may still be evident in the eighth decade.
• Additional pigmentary abnormalities that develop over time are epithelioid-type blue nevi (small, bluish, domed papules with a smooth surface), combined nevi, café au lait macules, and depigmented lesions.
• Cutaneous myxomas are papules or subcutaneous nodules that usually have a smooth surface and are white, flesh-colored, opalescent, or pink. They appear between birth and the fourth decade. Most individuals with CNC have multiple lesions. Myxomas occur on any part of the body except the hands and feet and typically affect the eyelids, external ear canal, and nipples.
• Cardiac myxomas occur at a young age and may occur in any or all cardiac chambers. Cardiac myxomas present with symptoms related to intracardiac obstruction of blood flow, embolic phenomenon (into the systemic circulation), and/or heart failure. Myxomas that completely occlude a valvular orifice can cause sudden death.
• Breast myxomas, often bilateral, occur in females after puberty. Both males and females may develop nipple myxomas at any age.
• Other sites for myxomas include the oropharynx (tongue, hard palate, pharynx) and the female genital tract (uterus, cervix, vagina).
• Osteochondromyxoma is a rare myxomatous tumor of the bone that affects nasal sinuses and long bones.
## Genotype-Phenotype Correlations
Clinical and genotypic data on more than 380 affected individuals are available from more than 20 years of study at the National Institutes of Health (Bethesda, MD) and the Hospital Côchin (Paris). Phenotype analysis in 353 individuals with 80 different
A
The "hot spot'' pathogenic variant
Individuals with CNC heterozygous for a
Those with isolated PPNAD (which was accompanied by lentiginosis in some individuals) diagnosed before age eight years were rarely heterozygous for a
Large
• A
• The "hot spot'' pathogenic variant
• Individuals with CNC heterozygous for a
• Those with isolated PPNAD (which was accompanied by lentiginosis in some individuals) diagnosed before age eight years were rarely heterozygous for a
• Large
## Penetrance
The overall penetrance of CNC in those with a
To date only two
## Nomenclature
Carney complex has also been designated by the following acronyms:
NAME (
LAMB (
• NAME (
• LAMB (
## Prevalence
More than 750 individuals with CNC are known to the author.
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Genes of interest in the differential diagnosis of Carney complex (CNC) are summarized in
Genes of Interest in the Differential Diagnosis of Carney Complex
Café au lait macules
Adrenal cortical tumors
Adrenal cortical tumors
GH-secreting pituitary adenomas (somatotropinomas) causing acromegaly
Café au lait macules
Schwannomas
Café au lait macules
Schwannomas
In PPNAD2, there is usually little pigmentation in adrenal histology.
Persons w/PPNAD2 usually do not have other tumors.
Lentigines in Bannayan-Riley-Ruvalcaba syndrome
Thyroid tumors in Cowden syndrome
Lentigines
Large cell calcifying Sertoli cell tumors (tumors may be hormone producing)
AD = autosomal dominant; AR = autosomal recessive; CNC = Carney complex; GH = growth hormone; MOI = mode of inheritance
Beckwith-Wiedemann syndrome (BWS) is associated with abnormal regulation of gene transcription in two imprinted domains on chromosome 11p15.5 (also known as the BWS critical region). Regulation may be disrupted by any one of numerous mechanisms; reliable recurrence risk assessment requires identification of the genetic mechanism in the proband that underlies the abnormal expression of imprinted genes in the BWS critical region (see
Noonan syndrome is most often inherited in an autosomal dominant manner; Noonan syndrome caused by pathogenic variants in
CNC is the only genetic condition other than neurofibromatosis 1, neurofibromatosis 2, and isolated familial schwannomatosis in which schwannomas occur.
Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome are phenotypes observed in
• Café au lait macules
• Adrenal cortical tumors
• Adrenal cortical tumors
• GH-secreting pituitary adenomas (somatotropinomas) causing acromegaly
• Café au lait macules
• Schwannomas
• Café au lait macules
• Schwannomas
• In PPNAD2, there is usually little pigmentation in adrenal histology.
• Persons w/PPNAD2 usually do not have other tumors.
• Lentigines in Bannayan-Riley-Ruvalcaba syndrome
• Thyroid tumors in Cowden syndrome
• Lentigines
• Large cell calcifying Sertoli cell tumors (tumors may be hormone producing)
## Management
To establish the extent of disease and needs in an individual diagnosed with Carney complex (CNC), the evaluations summarized in
Carney Complex: Recommended Evaluations Following Initial Diagnosis
Diurnal cortisol levels (11:30 pm, 12:00 am, & 7:30 am; 8:00 am sampling)
Dexamethasone stimulation test (modified Liddle's test)
Adrenal CT exam
Pituitary MRI
Three-hour oral glucose tolerance test
90-minute thyrotropin-releasing hormone testing
Testicular ultrasonography
Assessment of growth rate & pubertal staging
IGF-1 = insulin-like growth factor 1; MOI = mode of inheritance; PPNAD = primary pigmented nodular adrenocortical disease; US = ultrasound
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Carney Complex: Treatment of Manifestations
Orchiectomy usually required for boys w/aggressively growing LCCSCTs & gynecomastia to avoid premature epiphyseal fusion & induction of central precocious puberty.
Boys w/mild gynecomastia & tumor that is not growing can be treated medically w/aromatase inhibitors.
LCCSCT = large cell calcifying Sertoli cell tumor
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Carney Complex: Recommended Surveillance
Annually beginning in childhood (prior to puberty)
Biannually for those w/history of excised cardiac myxoma
Diurnal cortisol levels (11:30 pm, 12:00 am, & 7:30 am; 8:00 am sampling)
Dexamethasone stimulation test (modified Liddle's test)
Adrenal CT exam
Pituitary MRI
Three-hour oral glucose tolerance test
90-minute thyrotropin-releasing hormone testing
Clinical assessment for mass effects
MRI (brain, spine, chest, abdomen, retroperitoneum, pelvis) in those w/suspected tumor
IGF-1 = insulin-like growth factor 1; PPNAD = primary pigmented nodular adrenocortical disease; US = ultrasound
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the
When molecular genetic testing for a
See
Search
• Diurnal cortisol levels (11:30 pm, 12:00 am, & 7:30 am; 8:00 am sampling)
• Dexamethasone stimulation test (modified Liddle's test)
• Adrenal CT exam
• Pituitary MRI
• Three-hour oral glucose tolerance test
• 90-minute thyrotropin-releasing hormone testing
• Testicular ultrasonography
• Assessment of growth rate & pubertal staging
• Orchiectomy usually required for boys w/aggressively growing LCCSCTs & gynecomastia to avoid premature epiphyseal fusion & induction of central precocious puberty.
• Boys w/mild gynecomastia & tumor that is not growing can be treated medically w/aromatase inhibitors.
• Annually beginning in childhood (prior to puberty)
• Biannually for those w/history of excised cardiac myxoma
• Diurnal cortisol levels (11:30 pm, 12:00 am, & 7:30 am; 8:00 am sampling)
• Dexamethasone stimulation test (modified Liddle's test)
• Adrenal CT exam
• Pituitary MRI
• Three-hour oral glucose tolerance test
• 90-minute thyrotropin-releasing hormone testing
• Clinical assessment for mass effects
• MRI (brain, spine, chest, abdomen, retroperitoneum, pelvis) in those w/suspected tumor
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Carney complex (CNC), the evaluations summarized in
Carney Complex: Recommended Evaluations Following Initial Diagnosis
Diurnal cortisol levels (11:30 pm, 12:00 am, & 7:30 am; 8:00 am sampling)
Dexamethasone stimulation test (modified Liddle's test)
Adrenal CT exam
Pituitary MRI
Three-hour oral glucose tolerance test
90-minute thyrotropin-releasing hormone testing
Testicular ultrasonography
Assessment of growth rate & pubertal staging
IGF-1 = insulin-like growth factor 1; MOI = mode of inheritance; PPNAD = primary pigmented nodular adrenocortical disease; US = ultrasound
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Diurnal cortisol levels (11:30 pm, 12:00 am, & 7:30 am; 8:00 am sampling)
• Dexamethasone stimulation test (modified Liddle's test)
• Adrenal CT exam
• Pituitary MRI
• Three-hour oral glucose tolerance test
• 90-minute thyrotropin-releasing hormone testing
• Testicular ultrasonography
• Assessment of growth rate & pubertal staging
## Treatment of Manifestations
Carney Complex: Treatment of Manifestations
Orchiectomy usually required for boys w/aggressively growing LCCSCTs & gynecomastia to avoid premature epiphyseal fusion & induction of central precocious puberty.
Boys w/mild gynecomastia & tumor that is not growing can be treated medically w/aromatase inhibitors.
LCCSCT = large cell calcifying Sertoli cell tumor
• Orchiectomy usually required for boys w/aggressively growing LCCSCTs & gynecomastia to avoid premature epiphyseal fusion & induction of central precocious puberty.
• Boys w/mild gynecomastia & tumor that is not growing can be treated medically w/aromatase inhibitors.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Carney Complex: Recommended Surveillance
Annually beginning in childhood (prior to puberty)
Biannually for those w/history of excised cardiac myxoma
Diurnal cortisol levels (11:30 pm, 12:00 am, & 7:30 am; 8:00 am sampling)
Dexamethasone stimulation test (modified Liddle's test)
Adrenal CT exam
Pituitary MRI
Three-hour oral glucose tolerance test
90-minute thyrotropin-releasing hormone testing
Clinical assessment for mass effects
MRI (brain, spine, chest, abdomen, retroperitoneum, pelvis) in those w/suspected tumor
IGF-1 = insulin-like growth factor 1; PPNAD = primary pigmented nodular adrenocortical disease; US = ultrasound
• Annually beginning in childhood (prior to puberty)
• Biannually for those w/history of excised cardiac myxoma
• Diurnal cortisol levels (11:30 pm, 12:00 am, & 7:30 am; 8:00 am sampling)
• Dexamethasone stimulation test (modified Liddle's test)
• Adrenal CT exam
• Pituitary MRI
• Three-hour oral glucose tolerance test
• 90-minute thyrotropin-releasing hormone testing
• Clinical assessment for mass effects
• MRI (brain, spine, chest, abdomen, retroperitoneum, pelvis) in those w/suspected tumor
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the
When molecular genetic testing for a
See
## Therapies Under Investigation
Search
## Genetic Counseling
Carney complex (CNC) is inherited in an autosomal dominant manner.
Approximately 70% of individuals diagnosed with CNC have an affected parent.
Approximately 30% of individuals have CNC as the result of a
If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with CNC may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
If a parent of the proband is affected and/or known to be heterozygous for a
If the proband has a known
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
Each child of an individual with CNC has a 50% chance of inheriting the
Fertility may be impaired in males with CNC.
It is possible that pregnancies in which a
See Management,
If a clinically diagnosed relative has undergone molecular genetic testing and is found to have a pathogenic variant in
It is appropriate to consider molecular genetic testing of young at-risk family members in order to guide medical management (see Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Approximately 70% of individuals diagnosed with CNC have an affected parent.
• Approximately 30% of individuals have CNC as the result of a
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with CNC may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or known to be heterozygous for a
• If the proband has a known
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
• Each child of an individual with CNC has a 50% chance of inheriting the
• Fertility may be impaired in males with CNC.
• It is possible that pregnancies in which a
• If a clinically diagnosed relative has undergone molecular genetic testing and is found to have a pathogenic variant in
• It is appropriate to consider molecular genetic testing of young at-risk family members in order to guide medical management (see Management,
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Carney complex (CNC) is inherited in an autosomal dominant manner.
## Risk to Family Members
Approximately 70% of individuals diagnosed with CNC have an affected parent.
Approximately 30% of individuals have CNC as the result of a
If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with CNC may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
If a parent of the proband is affected and/or known to be heterozygous for a
If the proband has a known
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
Each child of an individual with CNC has a 50% chance of inheriting the
Fertility may be impaired in males with CNC.
It is possible that pregnancies in which a
• Approximately 70% of individuals diagnosed with CNC have an affected parent.
• Approximately 30% of individuals have CNC as the result of a
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with CNC may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or known to be heterozygous for a
• If the proband has a known
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
• Each child of an individual with CNC has a 50% chance of inheriting the
• Fertility may be impaired in males with CNC.
• It is possible that pregnancies in which a
## Related Genetic Counseling Issues
See Management,
If a clinically diagnosed relative has undergone molecular genetic testing and is found to have a pathogenic variant in
It is appropriate to consider molecular genetic testing of young at-risk family members in order to guide medical management (see Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• If a clinically diagnosed relative has undergone molecular genetic testing and is found to have a pathogenic variant in
• It is appropriate to consider molecular genetic testing of young at-risk family members in order to guide medical management (see Management,
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
•
•
•
•
•
## Molecular Genetics
Carney Complex: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Carney Complex (
Haploinsufficiency of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A) causes Carney complex (CNC). In tumors of individuals affected with CNC, biallelic inactivation of
The mechanism is therefore loss of function of a protein that controls almost all of cAMP signaling in all cells. PRKAR1A regulates the catalytic subunit of PKA, which when uncontrolled due to PRKAR1A's loss of function causes increased endocrine hormone signaling and the formation of tumors [
Common variant
See
Variants listed in the table have been provided by the author.
• Common variant
• See
## Molecular Pathogenesis
Haploinsufficiency of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A) causes Carney complex (CNC). In tumors of individuals affected with CNC, biallelic inactivation of
The mechanism is therefore loss of function of a protein that controls almost all of cAMP signaling in all cells. PRKAR1A regulates the catalytic subunit of PKA, which when uncontrolled due to PRKAR1A's loss of function causes increased endocrine hormone signaling and the formation of tumors [
Common variant
See
Variants listed in the table have been provided by the author.
• Common variant
• See
## Chapter Notes
Dr Stratakis has moved from the US National Institutes of Health to the Foundation for Research & Technology Hellas (FORTH) in Greece.
Dr Stratakis is actively involved in clinical research regarding individuals with CNC. Dr Stratakis would be happy to communicate with persons who have any questions regarding diagnosis of Carney complex (CNC) or other considerations.
Dr Stratakis is also interested in hearing from clinicians treating families affected by CNC in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
Contact Dr Stratakis to inquire about review of
The author wishes to thank the US National Institutes of Health for funding studies on CNC, the patients for participating in research, and the group at
Anelia Horvath, PhD; National Institutes of Health (2003-2015)
Margarita Raygada, MSc, PhD; National Institutes of Health (2015-2023)
Paraskevi Salpea, PhD; National Institutes of Health (2015-2018)
Constantine A Stratakis, MD, DSc (2003-present)
21 September 2023 (sw) Comprehensive update posted live
16 August 2018 (sw) Comprehensive update posted live
29 January 2015 (me) Comprehensive update posted live
20 September 2012 (me) Comprehensive update posted live
22 June 2010 (me) Comprehensive update posted live
10 January 2008 (me) Comprehensive update posted live
22 March 2005 (me) Comprehensive update posted live
5 February 2003 (me) Review posted live
7 October 2002 (cs) Original submission
• 21 September 2023 (sw) Comprehensive update posted live
• 16 August 2018 (sw) Comprehensive update posted live
• 29 January 2015 (me) Comprehensive update posted live
• 20 September 2012 (me) Comprehensive update posted live
• 22 June 2010 (me) Comprehensive update posted live
• 10 January 2008 (me) Comprehensive update posted live
• 22 March 2005 (me) Comprehensive update posted live
• 5 February 2003 (me) Review posted live
• 7 October 2002 (cs) Original submission
## Author Notes
Dr Stratakis has moved from the US National Institutes of Health to the Foundation for Research & Technology Hellas (FORTH) in Greece.
Dr Stratakis is actively involved in clinical research regarding individuals with CNC. Dr Stratakis would be happy to communicate with persons who have any questions regarding diagnosis of Carney complex (CNC) or other considerations.
Dr Stratakis is also interested in hearing from clinicians treating families affected by CNC in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
Contact Dr Stratakis to inquire about review of
## Acknowledgments
The author wishes to thank the US National Institutes of Health for funding studies on CNC, the patients for participating in research, and the group at
## Author History
Anelia Horvath, PhD; National Institutes of Health (2003-2015)
Margarita Raygada, MSc, PhD; National Institutes of Health (2015-2023)
Paraskevi Salpea, PhD; National Institutes of Health (2015-2018)
Constantine A Stratakis, MD, DSc (2003-present)
## Revision History
21 September 2023 (sw) Comprehensive update posted live
16 August 2018 (sw) Comprehensive update posted live
29 January 2015 (me) Comprehensive update posted live
20 September 2012 (me) Comprehensive update posted live
22 June 2010 (me) Comprehensive update posted live
10 January 2008 (me) Comprehensive update posted live
22 March 2005 (me) Comprehensive update posted live
5 February 2003 (me) Review posted live
7 October 2002 (cs) Original submission
• 21 September 2023 (sw) Comprehensive update posted live
• 16 August 2018 (sw) Comprehensive update posted live
• 29 January 2015 (me) Comprehensive update posted live
• 20 September 2012 (me) Comprehensive update posted live
• 22 June 2010 (me) Comprehensive update posted live
• 10 January 2008 (me) Comprehensive update posted live
• 22 March 2005 (me) Comprehensive update posted live
• 5 February 2003 (me) Review posted live
• 7 October 2002 (cs) Original submission
## References
American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available
• American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available
## Published Guidelines / Consensus Statements
American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available
• American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available
## Literature Cited
|
[] |
5/2/2003
|
21/9/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
cask-dis
|
cask-dis
|
[
"Intellectual Disability and Microcephaly with Pontine and Cerebellar Hypoplasia (MICPCH)",
"X-Linked Intellectual Disability (XLID) with or without Nystagmus",
"Peripheral plasma membrane protein CASK",
"CASK",
"CASK Disorders"
] |
Ute Moog, Kerstin Kutsche
|
Summary Microcephaly with pontine and cerebellar hypoplasia (MICPCH), generally associated with pathogenic loss-of-function variants in X-linked intellectual disability (XLID) with or without nystagmus, generally associated with hypomorphic MICPCH is typically seen in females with moderate-to-severe intellectual disability, progressive microcephaly with or without ophthalmologic anomalies, and sensorineural hearing loss. Most are able to sit independently; 20%-25% attain the ability to walk; language is nearly absent in most. Neurologic features may include axial hypotonia, hypertonia/spasticity of the extremities, and dystonia or other movement disorders. Nearly 40% have seizures by age ten years. Behaviors may include sleep disturbances, hand stereotypies, and self biting. MICPCH in males may occur with or without severe epileptic encephalopathy in addition to severe-to-profound developmental delay. When seizures are present they occur early and may be intractable. In individuals and families with milder (i.e., hypomorphic) pathogenic variants, the clinical phenotype is usually that of XLID with or without nystagmus and additional clinical features. Males have mild-to-severe intellectual disability, with or without nystagmus and other ocular features. Females typically have normal intelligence with some displaying mild-to-severe intellectual disability with or without ocular features. The diagnosis of a CASK disorder is established in a female who is heterozygous for a CASK pathogenic variant and in a male who is hemizygous for a CASK pathogenic variant on molecular genetic testing. Rarely, affected males have a mosaic pathogenic variant. Once the
|
Intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH)
X-linked intellectual disability (XLID) with or without nystagmus
For synonyms and outdated names see
For other genetic causes of these phenotypes see
• Intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH)
• X-linked intellectual disability (XLID) with or without nystagmus
## Diagnosis
Progressive microcephaly up to -10 SD
Pontine and cerebellar hypoplasia
Hypotonia, hypertonia, or a combination of both (central hypotonia and hypertonia of extremities)
Seizures (including early and intractable seizures comprising Ohtahara syndrome, West syndrome, or myoclonic epilepsy)
Nystagmus, strabismus, optic nerve hypoplasia, and/or retinopathy
Sensorineural hearing loss
Short stature
The diagnosis of a
Note: (1) Rarely, affected males have a mosaic pathogenic variant. (2) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
Because the phenotype of
Note: Single-gene testing (sequence analysis of
For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see
For an introduction to multigene panels click
Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/ duplication analysis (which may include
For an introduction to comprehensive genomic testing click
Note: (1) In a few males,
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Percentages are based on female probands. Surviving male probands are more likely to have a variant detected by sequence analysis (see
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Two females with a balanced Xp inversion disrupting
• Progressive microcephaly up to -10 SD
• Pontine and cerebellar hypoplasia
• Hypotonia, hypertonia, or a combination of both (central hypotonia and hypertonia of extremities)
• Seizures (including early and intractable seizures comprising Ohtahara syndrome, West syndrome, or myoclonic epilepsy)
• Nystagmus, strabismus, optic nerve hypoplasia, and/or retinopathy
• Sensorineural hearing loss
• Short stature
• For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see
• For an introduction to multigene panels click
• Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/ duplication analysis (which may include
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Progressive microcephaly up to -10 SD
Pontine and cerebellar hypoplasia
Hypotonia, hypertonia, or a combination of both (central hypotonia and hypertonia of extremities)
Seizures (including early and intractable seizures comprising Ohtahara syndrome, West syndrome, or myoclonic epilepsy)
Nystagmus, strabismus, optic nerve hypoplasia, and/or retinopathy
Sensorineural hearing loss
Short stature
• Progressive microcephaly up to -10 SD
• Pontine and cerebellar hypoplasia
• Hypotonia, hypertonia, or a combination of both (central hypotonia and hypertonia of extremities)
• Seizures (including early and intractable seizures comprising Ohtahara syndrome, West syndrome, or myoclonic epilepsy)
• Nystagmus, strabismus, optic nerve hypoplasia, and/or retinopathy
• Sensorineural hearing loss
• Short stature
## Establishing the Diagnosis
The diagnosis of a
Note: (1) Rarely, affected males have a mosaic pathogenic variant. (2) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
Because the phenotype of
Note: Single-gene testing (sequence analysis of
For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see
For an introduction to multigene panels click
Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/ duplication analysis (which may include
For an introduction to comprehensive genomic testing click
Note: (1) In a few males,
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Percentages are based on female probands. Surviving male probands are more likely to have a variant detected by sequence analysis (see
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Two females with a balanced Xp inversion disrupting
• For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see
• For an introduction to multigene panels click
• Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/ duplication analysis (which may include
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Females typically have moderate-to-severe intellectual disability and in most individuals, progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH). Possible findings are ophthalmologic anomalies and sensorineural hearing loss. Females who are relatives of males with the X-linked intellectual disability (XLID) ± nystagmus phenotype may rarely present with a mild-to-severe intellectual disability phenotype.
In males the spectrum is broad, ranging from severe (intellectual disability and MICPCH, or early-infantile epileptic encephalopathy [Ohtahara syndrome, West syndrome, or early myoclonic epilepsy]) to mild (XLID ± nystagmus and additional clinical features) [
To date, 130 individuals (45 males and 85 females) have been identified with a pathogenic variant in
A total of 85 females with MICPCH have been reported to date, the eldest of whom is age 25 years. The following information about the natural history is based on the recent reviews of
Language is nearly absent in most; some utter words. One individual could say two-word sentences. Intellectual development is severely impaired in nearly all affected females, with a few showing moderate ID.
The behavioral phenotype may include sleep disturbances, hand stereotypies, and self biting.
The severity of the pontocerebellar hypoplasia observed on MRI is not of prognostic value [
Pontine and cerebellar hypoplasia with diffuse mild-to-severe hypoplasia of the cerebellum affecting the hemispheres and vermis proportionally [
Cerebellar hemispheres can be affected asymmetrically.
Pontine hypoplasia may be mild to severe with relative sparing of the pontine bulging.
Normal- or low normal-sized corpus callosum with low cerebrum / corpus callosum ratio [
Associated MRI finding: mildly reduced number and complexity of gyri in the frontal region of the cerebral cortex and mild dilatation of the lateral ventricles [
Birth length is normal. Short stature is common by age four years [
Scoliosis is frequently observed.
Various ophthalmologic findings can be observed, in particular optic nerve hypoplasia, retinopathy, nystagmus, and strabismus [
Approximately 28% of affected females have sensorineural hearing loss [
Congenital visceral anomalies (e.g., renal/urologic or cardiac anomalies) are rarely seen; no particular anomaly occurs recurrently.
Recent reviews suggest a facial phenotype consisting of well-drawn arched eyebrows, a broad nasal bridge and tip, small or short nose, long philtrum or protruding maxilla, small chin, and large ears.
Clinical findings in the majority of heterozygotes (typically identified as relatives of more severely affected males):
Normal intelligence; mild-to-severe ID in some females only
Normal-to-mild ocular findings including congenital nystagmus and strabismus
No additional neurologic signs besides mild tremor or absence seizures
MRI finding: normal or mainly unknown
A total of 45 males from birth to age 59 years with a pathogenic
The phenotype in males represents a clinical continuum from the severe to the mild end of the spectrum and can be classified into three phenotypic groups [
Typically severe diffuse pontocerebellar hypoplasia
Simplified gyri, cortical atrophy, and hypomyelination may be also observed.
Multiple (minor) anomalies have been reported [
Septal heart defects, tetralogy of Fallot and hydronephrosis can be observed [
MICPCH in combination with a severe developmental disorder but without severe epilepsy has been reported in six males. The phenotype of male individuals in this group is comparable to MICPCH in females [
Mild-to-severe XLID with or without nystagmus and/or other anomalies have been reported in a total of 29 males [
DD / mild-to-severe ID
Seizures/epilepsy
Congenital nystagmus and other eye findings including strabismus and mild pallor of the optic disc
Brain MRI has been reported in a minority of individuals only and did not show pontocerebellar hypoplasia.
Other findings include microcephaly, hypotonia, autism spectrum disorder, behavioral problems, tremor and unsteady gait, sensorineural hearing loss, feeding difficulties, constipation, short stature, cryptorchidism, and gastrointestinal and gastroesophageal complications.
In females, microcephaly with pontine and cerebellar hypoplasia (MICPCH) is typically associated with heterozygous
In males, the three clinically distinguishable groups are associated with different classes of pathogenic
In males with MICPCH with severe epileptic encephalopathy, the most severe phenotype, the majority of
In the group with MICPCH, males are somatic mosaics of a
The largest group of males with XLID with or without nystagmus typically have
Penetrance for the MICPCH phenotype (associated with the heterozygous
Penetrance of
An FG syndrome (FGS)-like phenotype has been suggested as a distinct
The prevalence of
• Females typically have moderate-to-severe intellectual disability and in most individuals, progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH). Possible findings are ophthalmologic anomalies and sensorineural hearing loss. Females who are relatives of males with the X-linked intellectual disability (XLID) ± nystagmus phenotype may rarely present with a mild-to-severe intellectual disability phenotype.
• In males the spectrum is broad, ranging from severe (intellectual disability and MICPCH, or early-infantile epileptic encephalopathy [Ohtahara syndrome, West syndrome, or early myoclonic epilepsy]) to mild (XLID ± nystagmus and additional clinical features) [
• Pontine and cerebellar hypoplasia with diffuse mild-to-severe hypoplasia of the cerebellum affecting the hemispheres and vermis proportionally [
• Cerebellar hemispheres can be affected asymmetrically.
• Pontine hypoplasia may be mild to severe with relative sparing of the pontine bulging.
• Cerebellar hemispheres can be affected asymmetrically.
• Pontine hypoplasia may be mild to severe with relative sparing of the pontine bulging.
• Normal- or low normal-sized corpus callosum with low cerebrum / corpus callosum ratio [
• Associated MRI finding: mildly reduced number and complexity of gyri in the frontal region of the cerebral cortex and mild dilatation of the lateral ventricles [
• Cerebellar hemispheres can be affected asymmetrically.
• Pontine hypoplasia may be mild to severe with relative sparing of the pontine bulging.
• Birth length is normal. Short stature is common by age four years [
• Scoliosis is frequently observed.
• Various ophthalmologic findings can be observed, in particular optic nerve hypoplasia, retinopathy, nystagmus, and strabismus [
• Approximately 28% of affected females have sensorineural hearing loss [
• Congenital visceral anomalies (e.g., renal/urologic or cardiac anomalies) are rarely seen; no particular anomaly occurs recurrently.
• Recent reviews suggest a facial phenotype consisting of well-drawn arched eyebrows, a broad nasal bridge and tip, small or short nose, long philtrum or protruding maxilla, small chin, and large ears.
• Normal intelligence; mild-to-severe ID in some females only
• Normal-to-mild ocular findings including congenital nystagmus and strabismus
• No additional neurologic signs besides mild tremor or absence seizures
• MRI finding: normal or mainly unknown
• Typically severe diffuse pontocerebellar hypoplasia
• Simplified gyri, cortical atrophy, and hypomyelination may be also observed.
• Multiple (minor) anomalies have been reported [
• Septal heart defects, tetralogy of Fallot and hydronephrosis can be observed [
• DD / mild-to-severe ID
• Seizures/epilepsy
• Congenital nystagmus and other eye findings including strabismus and mild pallor of the optic disc
• In males with MICPCH with severe epileptic encephalopathy, the most severe phenotype, the majority of
• In the group with MICPCH, males are somatic mosaics of a
• The largest group of males with XLID with or without nystagmus typically have
## Clinical Description
Females typically have moderate-to-severe intellectual disability and in most individuals, progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH). Possible findings are ophthalmologic anomalies and sensorineural hearing loss. Females who are relatives of males with the X-linked intellectual disability (XLID) ± nystagmus phenotype may rarely present with a mild-to-severe intellectual disability phenotype.
In males the spectrum is broad, ranging from severe (intellectual disability and MICPCH, or early-infantile epileptic encephalopathy [Ohtahara syndrome, West syndrome, or early myoclonic epilepsy]) to mild (XLID ± nystagmus and additional clinical features) [
To date, 130 individuals (45 males and 85 females) have been identified with a pathogenic variant in
A total of 85 females with MICPCH have been reported to date, the eldest of whom is age 25 years. The following information about the natural history is based on the recent reviews of
Language is nearly absent in most; some utter words. One individual could say two-word sentences. Intellectual development is severely impaired in nearly all affected females, with a few showing moderate ID.
The behavioral phenotype may include sleep disturbances, hand stereotypies, and self biting.
The severity of the pontocerebellar hypoplasia observed on MRI is not of prognostic value [
Pontine and cerebellar hypoplasia with diffuse mild-to-severe hypoplasia of the cerebellum affecting the hemispheres and vermis proportionally [
Cerebellar hemispheres can be affected asymmetrically.
Pontine hypoplasia may be mild to severe with relative sparing of the pontine bulging.
Normal- or low normal-sized corpus callosum with low cerebrum / corpus callosum ratio [
Associated MRI finding: mildly reduced number and complexity of gyri in the frontal region of the cerebral cortex and mild dilatation of the lateral ventricles [
Birth length is normal. Short stature is common by age four years [
Scoliosis is frequently observed.
Various ophthalmologic findings can be observed, in particular optic nerve hypoplasia, retinopathy, nystagmus, and strabismus [
Approximately 28% of affected females have sensorineural hearing loss [
Congenital visceral anomalies (e.g., renal/urologic or cardiac anomalies) are rarely seen; no particular anomaly occurs recurrently.
Recent reviews suggest a facial phenotype consisting of well-drawn arched eyebrows, a broad nasal bridge and tip, small or short nose, long philtrum or protruding maxilla, small chin, and large ears.
Clinical findings in the majority of heterozygotes (typically identified as relatives of more severely affected males):
Normal intelligence; mild-to-severe ID in some females only
Normal-to-mild ocular findings including congenital nystagmus and strabismus
No additional neurologic signs besides mild tremor or absence seizures
MRI finding: normal or mainly unknown
A total of 45 males from birth to age 59 years with a pathogenic
The phenotype in males represents a clinical continuum from the severe to the mild end of the spectrum and can be classified into three phenotypic groups [
Typically severe diffuse pontocerebellar hypoplasia
Simplified gyri, cortical atrophy, and hypomyelination may be also observed.
Multiple (minor) anomalies have been reported [
Septal heart defects, tetralogy of Fallot and hydronephrosis can be observed [
MICPCH in combination with a severe developmental disorder but without severe epilepsy has been reported in six males. The phenotype of male individuals in this group is comparable to MICPCH in females [
Mild-to-severe XLID with or without nystagmus and/or other anomalies have been reported in a total of 29 males [
DD / mild-to-severe ID
Seizures/epilepsy
Congenital nystagmus and other eye findings including strabismus and mild pallor of the optic disc
Brain MRI has been reported in a minority of individuals only and did not show pontocerebellar hypoplasia.
Other findings include microcephaly, hypotonia, autism spectrum disorder, behavioral problems, tremor and unsteady gait, sensorineural hearing loss, feeding difficulties, constipation, short stature, cryptorchidism, and gastrointestinal and gastroesophageal complications.
• Females typically have moderate-to-severe intellectual disability and in most individuals, progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH). Possible findings are ophthalmologic anomalies and sensorineural hearing loss. Females who are relatives of males with the X-linked intellectual disability (XLID) ± nystagmus phenotype may rarely present with a mild-to-severe intellectual disability phenotype.
• In males the spectrum is broad, ranging from severe (intellectual disability and MICPCH, or early-infantile epileptic encephalopathy [Ohtahara syndrome, West syndrome, or early myoclonic epilepsy]) to mild (XLID ± nystagmus and additional clinical features) [
• Pontine and cerebellar hypoplasia with diffuse mild-to-severe hypoplasia of the cerebellum affecting the hemispheres and vermis proportionally [
• Cerebellar hemispheres can be affected asymmetrically.
• Pontine hypoplasia may be mild to severe with relative sparing of the pontine bulging.
• Cerebellar hemispheres can be affected asymmetrically.
• Pontine hypoplasia may be mild to severe with relative sparing of the pontine bulging.
• Normal- or low normal-sized corpus callosum with low cerebrum / corpus callosum ratio [
• Associated MRI finding: mildly reduced number and complexity of gyri in the frontal region of the cerebral cortex and mild dilatation of the lateral ventricles [
• Cerebellar hemispheres can be affected asymmetrically.
• Pontine hypoplasia may be mild to severe with relative sparing of the pontine bulging.
• Birth length is normal. Short stature is common by age four years [
• Scoliosis is frequently observed.
• Various ophthalmologic findings can be observed, in particular optic nerve hypoplasia, retinopathy, nystagmus, and strabismus [
• Approximately 28% of affected females have sensorineural hearing loss [
• Congenital visceral anomalies (e.g., renal/urologic or cardiac anomalies) are rarely seen; no particular anomaly occurs recurrently.
• Recent reviews suggest a facial phenotype consisting of well-drawn arched eyebrows, a broad nasal bridge and tip, small or short nose, long philtrum or protruding maxilla, small chin, and large ears.
• Normal intelligence; mild-to-severe ID in some females only
• Normal-to-mild ocular findings including congenital nystagmus and strabismus
• No additional neurologic signs besides mild tremor or absence seizures
• MRI finding: normal or mainly unknown
• Typically severe diffuse pontocerebellar hypoplasia
• Simplified gyri, cortical atrophy, and hypomyelination may be also observed.
• Multiple (minor) anomalies have been reported [
• Septal heart defects, tetralogy of Fallot and hydronephrosis can be observed [
• DD / mild-to-severe ID
• Seizures/epilepsy
• Congenital nystagmus and other eye findings including strabismus and mild pallor of the optic disc
## Females
A total of 85 females with MICPCH have been reported to date, the eldest of whom is age 25 years. The following information about the natural history is based on the recent reviews of
Language is nearly absent in most; some utter words. One individual could say two-word sentences. Intellectual development is severely impaired in nearly all affected females, with a few showing moderate ID.
The behavioral phenotype may include sleep disturbances, hand stereotypies, and self biting.
The severity of the pontocerebellar hypoplasia observed on MRI is not of prognostic value [
Pontine and cerebellar hypoplasia with diffuse mild-to-severe hypoplasia of the cerebellum affecting the hemispheres and vermis proportionally [
Cerebellar hemispheres can be affected asymmetrically.
Pontine hypoplasia may be mild to severe with relative sparing of the pontine bulging.
Normal- or low normal-sized corpus callosum with low cerebrum / corpus callosum ratio [
Associated MRI finding: mildly reduced number and complexity of gyri in the frontal region of the cerebral cortex and mild dilatation of the lateral ventricles [
Birth length is normal. Short stature is common by age four years [
Scoliosis is frequently observed.
Various ophthalmologic findings can be observed, in particular optic nerve hypoplasia, retinopathy, nystagmus, and strabismus [
Approximately 28% of affected females have sensorineural hearing loss [
Congenital visceral anomalies (e.g., renal/urologic or cardiac anomalies) are rarely seen; no particular anomaly occurs recurrently.
Recent reviews suggest a facial phenotype consisting of well-drawn arched eyebrows, a broad nasal bridge and tip, small or short nose, long philtrum or protruding maxilla, small chin, and large ears.
Clinical findings in the majority of heterozygotes (typically identified as relatives of more severely affected males):
Normal intelligence; mild-to-severe ID in some females only
Normal-to-mild ocular findings including congenital nystagmus and strabismus
No additional neurologic signs besides mild tremor or absence seizures
MRI finding: normal or mainly unknown
• Pontine and cerebellar hypoplasia with diffuse mild-to-severe hypoplasia of the cerebellum affecting the hemispheres and vermis proportionally [
• Cerebellar hemispheres can be affected asymmetrically.
• Pontine hypoplasia may be mild to severe with relative sparing of the pontine bulging.
• Cerebellar hemispheres can be affected asymmetrically.
• Pontine hypoplasia may be mild to severe with relative sparing of the pontine bulging.
• Normal- or low normal-sized corpus callosum with low cerebrum / corpus callosum ratio [
• Associated MRI finding: mildly reduced number and complexity of gyri in the frontal region of the cerebral cortex and mild dilatation of the lateral ventricles [
• Cerebellar hemispheres can be affected asymmetrically.
• Pontine hypoplasia may be mild to severe with relative sparing of the pontine bulging.
• Birth length is normal. Short stature is common by age four years [
• Scoliosis is frequently observed.
• Various ophthalmologic findings can be observed, in particular optic nerve hypoplasia, retinopathy, nystagmus, and strabismus [
• Approximately 28% of affected females have sensorineural hearing loss [
• Congenital visceral anomalies (e.g., renal/urologic or cardiac anomalies) are rarely seen; no particular anomaly occurs recurrently.
• Recent reviews suggest a facial phenotype consisting of well-drawn arched eyebrows, a broad nasal bridge and tip, small or short nose, long philtrum or protruding maxilla, small chin, and large ears.
• Normal intelligence; mild-to-severe ID in some females only
• Normal-to-mild ocular findings including congenital nystagmus and strabismus
• No additional neurologic signs besides mild tremor or absence seizures
• MRI finding: normal or mainly unknown
## Males
A total of 45 males from birth to age 59 years with a pathogenic
The phenotype in males represents a clinical continuum from the severe to the mild end of the spectrum and can be classified into three phenotypic groups [
Typically severe diffuse pontocerebellar hypoplasia
Simplified gyri, cortical atrophy, and hypomyelination may be also observed.
Multiple (minor) anomalies have been reported [
Septal heart defects, tetralogy of Fallot and hydronephrosis can be observed [
MICPCH in combination with a severe developmental disorder but without severe epilepsy has been reported in six males. The phenotype of male individuals in this group is comparable to MICPCH in females [
Mild-to-severe XLID with or without nystagmus and/or other anomalies have been reported in a total of 29 males [
DD / mild-to-severe ID
Seizures/epilepsy
Congenital nystagmus and other eye findings including strabismus and mild pallor of the optic disc
Brain MRI has been reported in a minority of individuals only and did not show pontocerebellar hypoplasia.
Other findings include microcephaly, hypotonia, autism spectrum disorder, behavioral problems, tremor and unsteady gait, sensorineural hearing loss, feeding difficulties, constipation, short stature, cryptorchidism, and gastrointestinal and gastroesophageal complications.
• Typically severe diffuse pontocerebellar hypoplasia
• Simplified gyri, cortical atrophy, and hypomyelination may be also observed.
• Multiple (minor) anomalies have been reported [
• Septal heart defects, tetralogy of Fallot and hydronephrosis can be observed [
• DD / mild-to-severe ID
• Seizures/epilepsy
• Congenital nystagmus and other eye findings including strabismus and mild pallor of the optic disc
## Genotype-Phenotype Correlations
In females, microcephaly with pontine and cerebellar hypoplasia (MICPCH) is typically associated with heterozygous
In males, the three clinically distinguishable groups are associated with different classes of pathogenic
In males with MICPCH with severe epileptic encephalopathy, the most severe phenotype, the majority of
In the group with MICPCH, males are somatic mosaics of a
The largest group of males with XLID with or without nystagmus typically have
• In males with MICPCH with severe epileptic encephalopathy, the most severe phenotype, the majority of
• In the group with MICPCH, males are somatic mosaics of a
• The largest group of males with XLID with or without nystagmus typically have
## Penetrance
Penetrance for the MICPCH phenotype (associated with the heterozygous
Penetrance of
## Nomenclature
An FG syndrome (FGS)-like phenotype has been suggested as a distinct
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of MICPCH
Generalized clonus ("jitteriness") w/lack of voluntary motor development & later development of chorea & spasticity, impaired swallowing, & (in some) epilepsy
Persons w/PCH2 usually live into childhood.
Cerebellar hemispheres are more affected than the vermis, → "dragonfly" appearance in coronal images.
Pontine hypoplasia is more severe than in females w/MICPCH.
Corpus callosum is often thin & hypoplastic.
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; PCH = pontocerebellar hypoplasia; XL = X-linked
See
In
• Generalized clonus ("jitteriness") w/lack of voluntary motor development & later development of chorea & spasticity, impaired swallowing, & (in some) epilepsy
• Persons w/PCH2 usually live into childhood.
• Cerebellar hemispheres are more affected than the vermis, → "dragonfly" appearance in coronal images.
• Pontine hypoplasia is more severe than in females w/MICPCH.
• Corpus callosum is often thin & hypoplastic.
## Intellectual Disability and Microcephaly with Pontine and Cerebellar Hypoplasia (MICPCH)
Genes of Interest in the Differential Diagnosis of MICPCH
Generalized clonus ("jitteriness") w/lack of voluntary motor development & later development of chorea & spasticity, impaired swallowing, & (in some) epilepsy
Persons w/PCH2 usually live into childhood.
Cerebellar hemispheres are more affected than the vermis, → "dragonfly" appearance in coronal images.
Pontine hypoplasia is more severe than in females w/MICPCH.
Corpus callosum is often thin & hypoplastic.
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; PCH = pontocerebellar hypoplasia; XL = X-linked
See
In
• Generalized clonus ("jitteriness") w/lack of voluntary motor development & later development of chorea & spasticity, impaired swallowing, & (in some) epilepsy
• Persons w/PCH2 usually live into childhood.
• Cerebellar hemispheres are more affected than the vermis, → "dragonfly" appearance in coronal images.
• Pontine hypoplasia is more severe than in females w/MICPCH.
• Corpus callosum is often thin & hypoplastic.
## X-Linked Intellectual Disability (XLID) ± Nystagmus
## Management
To establish the extent of disease and needs in an individual diagnosed with a
Recommended Evaluations Following Initial Diagnosis in Individuals with
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Gross motor & fine motor skills.
Scoliosis.
Mobility, activities of daily living, & need for adaptive devices.
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
To incl eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
Treatment of Manifestations in Individuals with
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one-on-one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Recommended Surveillance for Individuals with
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
OT = occupational therapy; PT = physical therapy
See
Search
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills.
• Scoliosis.
• Mobility, activities of daily living, & need for adaptive devices.
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a
Recommended Evaluations Following Initial Diagnosis in Individuals with
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Gross motor & fine motor skills.
Scoliosis.
Mobility, activities of daily living, & need for adaptive devices.
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
To incl eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills.
• Scoliosis.
• Mobility, activities of daily living, & need for adaptive devices.
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one-on-one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one-on-one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Recommended Surveillance for Individuals with
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
OT = occupational therapy; PT = physical therapy
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH) and X-linked intellectual disability (XLID) with or without nystagmus are caused by pathogenic variants in
Risk to the family members of a proband with a
If the parents of the proband are asymptomatic, they are unlikely to have the pathogenic variant because penetrance of the MICPCH phenotype appears to be complete. However, it is possible (though not likely) that a parent of the proband has somatic and/or germline mosaicism.
Molecular genetic testing of the mother (and possibly the father) may help to determine if the
Note: If the
The father of a male with a
If the mother of the proband is asymptomatic, she is unlikely to be heterozygous for the pathogenic variant because penetrance of the MICPCH phenotype appears to be complete. However, it is possible (though not likely) that the mother has somatic and/or germline mosaicism. (Mosaicism for a
Molecular genetic testing of the mother is recommended to confirm her genetic status. (Note: If a woman has more than one affected child and no other affected relatives and if the
* Heterozygous females are typically asymptomatic but may display mild-to-severe ID with or without ocular features, absence seizures, and/or tremor.
Note: If the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young women who are heterozygous (asymptomatic or symptomatic) or are at risk of being heterozygous.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal choice, discussion of these issues may be helpful.
• If the parents of the proband are asymptomatic, they are unlikely to have the pathogenic variant because penetrance of the MICPCH phenotype appears to be complete. However, it is possible (though not likely) that a parent of the proband has somatic and/or germline mosaicism.
• Molecular genetic testing of the mother (and possibly the father) may help to determine if the
• Note: If the
• The father of a male with a
• If the mother of the proband is asymptomatic, she is unlikely to be heterozygous for the pathogenic variant because penetrance of the MICPCH phenotype appears to be complete. However, it is possible (though not likely) that the mother has somatic and/or germline mosaicism. (Mosaicism for a
• Molecular genetic testing of the mother is recommended to confirm her genetic status. (Note: If a woman has more than one affected child and no other affected relatives and if the
• * Heterozygous females are typically asymptomatic but may display mild-to-severe ID with or without ocular features, absence seizures, and/or tremor.
• Note: If the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young women who are heterozygous (asymptomatic or symptomatic) or are at risk of being heterozygous.
## Mode of Inheritance
Intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH) and X-linked intellectual disability (XLID) with or without nystagmus are caused by pathogenic variants in
Risk to the family members of a proband with a
## Risk to Family Members
If the parents of the proband are asymptomatic, they are unlikely to have the pathogenic variant because penetrance of the MICPCH phenotype appears to be complete. However, it is possible (though not likely) that a parent of the proband has somatic and/or germline mosaicism.
Molecular genetic testing of the mother (and possibly the father) may help to determine if the
Note: If the
The father of a male with a
If the mother of the proband is asymptomatic, she is unlikely to be heterozygous for the pathogenic variant because penetrance of the MICPCH phenotype appears to be complete. However, it is possible (though not likely) that the mother has somatic and/or germline mosaicism. (Mosaicism for a
Molecular genetic testing of the mother is recommended to confirm her genetic status. (Note: If a woman has more than one affected child and no other affected relatives and if the
* Heterozygous females are typically asymptomatic but may display mild-to-severe ID with or without ocular features, absence seizures, and/or tremor.
Note: If the
• If the parents of the proband are asymptomatic, they are unlikely to have the pathogenic variant because penetrance of the MICPCH phenotype appears to be complete. However, it is possible (though not likely) that a parent of the proband has somatic and/or germline mosaicism.
• Molecular genetic testing of the mother (and possibly the father) may help to determine if the
• Note: If the
• The father of a male with a
• If the mother of the proband is asymptomatic, she is unlikely to be heterozygous for the pathogenic variant because penetrance of the MICPCH phenotype appears to be complete. However, it is possible (though not likely) that the mother has somatic and/or germline mosaicism. (Mosaicism for a
• Molecular genetic testing of the mother is recommended to confirm her genetic status. (Note: If a woman has more than one affected child and no other affected relatives and if the
• * Heterozygous females are typically asymptomatic but may display mild-to-severe ID with or without ocular features, absence seizures, and/or tremor.
• Note: If the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young women who are heterozygous (asymptomatic or symptomatic) or are at risk of being heterozygous.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young women who are heterozygous (asymptomatic or symptomatic) or are at risk of being heterozygous.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal choice, discussion of these issues may be helpful.
## Resources
Germany
•
• Germany
•
•
•
•
•
•
•
## Molecular Genetics
CASK Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CASK Disorders (
CASK contains:
An N-terminal calmodulin dependent protein kinase (CamK) domain
Two L27 (L27.1 and L27.2) domains
A PSD-95/discs large/ZO-1 (PDZ) domain
An src homology 3 (SH3)
A guanylate kinase (GK) domain at the C-terminus
CASK plays a critical role in brain development and function. It controls synapse formation and activity by (1) presynaptic organization and regulation of neurotransmitter release, (2) maintaining the morphology of dendritic spines and trafficking of glutamate receptors to postsynaptic sites, and (3) regulating the transcription of genes involved in cortical development [
A few heterozygous missense variants identified in females with MICPCH specifically impair binding of CASK to the interaction partner Mint1 or neurexin. The question remains whether this impairment is sufficient to cause the severe phenotype in females [
The hypomorphic
• An N-terminal calmodulin dependent protein kinase (CamK) domain
• Two L27 (L27.1 and L27.2) domains
• A PSD-95/discs large/ZO-1 (PDZ) domain
• An src homology 3 (SH3)
• A guanylate kinase (GK) domain at the C-terminus
## Molecular Pathogenesis
CASK contains:
An N-terminal calmodulin dependent protein kinase (CamK) domain
Two L27 (L27.1 and L27.2) domains
A PSD-95/discs large/ZO-1 (PDZ) domain
An src homology 3 (SH3)
A guanylate kinase (GK) domain at the C-terminus
CASK plays a critical role in brain development and function. It controls synapse formation and activity by (1) presynaptic organization and regulation of neurotransmitter release, (2) maintaining the morphology of dendritic spines and trafficking of glutamate receptors to postsynaptic sites, and (3) regulating the transcription of genes involved in cortical development [
A few heterozygous missense variants identified in females with MICPCH specifically impair binding of CASK to the interaction partner Mint1 or neurexin. The question remains whether this impairment is sufficient to cause the severe phenotype in females [
The hypomorphic
• An N-terminal calmodulin dependent protein kinase (CamK) domain
• Two L27 (L27.1 and L27.2) domains
• A PSD-95/discs large/ZO-1 (PDZ) domain
• An src homology 3 (SH3)
• A guanylate kinase (GK) domain at the C-terminus
## Chapter Notes
We are interested in determining the phenotypic spectrum and molecular pathogenesis of
We thank the families with individuals affected by MICPCH who are participating in our research programs.
Kerstin Kutsche, PhD (2013-present)Ute Moog, MD (2013-present)Gökhan Uyanik, MD; Hanusch Hospital, Vienna (2013-2020)
21 May 2020 (ha) Comprehensive update posted live
26 November 2013 (me) Review posted live
28 February 2013 (kk) Original submission
• 21 May 2020 (ha) Comprehensive update posted live
• 26 November 2013 (me) Review posted live
• 28 February 2013 (kk) Original submission
## Author Notes
We are interested in determining the phenotypic spectrum and molecular pathogenesis of
## Acknowledgments
We thank the families with individuals affected by MICPCH who are participating in our research programs.
## Author History
Kerstin Kutsche, PhD (2013-present)Ute Moog, MD (2013-present)Gökhan Uyanik, MD; Hanusch Hospital, Vienna (2013-2020)
## Revision History
21 May 2020 (ha) Comprehensive update posted live
26 November 2013 (me) Review posted live
28 February 2013 (kk) Original submission
• 21 May 2020 (ha) Comprehensive update posted live
• 26 November 2013 (me) Review posted live
• 28 February 2013 (kk) Original submission
## References
## Literature Cited
MRI of the brain of a girl age 2.5 years with MICPCH and a heterozygous
a. Sagittal image showing mild pontocerebellar hypoplasia with sparing of pontine bulging. The corpus callosum is normal.
b. Coronal image showing mild cerebellar hypoplasia affecting the vermis and hemispheres proportionally ("butterfly" appearance)
|
[
"L Burglen, S Chantot-Bastaraud, C Garel, M Milh, R Touraine, G Zanni, F Petit, A Afenjar, C Goizet, S Barresi, A Coussement, C Ioos, L Lazaro, S Joriot, I Desguerre, D Lacombe, V des Portes, E Bertini, JP Siffroi, TB de Villemeur, D Rodriguez. Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: confirmation of a recognizable phenotype and first description of a male mosaic patient.. Orphanet J Rare Dis. 2012;7:18",
"F Cristofoli, K Devriendt, EE Davis, H Van Esch, JR Vermeesch. Novel CASK mutations in cases with syndromic microcephaly.. Hum Mutat. 2018;39:993-1001",
"P Dunn, GP Prigatano, S Szelinger, J Roth, AL Siniard, AM Claasen, RF Richholt, M De Both, JJ Corneveaux, AM Moskowitz, C Balak, IS Piras, M Russell, AL Courtright, N Belnap, S Rangasamy, K Ramsey, JM Opitz, DW Craig, V Narayanan, MJ Huentelman, I Schrauwen. A de novo splice site mutation in CASK causes FG syndrome-4 and congenital nystagmus.. Am J Med Genet A. 2017;173:611-7",
"S Hayashi, N Okamoto, Y Chinen, J Takanashi, Y Makita, A Hata, I Imoto, J Inazawa. Novel intragenic duplications and mutations of CASK in patients with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH).. Hum Genet. 2012;131:99-110",
"S Hayashi, DT Uehara, K Tanimoto, S Mizuno, Y Chinen, S Fukumura, JI Takanashi, H Osaka, N Okamoto, J Inazawa. Comprehensive investigation of CASK mutations and other genetic etiologies in 41 patients with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH).. PLoS One. 2017;12",
"YP Hsueh. The role of the MAGUK protein CASK in neural development and synaptic function.. Curr Med Chem. 2006;13:1915-27",
"YP Hsueh. Calcium/calmodulin-dependent serine protein kinase and mental retardation.. Ann Neurol. 2009;66:438-43",
"LEW LaConte, V Chavan, S DeLuca, K Rubin, J Malc, S Berry, C Gail Summers, K Mukherjee. An N-terminal heterozygous missense CASK mutation is associated with microcephaly and bilateral retinal dystrophy plus optic nerve atrophy.. Am J Med Genet A. 2019;179:94-103",
"LEW LaConte, V Chavan, AF Elias, C Hudson, C Schwanke, K Styren, J Shoof, F Kok, S Srivastava, K Mukherjee. Two microcephaly-associated novel missense mutations in CASK specifically disrupt the CASK-neurexin interaction.. Hum Genet. 2018;137:231-46",
"U Moog, T Bierhals, K Brand, J Bautsch, S Biskup, T Brune, J Denecke, CE de Die-Smulders, C Evers, M Hempel, M Henneke, H Yntema, B Menten, J Pietz, R Pfundt, J Schmidtke, D Steinemann, CT Stumpel, L Van Maldergem, K Kutsche. Phenotypic and molecular insights into CASK-related disorders in males.. Orphanet J Rare Dis. 2015;10:44",
"U Moog, K Kutsche, F Kortüm, B Chilian, T Bierhals, N Apeshiotis, S Balg, N Chassaing, C Coubes, S Das, H Engels, H Van Esch, U Grasshoff, M Heise, B Isidor, J Jarvis, U Koehler, T Martin, B Oehl-Jaschkowitz, E Ortibus, DT Pilz, P Prabhakar, G Rappold, I Rau, G Rettenberger, G Schluter, RH Scott, M Shoukier, E Wohlleber, B Zirn, WB Dobyns, G Uyanik. Phenotypic spectrum associated with CASK loss-of-function mutations.. J Med Genet. 2011;48:741-51",
"B Muthusamy, LDN Selvan, TT Nguyen, J Manoj, EW Stawiski, BS Jaiswal, W Wang, R Raja, VL Ramprasad, R Gupta, S Murugan, JS Kadandale, TSK Prasad, K Reddy, A Peterson, A Pandey, S Seshagiri, SC Girimaji, H Gowda. Next-Generation Sequencing Reveals Novel Mutations in X-linked Intellectual Disability.. OMICS 2017;21:295-303",
"J Najm, D Horn, I Wimplinger, JA Golden, VV Chizhikov, J Sudi, SL Christian, R Ullmann, A Kuechler, CA Haas, A Flubacher, LR Charnas, G Uyanik, U Frank, E Klopocki, WB Dobyns, K Kutsche. Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum.. Nat Genet. 2008;40:1065-7",
"K Nakamura, K Nishiyama, H Kodera, M Nakashima, Y Tsurusaki, N Miyake, N Matsumoto, H Saitsu. A de novo CASK mutation in pontocerebellar hypoplasia type 3 with early myoclonic epilepsy and tetralogy of Fallot.. Brain Dev. 2014;36:272-3",
"G Piluso, F D'Amico, V Saccone, E Bismuto, IL Rotundo, M Di Domenico, S Aurino, CE Schwartz, G Neri, V Nigro. A missense mutation in CASK causes FG syndrome in an Italian family.. Am J Hum Genet. 2009;84:162-77",
"AR Rama Devi, L Lingappa, SM Naushad. Identification and in silico characterization of a novel CASK c.2546T>C (p.V849A) mutation in a male infant with pontocerebellar hypoplasia.. Ann Indian Acad Neurol. 2019;22:523-4",
"H Saitsu, M Kato, H Osaka, N Moriyama, H Horita, K Nishiyama, Y Yoneda, Y Kondo, Y Tsurusaki, H Doi, N Miyake, K Hayasaka, N Matsumoto. CASK aberrations in male patients with Ohtahara syndrome and cerebellar hypoplasia.. Epilepsia 2012;53:1441-9",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"J Takanashi, H Arai, S Nabatame, S Hirai, S Hayashi, J Inazawa, N Okamoto, AJ Barkovich. Neuroradiologic features of CASK mutations.. AJNR Am J Neuroradiol. 2010;31:1619-22",
"J Takanashi, N Okamoto, Y Yamamoto, S Hayashi, H Arai, Y Takahashi, K Maruyama, S Mizuno, S Shimakawa, H Ono, R Oyanagi, S Kubo, AJ Barkovich, J Inazawa. Clinical and radiological features of Japanese patients with a severe phenotype due to CASK mutations.. Am J Med Genet. 2012;158A:3112-8"
] |
26/11/2013
|
21/5/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
catsper-mi
|
catsper-mi
|
[
"CATSPER-Related Nonsyndromic Male Infertility",
"Deafness-Infertility Syndrome",
"Cation channel sperm-associated protein 1",
"Cation channel sperm-associated protein 2",
"Stereocilin",
"CATSPER1",
"CATSPER2",
"STRC",
"CATSPER-Related Male Infertility"
] |
Michael S Hildebrand, Matthew R Avenarius, Richard JH Smith
|
Summary The diagnosis of
|
Deafness-infertility syndrome (DIS)
For synonyms and outdated names, see
For other genetic causes of these phenotypes see
• Deafness-infertility syndrome (DIS)
## Diagnosis
Nonsyndromic (
Associated with non-progressive prelingual sensorineural hearing loss (deafness-infertility syndrome [DIS]).
Male factor infertility
Hearing loss in either a male or female:
In DIS, prelingual hearing loss in the moderate-to-severe range across all frequencies (0.25 kHz – 8 kHz)
Normal vestibular function
Semen Analysis
DIS = deafness-infertility syndrome; NSMI = nonsyndromic male infertility
Values from ASRM Practice Committee [
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
The diagnosis of
Molecular Genetic Testing Used in
DIS = deafness-infertility syndrome; NA = not applicable; NSMI = nonsyndromic male infertility
See
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Two families with homozygous loss-of-function variants in
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis in individuals with NSMI are available.
Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays or array comparative genomic hybridization (array CGH) using fluorescent probesThese approaches are in clinical use targeting the 15q15.3 region. Note: The 15q15.3 deletion may not have been detectable by older oligonucleotide or BAC platforms.
In all cases of
The contribution of the other
• Nonsyndromic (
• Associated with non-progressive prelingual sensorineural hearing loss (deafness-infertility syndrome [DIS]).
• Male factor infertility
• Hearing loss in either a male or female:
• In DIS, prelingual hearing loss in the moderate-to-severe range across all frequencies (0.25 kHz – 8 kHz)
• Normal vestibular function
• In DIS, prelingual hearing loss in the moderate-to-severe range across all frequencies (0.25 kHz – 8 kHz)
• Normal vestibular function
• In DIS, prelingual hearing loss in the moderate-to-severe range across all frequencies (0.25 kHz – 8 kHz)
• Normal vestibular function
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Male factor infertility
Hearing loss in either a male or female:
In DIS, prelingual hearing loss in the moderate-to-severe range across all frequencies (0.25 kHz – 8 kHz)
Normal vestibular function
Semen Analysis
DIS = deafness-infertility syndrome; NSMI = nonsyndromic male infertility
Values from ASRM Practice Committee [
• Male factor infertility
• Hearing loss in either a male or female:
• In DIS, prelingual hearing loss in the moderate-to-severe range across all frequencies (0.25 kHz – 8 kHz)
• Normal vestibular function
• In DIS, prelingual hearing loss in the moderate-to-severe range across all frequencies (0.25 kHz – 8 kHz)
• Normal vestibular function
• In DIS, prelingual hearing loss in the moderate-to-severe range across all frequencies (0.25 kHz – 8 kHz)
• Normal vestibular function
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
The diagnosis of
Molecular Genetic Testing Used in
DIS = deafness-infertility syndrome; NA = not applicable; NSMI = nonsyndromic male infertility
See
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Two families with homozygous loss-of-function variants in
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis in individuals with NSMI are available.
Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays or array comparative genomic hybridization (array CGH) using fluorescent probesThese approaches are in clinical use targeting the 15q15.3 region. Note: The 15q15.3 deletion may not have been detectable by older oligonucleotide or BAC platforms.
In all cases of
The contribution of the other
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Nonsyndromic Male Infertility (NSMI)
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Deafness-Infertility Syndrome (DIS)
The diagnosis of
Molecular Genetic Testing Used in
DIS = deafness-infertility syndrome; NA = not applicable; NSMI = nonsyndromic male infertility
See
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Two families with homozygous loss-of-function variants in
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis in individuals with NSMI are available.
Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays or array comparative genomic hybridization (array CGH) using fluorescent probesThese approaches are in clinical use targeting the 15q15.3 region. Note: The 15q15.3 deletion may not have been detectable by older oligonucleotide or BAC platforms.
In all cases of
The contribution of the other
## Clinical Characteristics
Females homozygous for the
Typically, the hearing loss in DIS is diagnosed in early childhood. It is non-progressive; vestibular function is normal.
In all reported affected males, the degree of hearing loss is moderate to severe across all frequencies (0.25 kHz - 8 kHz). This auditory phenotype is comparable to that observed in persons with DFNB16 [
Note: Knijnenburg and colleagues reported a male of nonconsanguineous parentage with a complex phenotype that included intellectual disability, short stature, dysmorphic features, and hearing loss associated with a homozygous
Since only two pathogenic loss-of-function variants for
Similarly, all families with DIS have homozygous deletions at 15q15.3 involving loss of
DIS was first identified by Avidan and colleagues in a French family segregating deafness, infertility, and
Deafness-infertility syndrome is also known as sensorineural deafness and male infertility.
The prevalence of
The prevalence of deletions at 15q15.3 involving
• Typically, the hearing loss in DIS is diagnosed in early childhood. It is non-progressive; vestibular function is normal.
• In all reported affected males, the degree of hearing loss is moderate to severe across all frequencies (0.25 kHz - 8 kHz). This auditory phenotype is comparable to that observed in persons with DFNB16 [
## Clinical Description
Females homozygous for the
Typically, the hearing loss in DIS is diagnosed in early childhood. It is non-progressive; vestibular function is normal.
In all reported affected males, the degree of hearing loss is moderate to severe across all frequencies (0.25 kHz - 8 kHz). This auditory phenotype is comparable to that observed in persons with DFNB16 [
Note: Knijnenburg and colleagues reported a male of nonconsanguineous parentage with a complex phenotype that included intellectual disability, short stature, dysmorphic features, and hearing loss associated with a homozygous
• Typically, the hearing loss in DIS is diagnosed in early childhood. It is non-progressive; vestibular function is normal.
• In all reported affected males, the degree of hearing loss is moderate to severe across all frequencies (0.25 kHz - 8 kHz). This auditory phenotype is comparable to that observed in persons with DFNB16 [
Females homozygous for the
## Deafness-Infertility Syndrome (DIS)
Typically, the hearing loss in DIS is diagnosed in early childhood. It is non-progressive; vestibular function is normal.
In all reported affected males, the degree of hearing loss is moderate to severe across all frequencies (0.25 kHz - 8 kHz). This auditory phenotype is comparable to that observed in persons with DFNB16 [
Note: Knijnenburg and colleagues reported a male of nonconsanguineous parentage with a complex phenotype that included intellectual disability, short stature, dysmorphic features, and hearing loss associated with a homozygous
• Typically, the hearing loss in DIS is diagnosed in early childhood. It is non-progressive; vestibular function is normal.
• In all reported affected males, the degree of hearing loss is moderate to severe across all frequencies (0.25 kHz - 8 kHz). This auditory phenotype is comparable to that observed in persons with DFNB16 [
## Genotype-Phenotype Correlations
Since only two pathogenic loss-of-function variants for
Similarly, all families with DIS have homozygous deletions at 15q15.3 involving loss of
## Historical Perspective
DIS was first identified by Avidan and colleagues in a French family segregating deafness, infertility, and
## Nomenclature
Deafness-infertility syndrome is also known as sensorineural deafness and male infertility.
## Prevalence
The prevalence of
The prevalence of deletions at 15q15.3 involving
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Obstruction of the ejaculatory ducts (e.g.,
Abnormal sperm motility (See
Immunologic abnormalities (e.g., anti-sperm antibodies)
Infection (e.g., mumps orchitis, epididymitis, urethritis)
Vascular abnormalities (e.g., varicocele)
Trauma
Endocrine abnormalities including congenital adrenal hyperplasia (see
Testicular tumor
Exposure to toxic agents (e.g., radiation, chemotherapy agents, heat)
Klinefelter syndrome (47,XXY)
Balanced chromosome rearrangements
Sertoli-cell-only syndrome
For review of these differential diagnoses refer to
Molecular genetic testing to attempt to identify the involved gene is appropriate. Pathogenic variants in a large number of genes cause male infertility (a partial list includes
See
• Obstruction of the ejaculatory ducts (e.g.,
• Abnormal sperm motility (See
• Immunologic abnormalities (e.g., anti-sperm antibodies)
• Infection (e.g., mumps orchitis, epididymitis, urethritis)
• Vascular abnormalities (e.g., varicocele)
• Trauma
• Endocrine abnormalities including congenital adrenal hyperplasia (see
• Testicular tumor
• Exposure to toxic agents (e.g., radiation, chemotherapy agents, heat)
• Klinefelter syndrome (47,XXY)
• Balanced chromosome rearrangements
• Sertoli-cell-only syndrome
## Management
To establish the extent of disease and needs in an individual diagnosed with
In males, pubertal age or older, semen analysis to assess sperm number, motility, and morphology
In males and females with DIS, hearing evaluation including otologic examination and audiologic assessment (including measurement of bone conduction)
Consultation with a clinical geneticist and/or genetic counselor
Regardless of its etiology, uncorrected hearing loss has consistent sequelae. Auditory deprivation through age two years is associated with poor reading performance, poor communication skills, and poor speech production.
Educational intervention is insufficient to completely remediate these deficiencies. In contrast, early auditory intervention, whether through amplification, otologic surgery, or cochlear implantation, is effective [
Although decreased cognitive skills and performance in mathematics and reading are associated with deafness, examination of persons with hereditary hearing loss has shown that these deficiencies are not intrinsically linked to the cause of the deafness.
Thus, early identification and timely intervention are essential for optimal cognitive development in children with prelingual deafness.
Annual monitoring of hearing loss is not required in individuals with DIS because hearing loss is non-progressive.
Individuals with DIS should avoid exposure to loud noise in the workplace or during recreation.
It is appropriate to evaluate the sibs of a proband with DIS in infancy or early childhood in order to identify as early as possible those who would benefit from early support and management of hearing loss. Evaluations can include:
Molecular genetic testing for the causative contiguous-gene deletion;
Otologic examination and audiologic assessment.
See
Search
• In males, pubertal age or older, semen analysis to assess sperm number, motility, and morphology
• In males and females with DIS, hearing evaluation including otologic examination and audiologic assessment (including measurement of bone conduction)
• Consultation with a clinical geneticist and/or genetic counselor
• Molecular genetic testing for the causative contiguous-gene deletion;
• Otologic examination and audiologic assessment.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
In males, pubertal age or older, semen analysis to assess sperm number, motility, and morphology
In males and females with DIS, hearing evaluation including otologic examination and audiologic assessment (including measurement of bone conduction)
Consultation with a clinical geneticist and/or genetic counselor
• In males, pubertal age or older, semen analysis to assess sperm number, motility, and morphology
• In males and females with DIS, hearing evaluation including otologic examination and audiologic assessment (including measurement of bone conduction)
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
## Prevention of Secondary Complications
Regardless of its etiology, uncorrected hearing loss has consistent sequelae. Auditory deprivation through age two years is associated with poor reading performance, poor communication skills, and poor speech production.
Educational intervention is insufficient to completely remediate these deficiencies. In contrast, early auditory intervention, whether through amplification, otologic surgery, or cochlear implantation, is effective [
Although decreased cognitive skills and performance in mathematics and reading are associated with deafness, examination of persons with hereditary hearing loss has shown that these deficiencies are not intrinsically linked to the cause of the deafness.
Thus, early identification and timely intervention are essential for optimal cognitive development in children with prelingual deafness.
## Surveillance
Annual monitoring of hearing loss is not required in individuals with DIS because hearing loss is non-progressive.
## Agents/Circumstances to Avoid
Individuals with DIS should avoid exposure to loud noise in the workplace or during recreation.
## Evaluation of Relatives at Risk
It is appropriate to evaluate the sibs of a proband with DIS in infancy or early childhood in order to identify as early as possible those who would benefit from early support and management of hearing loss. Evaluations can include:
Molecular genetic testing for the causative contiguous-gene deletion;
Otologic examination and audiologic assessment.
See
• Molecular genetic testing for the causative contiguous-gene deletion;
• Otologic examination and audiologic assessment.
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of a male with
Less likely, the mother may have two pathogenic variants and the father has one or, if the pregnancy was conceived using ICSI, the father may be infertile (as a result of having two
Women with two
When both parents are carriers:
At conception, each sib of an individual with
Males who inherit biallelic pathogenic variants will be infertile.
Females who inherit biallelic pathogenic variants will have no signs/symptoms.
When one parent has two
Each sib has a 50% chance of inheriting biallelic pathogenic variants (one from each parent) and a 50% chance of inheriting one pathogenic variant.
Males who inherit biallelic pathogenic variants will be infertile.
Females who inherit biallelic pathogenic variants will have no signs/symptoms.
Women with biallelic
Typically, the parents of a male with DIS are obligate heterozygotes (i.e., carriers of a deletion that includes
Less likely, the mother may be deaf as a result of being homozygous for the deletion or, if the pregnancy was conceived using ICSI, the father may be deaf and infertile as a result of being homozygous for the deletion. In such cases, the other parent is heterozygous for the
Heterozygotes (carriers) for the
When both parents are carriers:
At conception, each sib of an individual with DIS has a 25% chance of inheriting biallelic
Males who inherit biallelic
Females who inherit biallelic
When one parent has biallelic
Each sib has a 50% chance of inheriting biallelic deletions (1 from each parent) and a 50% chance of inheriting one deletion.
Males who inherit biallelic
Females who inherit biallelic
See Management,
The following points regarding hearing loss/deafness are noteworthy:
Communication with individuals who are members of the Deaf community and who sign requires the services of a skilled interpreter.
Members of the Deaf community may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a "treatment" or "cure," or to be "prevented."
Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services, rather than information about prevention, reproduction, or family planning.
The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as "abnormal" should be avoided.
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are infertile or deaf.
Once the pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of a male with
• Less likely, the mother may have two pathogenic variants and the father has one or, if the pregnancy was conceived using ICSI, the father may be infertile (as a result of having two
• Women with two
• When both parents are carriers:
• At conception, each sib of an individual with
• Males who inherit biallelic pathogenic variants will be infertile.
• Females who inherit biallelic pathogenic variants will have no signs/symptoms.
• At conception, each sib of an individual with
• Males who inherit biallelic pathogenic variants will be infertile.
• Females who inherit biallelic pathogenic variants will have no signs/symptoms.
• When one parent has two
• Each sib has a 50% chance of inheriting biallelic pathogenic variants (one from each parent) and a 50% chance of inheriting one pathogenic variant.
• Males who inherit biallelic pathogenic variants will be infertile.
• Females who inherit biallelic pathogenic variants will have no signs/symptoms.
• Each sib has a 50% chance of inheriting biallelic pathogenic variants (one from each parent) and a 50% chance of inheriting one pathogenic variant.
• Males who inherit biallelic pathogenic variants will be infertile.
• Females who inherit biallelic pathogenic variants will have no signs/symptoms.
• Women with biallelic
• At conception, each sib of an individual with
• Males who inherit biallelic pathogenic variants will be infertile.
• Females who inherit biallelic pathogenic variants will have no signs/symptoms.
• Each sib has a 50% chance of inheriting biallelic pathogenic variants (one from each parent) and a 50% chance of inheriting one pathogenic variant.
• Males who inherit biallelic pathogenic variants will be infertile.
• Females who inherit biallelic pathogenic variants will have no signs/symptoms.
• Typically, the parents of a male with DIS are obligate heterozygotes (i.e., carriers of a deletion that includes
• Less likely, the mother may be deaf as a result of being homozygous for the deletion or, if the pregnancy was conceived using ICSI, the father may be deaf and infertile as a result of being homozygous for the deletion. In such cases, the other parent is heterozygous for the
• Heterozygotes (carriers) for the
• When both parents are carriers:
• At conception, each sib of an individual with DIS has a 25% chance of inheriting biallelic
• Males who inherit biallelic
• Females who inherit biallelic
• At conception, each sib of an individual with DIS has a 25% chance of inheriting biallelic
• Males who inherit biallelic
• Females who inherit biallelic
• When one parent has biallelic
• Each sib has a 50% chance of inheriting biallelic deletions (1 from each parent) and a 50% chance of inheriting one deletion.
• Males who inherit biallelic
• Females who inherit biallelic
• Each sib has a 50% chance of inheriting biallelic deletions (1 from each parent) and a 50% chance of inheriting one deletion.
• Males who inherit biallelic
• Females who inherit biallelic
• At conception, each sib of an individual with DIS has a 25% chance of inheriting biallelic
• Males who inherit biallelic
• Females who inherit biallelic
• Each sib has a 50% chance of inheriting biallelic deletions (1 from each parent) and a 50% chance of inheriting one deletion.
• Males who inherit biallelic
• Females who inherit biallelic
• Communication with individuals who are members of the Deaf community and who sign requires the services of a skilled interpreter.
• Members of the Deaf community may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a "treatment" or "cure," or to be "prevented."
• Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services, rather than information about prevention, reproduction, or family planning.
• The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as "abnormal" should be avoided.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are infertile or deaf.
## Mode of Inheritance
The parents of a male with
Less likely, the mother may have two pathogenic variants and the father has one or, if the pregnancy was conceived using ICSI, the father may be infertile (as a result of having two
Women with two
When both parents are carriers:
At conception, each sib of an individual with
Males who inherit biallelic pathogenic variants will be infertile.
Females who inherit biallelic pathogenic variants will have no signs/symptoms.
When one parent has two
Each sib has a 50% chance of inheriting biallelic pathogenic variants (one from each parent) and a 50% chance of inheriting one pathogenic variant.
Males who inherit biallelic pathogenic variants will be infertile.
Females who inherit biallelic pathogenic variants will have no signs/symptoms.
Women with biallelic
• The parents of a male with
• Less likely, the mother may have two pathogenic variants and the father has one or, if the pregnancy was conceived using ICSI, the father may be infertile (as a result of having two
• Women with two
• When both parents are carriers:
• At conception, each sib of an individual with
• Males who inherit biallelic pathogenic variants will be infertile.
• Females who inherit biallelic pathogenic variants will have no signs/symptoms.
• At conception, each sib of an individual with
• Males who inherit biallelic pathogenic variants will be infertile.
• Females who inherit biallelic pathogenic variants will have no signs/symptoms.
• When one parent has two
• Each sib has a 50% chance of inheriting biallelic pathogenic variants (one from each parent) and a 50% chance of inheriting one pathogenic variant.
• Males who inherit biallelic pathogenic variants will be infertile.
• Females who inherit biallelic pathogenic variants will have no signs/symptoms.
• Each sib has a 50% chance of inheriting biallelic pathogenic variants (one from each parent) and a 50% chance of inheriting one pathogenic variant.
• Males who inherit biallelic pathogenic variants will be infertile.
• Females who inherit biallelic pathogenic variants will have no signs/symptoms.
• Women with biallelic
• At conception, each sib of an individual with
• Males who inherit biallelic pathogenic variants will be infertile.
• Females who inherit biallelic pathogenic variants will have no signs/symptoms.
• Each sib has a 50% chance of inheriting biallelic pathogenic variants (one from each parent) and a 50% chance of inheriting one pathogenic variant.
• Males who inherit biallelic pathogenic variants will be infertile.
• Females who inherit biallelic pathogenic variants will have no signs/symptoms.
## DIS – Risk to Family Members
Typically, the parents of a male with DIS are obligate heterozygotes (i.e., carriers of a deletion that includes
Less likely, the mother may be deaf as a result of being homozygous for the deletion or, if the pregnancy was conceived using ICSI, the father may be deaf and infertile as a result of being homozygous for the deletion. In such cases, the other parent is heterozygous for the
Heterozygotes (carriers) for the
When both parents are carriers:
At conception, each sib of an individual with DIS has a 25% chance of inheriting biallelic
Males who inherit biallelic
Females who inherit biallelic
When one parent has biallelic
Each sib has a 50% chance of inheriting biallelic deletions (1 from each parent) and a 50% chance of inheriting one deletion.
Males who inherit biallelic
Females who inherit biallelic
• Typically, the parents of a male with DIS are obligate heterozygotes (i.e., carriers of a deletion that includes
• Less likely, the mother may be deaf as a result of being homozygous for the deletion or, if the pregnancy was conceived using ICSI, the father may be deaf and infertile as a result of being homozygous for the deletion. In such cases, the other parent is heterozygous for the
• Heterozygotes (carriers) for the
• When both parents are carriers:
• At conception, each sib of an individual with DIS has a 25% chance of inheriting biallelic
• Males who inherit biallelic
• Females who inherit biallelic
• At conception, each sib of an individual with DIS has a 25% chance of inheriting biallelic
• Males who inherit biallelic
• Females who inherit biallelic
• When one parent has biallelic
• Each sib has a 50% chance of inheriting biallelic deletions (1 from each parent) and a 50% chance of inheriting one deletion.
• Males who inherit biallelic
• Females who inherit biallelic
• Each sib has a 50% chance of inheriting biallelic deletions (1 from each parent) and a 50% chance of inheriting one deletion.
• Males who inherit biallelic
• Females who inherit biallelic
• At conception, each sib of an individual with DIS has a 25% chance of inheriting biallelic
• Males who inherit biallelic
• Females who inherit biallelic
• Each sib has a 50% chance of inheriting biallelic deletions (1 from each parent) and a 50% chance of inheriting one deletion.
• Males who inherit biallelic
• Females who inherit biallelic
## Related Genetic Counseling Issues
See Management,
The following points regarding hearing loss/deafness are noteworthy:
Communication with individuals who are members of the Deaf community and who sign requires the services of a skilled interpreter.
Members of the Deaf community may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a "treatment" or "cure," or to be "prevented."
Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services, rather than information about prevention, reproduction, or family planning.
The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as "abnormal" should be avoided.
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are infertile or deaf.
• Communication with individuals who are members of the Deaf community and who sign requires the services of a skilled interpreter.
• Members of the Deaf community may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a "treatment" or "cure," or to be "prevented."
• Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services, rather than information about prevention, reproduction, or family planning.
• The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as "abnormal" should be avoided.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are infertile or deaf.
## Prenatal Testing and Preimplantation Genetic Testing
Once the pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
7918 Jones Branch Drive
Suite 300
McLean VA 22102
•
•
•
•
•
• 7918 Jones Branch Drive
• Suite 300
• McLean VA 22102
•
## Molecular Genetics
CATSPER-Related Male Infertility: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CATSPER-Related Male Infertility (
Based on these data, loss-of-function variants of
Selected
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
It is unclear whether nonsense or missense variants in
Selected
Variants listed in the table have been provided by the authors.
Deletion of
Deletion of
## Molecular Pathogenesis
Based on these data, loss-of-function variants of
Selected
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
It is unclear whether nonsense or missense variants in
Selected
Variants listed in the table have been provided by the authors.
Deletion of
Deletion of
##
Based on these data, loss-of-function variants of
Selected
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
##
It is unclear whether nonsense or missense variants in
Selected
Variants listed in the table have been provided by the authors.
Deletion of
##
Deletion of
## Chapter Notes
RJHS is the Sterba Hearing Research Professor, University of Iowa College of Medicine and is supported by NIH NIDCD grants RO1DC00354 and RO1 DC002842. MSH is supported by an Australian National Health and Medical Research (NHMRC) Overseas Biomedical Postdoctoral Training Fellowship.
14 December 2023 (ma) Chapter retired: covered in
23 March 2017 (ma) Comprehensive update posted live
7 August 2014 (me) Comprehensive update posted live
9 August 2012 (me) Comprehensive update posted live
3 December 2009 (me) Review posted live
13 August 2009 (rjhs) Initial submission
• 14 December 2023 (ma) Chapter retired: covered in
• 23 March 2017 (ma) Comprehensive update posted live
• 7 August 2014 (me) Comprehensive update posted live
• 9 August 2012 (me) Comprehensive update posted live
• 3 December 2009 (me) Review posted live
• 13 August 2009 (rjhs) Initial submission
## Author Notes
## Acknowledgments
RJHS is the Sterba Hearing Research Professor, University of Iowa College of Medicine and is supported by NIH NIDCD grants RO1DC00354 and RO1 DC002842. MSH is supported by an Australian National Health and Medical Research (NHMRC) Overseas Biomedical Postdoctoral Training Fellowship.
## Revision History
14 December 2023 (ma) Chapter retired: covered in
23 March 2017 (ma) Comprehensive update posted live
7 August 2014 (me) Comprehensive update posted live
9 August 2012 (me) Comprehensive update posted live
3 December 2009 (me) Review posted live
13 August 2009 (rjhs) Initial submission
• 14 December 2023 (ma) Chapter retired: covered in
• 23 March 2017 (ma) Comprehensive update posted live
• 7 August 2014 (me) Comprehensive update posted live
• 9 August 2012 (me) Comprehensive update posted live
• 3 December 2009 (me) Review posted live
• 13 August 2009 (rjhs) Initial submission
## References
## Literature Cited
|
[] |
3/12/2009
|
23/3/2017
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
cav
|
cav
|
[
"Caveolin-3 Deficiency",
"Caveolin-3 Deficiency",
"Limb-Girdle Muscular Dystrophy Type 1C",
"Isolated HyperCKemia",
"Rippling Muscle Disease",
"Distal Myopathy",
"CAV3-Related Hypertrophic Cardiomyopathy",
"Caveolin-3",
"CAV3",
"Caveolinopathies"
] |
Caveolinopathies – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Claudio Bruno, Federica Sotgia, Elisabetta Gazzerro, Carlo Minetti, Michael P Lisanti
|
Summary The caveolinopathies, a group of muscle diseases, can be classified into five phenotypes, which can be seen in different members of the same family: Limb-girdle muscular dystrophy 1C (LGMD1C), characterized by onset usually in the first decade, mild-to-moderate proximal muscle weakness, calf hypertrophy, positive Gower sign, and variable muscle cramps after exercise Isolated hyperCKemia (i.e., elevated serum concentration of creatine kinase (CK) in the absence of signs of muscle disease) (HCK) Rippling muscle disease (RMD), characterized by signs of increased muscle irritability, such as percussion-induced rapid contraction (PIRC), percussion-induced muscle mounding (PIMM), and/or electrically silent muscle contractions (rippling muscle) Distal myopathy (DM), observed in one individual only Hypertrophic cardiomyopathy (HCM), without skeletal muscle manifestations Most caveolinopathies are inherited in an autosomal dominant manner; they may also be inherited in an autosomal recessive manner. Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant(s) have been identified in an affected family member.
|
Limb-girdle muscular dystrophy 1C
Isolated hyperCKemia
Rippling muscle disease
Distal myopathy
Hypertrophic cardiomyopathy
For other genetic causes of these phenotypes see
• Limb-girdle muscular dystrophy 1C
• Isolated hyperCKemia
• Rippling muscle disease
• Distal myopathy
• Hypertrophic cardiomyopathy
## Diagnosis
Caveolinopathies have a wide spectrum of clinical presentations.
Onset usually in the first two decades
Progressive, proximal, symmetric muscle weakness
Calf hypertrophy
Myalgia, cramps, and/or stiffness after exercise
Muscle hyperirritability manifest as:
Percussion-induced rapid contraction (PIRC) in which tapping the muscle belly results in rapid contraction of the muscle;
Percussion-induced muscle mounding (PIMM) in which a visible localized swelling of the muscle is caused by contraction at the point of contact;
Muscle rippling - a silent (absence of action potentials) wave of muscle contractions that occurs on mechanical stretching of the muscle.
Positive Gowers sign
In a study of two members of an Italian family with HCK, muscle biopsy revealed a partial caveolin-3 deficiency [
Note: Individuals affected by hyperCKemia or hypertrophic cardiomyopathy often display normal muscle histology.
Anti-caveolin-3 antibodies: reduced or nearly complete absence of caveolin-3 immuno-reactivity on the plasma membrane
Dysferlin membrane staining: reduced or altered (Instead of a uniform immunostaining on the plasma membrane, dysferlin exhibits a "patchy-like" distribution, and accumulates in the cytoplasm.)
Molecular Genetic Testing Used in Caveolinopathies
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.For issues to consider in interpretation of sequence analysis results click
Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
Obtain serum CK concentration.
Obtain muscle biopsy for histologic evaluation, ultrastructural analysis, and immunohistochemical staining.
In those with findings consistent with a caveolinopathy, perform molecular genetic testing of CAV.
• Onset usually in the first two decades
• Progressive, proximal, symmetric muscle weakness
• Calf hypertrophy
• Myalgia, cramps, and/or stiffness after exercise
• Muscle hyperirritability manifest as:
• Percussion-induced rapid contraction (PIRC) in which tapping the muscle belly results in rapid contraction of the muscle;
• Percussion-induced muscle mounding (PIMM) in which a visible localized swelling of the muscle is caused by contraction at the point of contact;
• Muscle rippling - a silent (absence of action potentials) wave of muscle contractions that occurs on mechanical stretching of the muscle.
• Percussion-induced rapid contraction (PIRC) in which tapping the muscle belly results in rapid contraction of the muscle;
• Percussion-induced muscle mounding (PIMM) in which a visible localized swelling of the muscle is caused by contraction at the point of contact;
• Muscle rippling - a silent (absence of action potentials) wave of muscle contractions that occurs on mechanical stretching of the muscle.
• Positive Gowers sign
• Percussion-induced rapid contraction (PIRC) in which tapping the muscle belly results in rapid contraction of the muscle;
• Percussion-induced muscle mounding (PIMM) in which a visible localized swelling of the muscle is caused by contraction at the point of contact;
• Muscle rippling - a silent (absence of action potentials) wave of muscle contractions that occurs on mechanical stretching of the muscle.
• In a study of two members of an Italian family with HCK, muscle biopsy revealed a partial caveolin-3 deficiency [
• Note: Individuals affected by hyperCKemia or hypertrophic cardiomyopathy often display normal muscle histology.
• In a study of two members of an Italian family with HCK, muscle biopsy revealed a partial caveolin-3 deficiency [
• Note: Individuals affected by hyperCKemia or hypertrophic cardiomyopathy often display normal muscle histology.
• Anti-caveolin-3 antibodies: reduced or nearly complete absence of caveolin-3 immuno-reactivity on the plasma membrane
• Dysferlin membrane staining: reduced or altered (Instead of a uniform immunostaining on the plasma membrane, dysferlin exhibits a "patchy-like" distribution, and accumulates in the cytoplasm.)
• Anti-caveolin-3 antibodies: reduced or nearly complete absence of caveolin-3 immuno-reactivity on the plasma membrane
• Dysferlin membrane staining: reduced or altered (Instead of a uniform immunostaining on the plasma membrane, dysferlin exhibits a "patchy-like" distribution, and accumulates in the cytoplasm.)
• In a study of two members of an Italian family with HCK, muscle biopsy revealed a partial caveolin-3 deficiency [
• Note: Individuals affected by hyperCKemia or hypertrophic cardiomyopathy often display normal muscle histology.
• Anti-caveolin-3 antibodies: reduced or nearly complete absence of caveolin-3 immuno-reactivity on the plasma membrane
• Dysferlin membrane staining: reduced or altered (Instead of a uniform immunostaining on the plasma membrane, dysferlin exhibits a "patchy-like" distribution, and accumulates in the cytoplasm.)
• Obtain serum CK concentration.
• Obtain muscle biopsy for histologic evaluation, ultrastructural analysis, and immunohistochemical staining.
• In those with findings consistent with a caveolinopathy, perform molecular genetic testing of CAV.
## Clinical Diagnosis
Caveolinopathies have a wide spectrum of clinical presentations.
Onset usually in the first two decades
Progressive, proximal, symmetric muscle weakness
Calf hypertrophy
Myalgia, cramps, and/or stiffness after exercise
Muscle hyperirritability manifest as:
Percussion-induced rapid contraction (PIRC) in which tapping the muscle belly results in rapid contraction of the muscle;
Percussion-induced muscle mounding (PIMM) in which a visible localized swelling of the muscle is caused by contraction at the point of contact;
Muscle rippling - a silent (absence of action potentials) wave of muscle contractions that occurs on mechanical stretching of the muscle.
Positive Gowers sign
In a study of two members of an Italian family with HCK, muscle biopsy revealed a partial caveolin-3 deficiency [
Note: Individuals affected by hyperCKemia or hypertrophic cardiomyopathy often display normal muscle histology.
Anti-caveolin-3 antibodies: reduced or nearly complete absence of caveolin-3 immuno-reactivity on the plasma membrane
Dysferlin membrane staining: reduced or altered (Instead of a uniform immunostaining on the plasma membrane, dysferlin exhibits a "patchy-like" distribution, and accumulates in the cytoplasm.)
• Onset usually in the first two decades
• Progressive, proximal, symmetric muscle weakness
• Calf hypertrophy
• Myalgia, cramps, and/or stiffness after exercise
• Muscle hyperirritability manifest as:
• Percussion-induced rapid contraction (PIRC) in which tapping the muscle belly results in rapid contraction of the muscle;
• Percussion-induced muscle mounding (PIMM) in which a visible localized swelling of the muscle is caused by contraction at the point of contact;
• Muscle rippling - a silent (absence of action potentials) wave of muscle contractions that occurs on mechanical stretching of the muscle.
• Percussion-induced rapid contraction (PIRC) in which tapping the muscle belly results in rapid contraction of the muscle;
• Percussion-induced muscle mounding (PIMM) in which a visible localized swelling of the muscle is caused by contraction at the point of contact;
• Muscle rippling - a silent (absence of action potentials) wave of muscle contractions that occurs on mechanical stretching of the muscle.
• Positive Gowers sign
• Percussion-induced rapid contraction (PIRC) in which tapping the muscle belly results in rapid contraction of the muscle;
• Percussion-induced muscle mounding (PIMM) in which a visible localized swelling of the muscle is caused by contraction at the point of contact;
• Muscle rippling - a silent (absence of action potentials) wave of muscle contractions that occurs on mechanical stretching of the muscle.
• In a study of two members of an Italian family with HCK, muscle biopsy revealed a partial caveolin-3 deficiency [
• Note: Individuals affected by hyperCKemia or hypertrophic cardiomyopathy often display normal muscle histology.
• In a study of two members of an Italian family with HCK, muscle biopsy revealed a partial caveolin-3 deficiency [
• Note: Individuals affected by hyperCKemia or hypertrophic cardiomyopathy often display normal muscle histology.
• Anti-caveolin-3 antibodies: reduced or nearly complete absence of caveolin-3 immuno-reactivity on the plasma membrane
• Dysferlin membrane staining: reduced or altered (Instead of a uniform immunostaining on the plasma membrane, dysferlin exhibits a "patchy-like" distribution, and accumulates in the cytoplasm.)
• Anti-caveolin-3 antibodies: reduced or nearly complete absence of caveolin-3 immuno-reactivity on the plasma membrane
• Dysferlin membrane staining: reduced or altered (Instead of a uniform immunostaining on the plasma membrane, dysferlin exhibits a "patchy-like" distribution, and accumulates in the cytoplasm.)
• In a study of two members of an Italian family with HCK, muscle biopsy revealed a partial caveolin-3 deficiency [
• Note: Individuals affected by hyperCKemia or hypertrophic cardiomyopathy often display normal muscle histology.
• Anti-caveolin-3 antibodies: reduced or nearly complete absence of caveolin-3 immuno-reactivity on the plasma membrane
• Dysferlin membrane staining: reduced or altered (Instead of a uniform immunostaining on the plasma membrane, dysferlin exhibits a "patchy-like" distribution, and accumulates in the cytoplasm.)
## Molecular Genetic Testing
Molecular Genetic Testing Used in Caveolinopathies
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.For issues to consider in interpretation of sequence analysis results click
Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
## Testing Strategy
Obtain serum CK concentration.
Obtain muscle biopsy for histologic evaluation, ultrastructural analysis, and immunohistochemical staining.
In those with findings consistent with a caveolinopathy, perform molecular genetic testing of CAV.
• Obtain serum CK concentration.
• Obtain muscle biopsy for histologic evaluation, ultrastructural analysis, and immunohistochemical staining.
• In those with findings consistent with a caveolinopathy, perform molecular genetic testing of CAV.
## Clinical Characteristics
The caveolinopathies are a clinically heterogeneous group of muscle diseases that can be classified into the five following phenotypes [
Limb-girdle muscular dystrophy 1C (LGMD1C)
Isolated hyperCKemia (i.e., in the absence of any signs of muscle disease) (HCK)
Rippling muscle disease (RMD)
Distal myopathy (DM)
Hypertrophic cardiomyopathy (HCM)
The five phenotypes are not family specific: families with overlapping phenotypes have been reported [
Myalgia is a common presenting symptom [
Subsequent reports included:
A German girl age four years with myalgia and muscle cramps in the lower limbs but no muscle weakness [
A Japanese girl age 11 years with a history of floppiness at birth, marginally delayed motor milestones, progressive proximal muscle weakness, and exercise-induced myalgia [
A woman age 71 years without any previous neuromuscular symptoms, who had mild proximal muscle weakness, scapular winging, slight calf hypertrophy, and a positive Gower sign [
Two additional unrelated Japanese families with LGMD1C have been reported [
In two unrelated Italian children (age 4 and 6 years), the sole finding was variable but persistent hyperCKemia (~4- to 8-fold higher than normal) [
In two members of an Italian family (the proband and his mother), persistent hyperCKemia was associated with serum CK concentrations that were 17-fold and fourfold higher than normal, respectively, without any signs or symptoms of myopathy [
In three members of a Spanish family, persistent elevated serum CK concentrations (from 3- to 10-fold higher than normal) without any muscle weakness were reported. Calf hypertrophy was present in the proband [
Recently,
Eight of ten patients in the UK with a caveolinopathy had rippling muscle movements [
Overlapping phenotypes were also found within two Japanese families; four of six individuals with RMD also had DM [
An Italian family showed the LGMD1C, RMD, and HCK phenotypes [
Genotype-phenotype correlations do not exist, as studies have shown that the same pathogenic variant can lead to heterogeneous clinical phenotypes and muscle histopathologic changes [
This observed intrafamilial phenotypic variability suggests that other genetic modifiers may exist.
Higher penetrance of isolated hyperCKemia (both familial and simplex [i.e., a single occurrence in a family]) has been reported in men [
Anticipation is not observed.
• Limb-girdle muscular dystrophy 1C (LGMD1C)
• Isolated hyperCKemia (i.e., in the absence of any signs of muscle disease) (HCK)
• Rippling muscle disease (RMD)
• Distal myopathy (DM)
• Hypertrophic cardiomyopathy (HCM)
• A German girl age four years with myalgia and muscle cramps in the lower limbs but no muscle weakness [
• A Japanese girl age 11 years with a history of floppiness at birth, marginally delayed motor milestones, progressive proximal muscle weakness, and exercise-induced myalgia [
• A woman age 71 years without any previous neuromuscular symptoms, who had mild proximal muscle weakness, scapular winging, slight calf hypertrophy, and a positive Gower sign [
## Clinical Description
The caveolinopathies are a clinically heterogeneous group of muscle diseases that can be classified into the five following phenotypes [
Limb-girdle muscular dystrophy 1C (LGMD1C)
Isolated hyperCKemia (i.e., in the absence of any signs of muscle disease) (HCK)
Rippling muscle disease (RMD)
Distal myopathy (DM)
Hypertrophic cardiomyopathy (HCM)
The five phenotypes are not family specific: families with overlapping phenotypes have been reported [
Myalgia is a common presenting symptom [
Subsequent reports included:
A German girl age four years with myalgia and muscle cramps in the lower limbs but no muscle weakness [
A Japanese girl age 11 years with a history of floppiness at birth, marginally delayed motor milestones, progressive proximal muscle weakness, and exercise-induced myalgia [
A woman age 71 years without any previous neuromuscular symptoms, who had mild proximal muscle weakness, scapular winging, slight calf hypertrophy, and a positive Gower sign [
Two additional unrelated Japanese families with LGMD1C have been reported [
In two unrelated Italian children (age 4 and 6 years), the sole finding was variable but persistent hyperCKemia (~4- to 8-fold higher than normal) [
In two members of an Italian family (the proband and his mother), persistent hyperCKemia was associated with serum CK concentrations that were 17-fold and fourfold higher than normal, respectively, without any signs or symptoms of myopathy [
In three members of a Spanish family, persistent elevated serum CK concentrations (from 3- to 10-fold higher than normal) without any muscle weakness were reported. Calf hypertrophy was present in the proband [
Recently,
Eight of ten patients in the UK with a caveolinopathy had rippling muscle movements [
Overlapping phenotypes were also found within two Japanese families; four of six individuals with RMD also had DM [
An Italian family showed the LGMD1C, RMD, and HCK phenotypes [
• Limb-girdle muscular dystrophy 1C (LGMD1C)
• Isolated hyperCKemia (i.e., in the absence of any signs of muscle disease) (HCK)
• Rippling muscle disease (RMD)
• Distal myopathy (DM)
• Hypertrophic cardiomyopathy (HCM)
• A German girl age four years with myalgia and muscle cramps in the lower limbs but no muscle weakness [
• A Japanese girl age 11 years with a history of floppiness at birth, marginally delayed motor milestones, progressive proximal muscle weakness, and exercise-induced myalgia [
• A woman age 71 years without any previous neuromuscular symptoms, who had mild proximal muscle weakness, scapular winging, slight calf hypertrophy, and a positive Gower sign [
## Genotype-Phenotype Correlations
Genotype-phenotype correlations do not exist, as studies have shown that the same pathogenic variant can lead to heterogeneous clinical phenotypes and muscle histopathologic changes [
This observed intrafamilial phenotypic variability suggests that other genetic modifiers may exist.
## Penetrance
Higher penetrance of isolated hyperCKemia (both familial and simplex [i.e., a single occurrence in a family]) has been reported in men [
## Anticipation
Anticipation is not observed.
## Prevalence
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The severe end of the spectrum includes progressive muscle diseases that are classified as Duchenne/Becker muscular dystrophy when skeletal muscle is primarily affected and as
Molecular genetic testing of
Although LGMD previously referred to muscular dystrophies inherited in an autosomal recessive manner, it is now recognized that limb-girdle muscular dystrophy also includes rare dominantly inherited subtypes.
However, the percussion or rapid pressing of selective muscles (biceps, forearm extensor and flexor, anterior tibial) inducing rapid contraction can be suggestive of rippling muscle disease (RMD). In addition, EMG in persons with RMD does not show the typical myotonic runs of myotonia.
Miyoshi myopathy, characterized in young adults by distal muscle weakness and atrophy, most marked in the gastrocnemius and soleus muscles. Over a period of years, weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength, but the small muscles of the hands are spared.
Limb-girdle muscular dystrophy syndrome (LGMD2B), characterized by early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with slow progression
Serum CK concentration is markedly elevated and the muscle biopsy demonstrates signs of a dystrophy with deficiency of dysferlin. Inheritance is autosomal recessive.
•
•
•
• Miyoshi myopathy, characterized in young adults by distal muscle weakness and atrophy, most marked in the gastrocnemius and soleus muscles. Over a period of years, weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength, but the small muscles of the hands are spared.
• Limb-girdle muscular dystrophy syndrome (LGMD2B), characterized by early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with slow progression
## Management
To establish the extent of disease and needs of an individual diagnosed with caveolinopathies, initial evaluation includes the following:
Orthopedic examination to assess the presence of scoliosis
Analysis of respiratory function: spirometry (patients age >5 years), measurement of arterial pO
Cardiac examination: 24-hour electrocardiogram and echocardiogram
Consultation with a clinical geneticist and/or genetic counselor
No specific treatment is currently available for caveolinopathies.
Aggressive supportive care is essential to preserve muscle function, to maximize functional ability, and to treat complications, especially in cases with LGMD features. Management should include the following:
Weight control to avoid obesity
Physical therapy and stretching exercises to promote mobility and prevent contractures
Use of mechanical aids such as canes, walkers, orthotics, and wheelchairs as needed to help ambulation and mobility
Social and emotional support and stimulation to maximize a sense of social involvement and productivity and to reduce the sense of social isolation common in these disorders [
In individuals with isolated hyperCKemia, special precautions during surgical procedures and anesthesia should be considered, despite the fact that malignant hyperthermia (MH) has not been reported in association with
Periodic monitoring of the following is recommended:
Spine: orthopedic consultation and, if needed, x-ray analysis
Respiratory function: spirometry
Cardiac function: 24-hour electrocardiography and echocardiography
Mobility and muscle function: consultation with a physiatrist and physical therapist
The interval between visits is determined based on the symptoms and signs observed in the individual patient.
See
Search
• Orthopedic examination to assess the presence of scoliosis
• Analysis of respiratory function: spirometry (patients age >5 years), measurement of arterial pO
• Cardiac examination: 24-hour electrocardiogram and echocardiogram
• Consultation with a clinical geneticist and/or genetic counselor
• Weight control to avoid obesity
• Physical therapy and stretching exercises to promote mobility and prevent contractures
• Use of mechanical aids such as canes, walkers, orthotics, and wheelchairs as needed to help ambulation and mobility
• Social and emotional support and stimulation to maximize a sense of social involvement and productivity and to reduce the sense of social isolation common in these disorders [
• Spine: orthopedic consultation and, if needed, x-ray analysis
• Respiratory function: spirometry
• Cardiac function: 24-hour electrocardiography and echocardiography
• Mobility and muscle function: consultation with a physiatrist and physical therapist
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with caveolinopathies, initial evaluation includes the following:
Orthopedic examination to assess the presence of scoliosis
Analysis of respiratory function: spirometry (patients age >5 years), measurement of arterial pO
Cardiac examination: 24-hour electrocardiogram and echocardiogram
Consultation with a clinical geneticist and/or genetic counselor
• Orthopedic examination to assess the presence of scoliosis
• Analysis of respiratory function: spirometry (patients age >5 years), measurement of arterial pO
• Cardiac examination: 24-hour electrocardiogram and echocardiogram
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
No specific treatment is currently available for caveolinopathies.
Aggressive supportive care is essential to preserve muscle function, to maximize functional ability, and to treat complications, especially in cases with LGMD features. Management should include the following:
Weight control to avoid obesity
Physical therapy and stretching exercises to promote mobility and prevent contractures
Use of mechanical aids such as canes, walkers, orthotics, and wheelchairs as needed to help ambulation and mobility
Social and emotional support and stimulation to maximize a sense of social involvement and productivity and to reduce the sense of social isolation common in these disorders [
• Weight control to avoid obesity
• Physical therapy and stretching exercises to promote mobility and prevent contractures
• Use of mechanical aids such as canes, walkers, orthotics, and wheelchairs as needed to help ambulation and mobility
• Social and emotional support and stimulation to maximize a sense of social involvement and productivity and to reduce the sense of social isolation common in these disorders [
## Prevention of Secondary Complications
In individuals with isolated hyperCKemia, special precautions during surgical procedures and anesthesia should be considered, despite the fact that malignant hyperthermia (MH) has not been reported in association with
## Surveillance
Periodic monitoring of the following is recommended:
Spine: orthopedic consultation and, if needed, x-ray analysis
Respiratory function: spirometry
Cardiac function: 24-hour electrocardiography and echocardiography
Mobility and muscle function: consultation with a physiatrist and physical therapist
The interval between visits is determined based on the symptoms and signs observed in the individual patient.
• Spine: orthopedic consultation and, if needed, x-ray analysis
• Respiratory function: spirometry
• Cardiac function: 24-hour electrocardiography and echocardiography
• Mobility and muscle function: consultation with a physiatrist and physical therapist
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Most of the caveolinopathies are inherited in an autosomal dominant manner.
Caveolinopathies may also be inherited in an autosomal recessive manner.
Most individuals diagnosed with a caveolinopathy have an affected parent.
A proband with a caveolinopathy may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
Note: Although most individuals diagnosed with caveolinopathy have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, autosomal recessive inheritance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
If a parent of the proband is affected, the risk to the sibs is 50%.
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
Although no instances of germline mosaicism have been reported, it remains a possibility.
The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
Heterozygotes (carriers) can be asymptomatic or can display modest elevation of serum CK levels and/or calf hypertrophy.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) can be asymptomatic or can display modest elevation of serum CK levels and/or calf hypertrophy.
Carrier testing for family members at risk for an autosomal recessive caveolinopathy is possible once the pathogenic variants have been identified in an affected family member.
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
• Most individuals diagnosed with a caveolinopathy have an affected parent.
• A proband with a caveolinopathy may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• Although no instances of germline mosaicism have been reported, it remains a possibility.
• The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
• Heterozygotes (carriers) can be asymptomatic or can display modest elevation of serum CK levels and/or calf hypertrophy.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) can be asymptomatic or can display modest elevation of serum CK levels and/or calf hypertrophy.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Most of the caveolinopathies are inherited in an autosomal dominant manner.
Caveolinopathies may also be inherited in an autosomal recessive manner.
## Autosomal Dominant Inheritance – Risk to Family Members
Most individuals diagnosed with a caveolinopathy have an affected parent.
A proband with a caveolinopathy may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
Note: Although most individuals diagnosed with caveolinopathy have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, autosomal recessive inheritance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
If a parent of the proband is affected, the risk to the sibs is 50%.
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
Although no instances of germline mosaicism have been reported, it remains a possibility.
• Most individuals diagnosed with a caveolinopathy have an affected parent.
• A proband with a caveolinopathy may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• Although no instances of germline mosaicism have been reported, it remains a possibility.
## Autosomal Recessive Inheritance
The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
Heterozygotes (carriers) can be asymptomatic or can display modest elevation of serum CK levels and/or calf hypertrophy.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) can be asymptomatic or can display modest elevation of serum CK levels and/or calf hypertrophy.
Carrier testing for family members at risk for an autosomal recessive caveolinopathy is possible once the pathogenic variants have been identified in an affected family member.
• The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
• Heterozygotes (carriers) can be asymptomatic or can display modest elevation of serum CK levels and/or calf hypertrophy.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) can be asymptomatic or can display modest elevation of serum CK levels and/or calf hypertrophy.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
Heterozygotes (carriers) can be asymptomatic or can display modest elevation of serum CK levels and/or calf hypertrophy.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) can be asymptomatic or can display modest elevation of serum CK levels and/or calf hypertrophy.
• The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
• Heterozygotes (carriers) can be asymptomatic or can display modest elevation of serum CK levels and/or calf hypertrophy.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) can be asymptomatic or can display modest elevation of serum CK levels and/or calf hypertrophy.
## Carrier (Heterozygote) Detection
Carrier testing for family members at risk for an autosomal recessive caveolinopathy is possible once the pathogenic variants have been identified in an affected family member.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
## Resources
222 South Riverside Plaza
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• 222 South Riverside Plaza
• Suite 1500
• Chicago IL 60606
•
•
• 61A Great Suffolk Street
• London SE1 0BU
• United Kingdom
•
•
•
## Molecular Genetics
Caveolinopathies: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Caveolinopathies (
Caveolin-3 is essential for the biogenesis of caveolae, small invaginations of the muscle plasma membrane that play a critical role in the maintenance of muscle cell structural integrity and signaling.
The role of caveolae and caveolin-3 in muscle has become clinically relevant with the finding that pathogenic variants in
Phenotypic characterization of the first two
A similar experimental approach was utilized to complete a functional characterization of the
It is important to note that individuals with LGMD1C and experimental models of p.Pro104Leu and ΔTFT
Cav3 knockout mice lack muscle cell caveolae and display a number of myopathic changes consistent with mild muscular dystrophy. Soleus muscle degenerates in the knockout animals by age eight weeks, as does the diaphragm at eight to thirty weeks, but there is otherwise no effect on growth and motor movement relative to wild-type mice. Cav3 +/- hemizygotes have no muscle myopathy, indicating an autosomal recessive transmission of the myopathic phenotype, which contrasts with the dominant-negative Cav3 pathogenic missense variants associated with LGMD1C [
See
Caveolin-3 is a muscle-specific membrane protein and the principal component of caveolae membrane in muscle cells in vivo [
The expression of caveolin-3 is induced during the differentiation of skeletal myoblast, and caveolin-3 displays several functions in muscle cells. On the muscle sarcolemma it forms a complex with dystrophin and its associated glycoproteins, thus contributing to the structural stability of the plasma membrane [
In addition to its structural functions, caveolin-3 is required for the insulin receptor-mediated activation of glucose uptake and it regulates the subcellular distribution of phosphofructokinase (PFK), a key enzyme of carbohydrate metabolism [
Functional studies utilizing overexpression of p.Pro104Leu, ΔTFT, and p.Arg26Gln pathogenic variants in a heterologous cell system (NIH3T3) have indicated that these mutated forms of caveolin-3 display an impaired homo-oligomerization, are retained within the Golgi complex, and do not localize at the plasma membrane. In addition, misfolded caveolin-3 oligomers are targeted to proteasomal degradation and can exert a dominant-negative effect on wild-type protein [
## Molecular Pathogenesis
Caveolin-3 is essential for the biogenesis of caveolae, small invaginations of the muscle plasma membrane that play a critical role in the maintenance of muscle cell structural integrity and signaling.
The role of caveolae and caveolin-3 in muscle has become clinically relevant with the finding that pathogenic variants in
Phenotypic characterization of the first two
A similar experimental approach was utilized to complete a functional characterization of the
It is important to note that individuals with LGMD1C and experimental models of p.Pro104Leu and ΔTFT
Cav3 knockout mice lack muscle cell caveolae and display a number of myopathic changes consistent with mild muscular dystrophy. Soleus muscle degenerates in the knockout animals by age eight weeks, as does the diaphragm at eight to thirty weeks, but there is otherwise no effect on growth and motor movement relative to wild-type mice. Cav3 +/- hemizygotes have no muscle myopathy, indicating an autosomal recessive transmission of the myopathic phenotype, which contrasts with the dominant-negative Cav3 pathogenic missense variants associated with LGMD1C [
See
Caveolin-3 is a muscle-specific membrane protein and the principal component of caveolae membrane in muscle cells in vivo [
The expression of caveolin-3 is induced during the differentiation of skeletal myoblast, and caveolin-3 displays several functions in muscle cells. On the muscle sarcolemma it forms a complex with dystrophin and its associated glycoproteins, thus contributing to the structural stability of the plasma membrane [
In addition to its structural functions, caveolin-3 is required for the insulin receptor-mediated activation of glucose uptake and it regulates the subcellular distribution of phosphofructokinase (PFK), a key enzyme of carbohydrate metabolism [
Functional studies utilizing overexpression of p.Pro104Leu, ΔTFT, and p.Arg26Gln pathogenic variants in a heterologous cell system (NIH3T3) have indicated that these mutated forms of caveolin-3 display an impaired homo-oligomerization, are retained within the Golgi complex, and do not localize at the plasma membrane. In addition, misfolded caveolin-3 oligomers are targeted to proteasomal degradation and can exert a dominant-negative effect on wild-type protein [
## References
## Literature Cited
## Chapter Notes
Drs Sotgia and Lisanti were supported by grants from the Muscular Dystrophy Association (MDA USA) and the National Institutes of Health (NIAMS).
Drs Bruno, Gazzerro, and Minetti were supported by grants from Telethon-Italia and the Italian Ministry of Health.
31 October 2019 (ma) Chapter retired: outdated; qualified authors not available for update
6 September 2012 (me) Comprehensive update posted live
14 May 2007 (me) Review posted live
30 March 2005 (mpl) Original submission
• 31 October 2019 (ma) Chapter retired: outdated; qualified authors not available for update
• 6 September 2012 (me) Comprehensive update posted live
• 14 May 2007 (me) Review posted live
• 30 March 2005 (mpl) Original submission
## Acknowledgments
Drs Sotgia and Lisanti were supported by grants from the Muscular Dystrophy Association (MDA USA) and the National Institutes of Health (NIAMS).
Drs Bruno, Gazzerro, and Minetti were supported by grants from Telethon-Italia and the Italian Ministry of Health.
## Revision History
31 October 2019 (ma) Chapter retired: outdated; qualified authors not available for update
6 September 2012 (me) Comprehensive update posted live
14 May 2007 (me) Review posted live
30 March 2005 (mpl) Original submission
• 31 October 2019 (ma) Chapter retired: outdated; qualified authors not available for update
• 6 September 2012 (me) Comprehensive update posted live
• 14 May 2007 (me) Review posted live
• 30 March 2005 (mpl) Original submission
|
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"F Galbiati, D Volonte, C Minetti, JB Chu, MP Lisanti. Phenotypic behavior of caveolin-3 mutations that cause autosomal dominant limb girdle muscular dystrophy (LGMD-1C). Retention of LGMD-1C caveolin-3 mutants within the golgi complex.. J Biol Chem 1999b;274:25632-41",
"G García-Cardeña, P Martasek, BS Masters, PM Skidd, J Couet, S Li, MP Lisanti, WC Sessa. Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo.. J Biol Chem 1997;272:25437-40",
"E Gazzerro, F Sotgia, C Bruno, MP Lisanti, C Minetti. Caveolinopathies: from the biology of caveolin-3 to human diseases.. Eur J Hum Genet 2010;18:137-45",
"P González-Pérez, P Gallano, L González-Quereda, E Rivas-Infante, S Teijeira, C Navarro, J Bautista-Lorite. Phenotypic variability in a Spanish family with a Caveolin-3 mutation.. J Neurol Sci 2009;276:95-8",
"Y Hagiwara, T Sasaoka, K Araishi, M Imamura, H Yorifuji, I Nonaka, E Ozawa, T Kikuchi. Caveolin-3 deficiency causes muscle degeneration in mice.. Hum Mol Genet 2000;9:3047-54",
"T Hayashi, T Arimura, K Ueda, H Shibata, S Hohda, M Takahashi, H Hori, Y Koga, N Oka, T Imaizumi, M Yasunami, A Kimura. Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy.. Biochem Biophys Res Commun 2004;313:178-84",
"DJ Hernández-Deviez, S Martin, SH Laval, HP Lo, ST Cooper, KN North, K Bushby, RG Parton. Aberrant dysferlin trafficking in cells lacking caveolin or expressing dystrophy mutants of caveolin-3.. Hum Mol Genet 2006;15:129-42",
"R Herrmann, V Straub, M Blank, C Kutzick, N Franke, EN Jacob, HG Lenard, S Kroger, T Voit. Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy.. Hum Mol Genet 2000;9:2335-40",
"R Hnasko, MP Lisanti. The biology of caveolae: lessons from caveolin knockout mice and implications for human disease.. Mol Interv. 2003;3:445-64",
"C Kubisch, UP Ketelsen, I Goebel, H Omran. Autosomal recessive rippling muscle disease with homozygous CAV3 mutations.. Ann Neurol 2005;57:303-4",
"C Kubisch, BG Schoser, M von During, RC Betz, HH Goebel, S Zahn, A Ehrbrecht, J Aasly, A Schroers, N Popovic, H Lochmuller, JM Schroder, T Bruning, JP Malin, B Fricke, HM Meinck, T Torbergsen, H Engels, B Voss, M Vorgerd. Homozygous mutations in caveolin-3 cause a severe form of rippling muscle disease.. Ann Neurol 2003;53:512-20",
"L Kunkel. Caveolin-3 deficiency as a cause of limb-girdle muscular dystrophy.. J Child Neurol 1999;14:33-4",
"C Matsuda, YK Hayashi, M Ogawa, M Aoki, K Murayama, I Nishino, I Nonaka, K Arahata, RH Brown. The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle.. Hum Mol Genet 2001;10:1761-6",
"EM McNally, E de Sa Moreira, DJ Duggan, CG Bonnemann, MP Lisanti, HG Lidov, M Vainzof, MR Passos-Bueno, EP Hoffman, M Zatz, LM Kunkel. Caveolin-3 in muscular dystrophy.. Hum Mol Genet 1998;7:871-7",
"L Merlini, I Carbone, C Capanni, P Sabatelli, S Tortorelli, F Sotgia, MP Lisanti, C Bruno, C Minetti. Familial isolated hyperCKaemia associated with a new mutation in the caveolin-3 (CAV-3) gene.. J Neurol Neurosurg Psychiatry 2002;73:65-7",
"C Minetti, F Sotgia, C Bruno, P Scartezzini, P Broda, M Bado, E Masetti, M Mazzocco, A Egeo, MA Donati, D Volonte, F Galbiati, G Cordone, FD Bricarelli, MP Lisanti, F Zara. Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy.. Nat Genet 1998;18:365-8",
"JS Müller, H Piko, BG Schoser, B Schlotter-Weigel, P Reilich, S Gürster, C Born, V Karcagi, D Pongratz, H Lochmüller, MC Walter. Novel splice site mutation in the caveolin-3 gene leading to autosomal recessive limb girdle muscular dystrophy.. Neuromuscul Disord 2006;16:432-6",
"U Schara, M Vorgerd, N Popovic, BG Schoser, K Ricker, W Mortier. Rippling muscle disease in childhood.. J Child Neurol 2002;17:483-90",
"D Selcen, G Stilling, AG Engel. The earliest pathologic alterations in dysferlinopathy.. Neurology 2001;56:1472-81",
"GM Smythe, JC Eby, MH Disatnik, TA Rando. A caveolin-3 mutant that causes limb girdle muscular dystrophy type 1C disrupts Src localization and activity and induces apoptosis in skeletal myotubes.. J Cell Sci 2003;116:4739-49",
"KS Song, PE Scherer, Z Tang, T Okamoto, S Li, M Chafel, C Chu, DS Kohtz, MP Lisanti. Expression of caveolin-3 in skeletal, cardiac, and smooth muscle cells. Caveolin-3 is a component of the sarcolemma and co-fractionates with dystrophin and dystrophin-associated glycoproteins.. J Biol Chem 1996;271:15160-5",
"F Sotgia, G Bonuccelli, C Minetti, SE Woodman, F Capozza, RG Kemp, PE Scherer, MP Lisanti. Phosphofructokinase muscle-specific isoform requires caveolin-3 expression for plasma membrane recruitment and caveolar targeting: implications for the pathogenesis of caveolin-related muscle diseases.. Am J Pathol 2003a;163:2619-34",
"F Sotgia, JK Lee, K Das, M Bedford, TC Petrucci, P Macioce, M Sargiacomo, FD Bricarelli, C Minetti, M Sudol, MP Lisanti. Caveolin-3 directly interacts with the C-terminal tail of beta -dystroglycan. Identification of a central WW-like domain within caveolin family members.. J Biol Chem. 2000;275:38048-58",
"F Sotgia, SE Woodman, G Bonuccelli, F Capozza, C Minetti, PE Scherer, MP Lisanti. Phenotypic behavior of caveolin-3 R26Q, a mutant associated with hyperCKemia, distal myopathy, and rippling muscle disease.. Am J Physiol Cell Physiol 2003b;285:C1150-60",
"K Sugie, K Murayama, S Noguchi, N Murakami, M Mochizuki, YK Hayashi, I Nonaka, I Nishino. Two novel CAV3 gene mutations in Japanese families.. Neuromuscul Disord 2004;14:810-4",
"Z Tang, PE Scherer, T Okamoto, K Song, C Chu, DS Kohtz, I Nishimoto, HF Lodish, MP Lisanti. Molecular cloning of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle.. J Biol Chem 1996;271:2255-61",
"M Tateyama, M Aoki, I Nishino, YK Hayashi, S Sekiguchi, Y Shiga, T Takahashi, Y Onodera, K Haginoya, K Kobayashi, K Iinuma, I Nonaka, K Arahata, Y Itoyama. Mutation in the caveolin-3 gene causes a peculiar form of distal myopathy.. Neurology 2002;58:323-5",
"M Traverso, C Bruno, A Broccolini, F Sotgia, MA Donati, S Assereto, E Gazzerro, M Lo Monaco, A Modoni, A D'Amico, S Gasperini, E Ricci, F Zara, M Lisanti, C Minetti. Truncation of Caveolin-3 causes autosomal-recessive Rippling Muscle Disease.. J Neurol Neurosurg Psychiatry. 2008;79:735-7",
"PY Van den Bergh, JM Gerard, JA Elosegi, MU Manto, C Kubisch, BG Schoser. Novel missense mutation in the caveolin-3 gene in a Belgian family with rippling muscle disease.. J Neurol Neurosurg Psychiatry 2004;75:1349-51",
"M Vatta, MJ Ackerman, B Ye, JC Makielski, EE Ughanze, EW Taylor, DJ Tester, RC Balijepalli, JD Foell, Z Li, TJ Kamp, JA Towbin. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome.. Circulation 2006;114:2104-12",
"D Volonte, AJ Peoples, F Galbiati. Modulation of myoblast fusion by caveolin-3 in dystrophic skeletal muscle cells: implications for Duchenne muscular dystrophy and limb-girdle muscular dystrophy-1C.. Mol Biol Cell 2003;14:4075-88",
"M Vorgerd, K Ricker, F Ziemssen, W Kress, HH Goebel, WA Nix, C Kubisch, BG Schoser, W Mortier. A sporadic case of rippling muscle disease caused by a de novo caveolin-3 mutation.. Neurology 2001;57:2273-7",
"M Way, RG Parton. M-caveolin, a muscle-specific caveolin-related protein.. FEBS Lett. 1996;378:108-12",
"TM Williams, MP Lisanti. The caveolin proteins.. Genome Biol 2004;5:214",
"SE Woodman, F Sotgia, F Galbiati, C Minetti, MP Lisanti. Caveolinopathies: mutations in caveolin-3 cause four distinct autosomal dominant muscle diseases.. Neurology 2004;62:538-43",
"I Yabe, A Kawashima, S Kikuchi, T Higashi, T Fukazawa, T Hamada, H Sasaki, K Tashiro. Caveolin-3 gene mutation in Japanese with rippling muscle disease.. Acta Neurol Scand 2003;108:47-51"
] |
14/5/2007
|
6/9/2012
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
cbl
|
cbl
|
[
"cblE",
"cblC",
"cblG",
"cblD-combined",
"cblD-homocystinuria",
"cblX",
"cblF",
"cbIJ",
"Cobalamin trafficking protein CblD",
"Cyanocobalamin reductase / alkylcobalamin dealkylase",
"Host cell factor 1",
"Lysosomal cobalamin transport escort protein LMBD1",
"Lysosomal cobalamin transporter ABCD4",
"Methionine synthase",
"Methionine synthase reductase",
"THAP domain-containing protein 11",
"Zinc finger protein 143",
"ABCD4",
"HCFC1",
"LMBRD1",
"MMACHC",
"MMADHC",
"MTR",
"MTRR",
"THAP11",
"ZNF143",
"Disorders of Intracellular Cobalamin Metabolism"
] |
Disorders of Intracellular Cobalamin Metabolism
|
Jennifer L Sloan, Nuria Carrillo, David Adams, Charles P Venditti
|
Summary Disorders of intracellular cobalamin metabolism have a variable phenotype and age of onset that are influenced by the severity and location within the pathway of the defect. The prototype and best understood phenotype is In utero with fetal presentation of nonimmune hydrops, cardiomyopathy, and intrauterine growth restriction Newborns, who can have microcephaly, poor feeding, and encephalopathy Infants, who can have poor feeding and slow growth, neurologic abnormality, and, rarely, hemolytic uremic syndrome (HUS) Toddlers, who can have poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, thromboembolic complications, and/or subacute combined degeneration of the spinal cord The diagnosis of a disorder of intracellular cobalamin metabolism in a symptomatic individual is based on clinical, biochemical, and molecular genetic data. Evaluation of the methylmalonic acid (MMA) level in urine and blood and plasma total homocysteine (tHcy) level are the mainstays of biochemical testing. Diagnosis is confirmed by identification of biallelic pathogenic variants in one of the following genes (associated complementation groups indicated in parentheses): If the newborn sib of an affected individual has not undergone prenatal testing, molecular genetic testing can be performed in the first week of life if the pathogenic variants in the family are known. Otherwise, evaluation of urine organic acids and plasma amino acids, measurement of total plasma homocysteine, serum methylmalonic acid analysis, and acylcarnitine profile analysis can be used for the purpose of early diagnosis and treatment. The majority of disorders of intracellular cobalamin metabolism are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. The disorder of intracellular cobalamin metabolism caused by pathogenic variants in Once the pathogenic variant(s) have been identified in an affected family member, carrier testing for at-risk relatives, molecular genetic prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
|
## Diagnosis
The disorders of intracellular cobalamin metabolism result from deficient synthesis of the coenzymes derived from vitamin B
Adenosylcobalamin (AdoCbl) – the coenzyme for methylmalonyl-CoA mutase enzyme
Methylcobalamin (MeCbl) – the coenzyme for the enzyme methionine synthase (MTR) (
This
Note: All the disorders of intracellular cobalamin metabolism are inherited in an autosomal recessive manner except for
Disorders of Intracellular Cobalamin Metabolism by Biochemical Phenotype
Note: The terms methylmalonic acidemia and methylmalonic aciduria are synonymous, as are the terms hyperhomocysteinemia and homocystinuria.
The nomenclature for inherited disorders of intracellular cobalamin metabolism is based on cellular complementation analysis that defines cobalamin groups A-J (
The homocystinuria seen in disorders of intracellular cobalamin metabolism is associated with low/normal methionine in contrast to the
Individuals with
A rare complex variant of
The diagnosis of a disorder of intracellular cobalamin metabolism in a symptomatic individual is based on clinical, biochemical, and molecular genetic data. With the availability of molecular genetic testing,
A disorder of intracellular cobalamin metabolism
Macrocytic anemia with normal B
Hyperammonemia and/or metabolic acidosis in infancy (rare)
Detection by newborn screening (NBS) depends on the C3 and C3/C2 ratio cutoff values used by reference laboratories and the availability of detection of low methionine [
Since NBS potentially allows early detection of certain disorders of intracellular cobalamin metabolism, some affected individuals may be diagnosed before the onset of symptoms.
The diagnosis of a disorder of intracellular cobalamin metabolism
The identification of disorders of intracellular cobalamin metabolism relies on the following testing (
Note: Delays in separating serum from plasma after obtaining a blood sample can artificially increase total homocysteine by as much as 10% an hour [
Other findings that can be seen on PAA analysis:
Hyperhomocysteinemia and mixed disulfides (which are also excreted in the urine)
Cystathionine (which is also excreted in the urine) in individuals with
Note:
Metabolite Concentrations in Disorders of Intracellular Cobalamin Metabolism
NR = not reported
Standard values have not been exclusively derived from children or neonates. Some laboratories report urine methylmalonic acid (MMA) concentrations in mg/g/Cr (normal: <3 mg/g/Cr) and serum concentrations in nmol/L (normal: <271 nmol/L). The molecular weight of MMA is 118 g/mol.
Authors' experience with >50 affected individuals
Values refer to
Mild elevation uncommon [
Molecular genetic testing approaches can include a combination of
Individuals with the distinctive laboratory findings of a specific disorder of intracellular cobalamin metabolism described in
When the phenotypic and laboratory findings suggest the diagnosis of a disorder of intracellular cobalamin metabolism, molecular genetic testing approaches can include
For this disorder a multigene panel that also includes deletion/duplication analysis can be considered if sequence analysis has not identified two pathogenic variants in an individual with strong biochemical evidence for a disorder of intracellular cobalamin metabolism.
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by the wide of array of possible nonspecific clinical findings or an individual has atypical phenotypic features of a disorder of intracellular cobalamin metabolism,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Disorders of Intracellular Cobalamin Metabolism
Genes are listed in order of complementation group number.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A rare complex variant of
No data on detection rate of gene-targeted deletion/duplication analysis are available.
One consanguineous individual has been found to have biallelic
A deletion spanning exon 2 was reported by
Complementation analysis is a method used historically to diagnose the specific defects of intracellular cobalamin metabolism using cultured skin fibroblasts [
• Adenosylcobalamin (AdoCbl) – the coenzyme for methylmalonyl-CoA mutase enzyme
• Methylcobalamin (MeCbl) – the coenzyme for the enzyme methionine synthase (MTR) (
• Macrocytic anemia with normal B
• Hyperammonemia and/or metabolic acidosis in infancy (rare)
• Detection by newborn screening (NBS) depends on the C3 and C3/C2 ratio cutoff values used by reference laboratories and the availability of detection of low methionine [
• Since NBS potentially allows early detection of certain disorders of intracellular cobalamin metabolism, some affected individuals may be diagnosed before the onset of symptoms.
• Note: Delays in separating serum from plasma after obtaining a blood sample can artificially increase total homocysteine by as much as 10% an hour [
• Other findings that can be seen on PAA analysis:
• Hyperhomocysteinemia and mixed disulfides (which are also excreted in the urine)
• Cystathionine (which is also excreted in the urine) in individuals with
• Hyperhomocysteinemia and mixed disulfides (which are also excreted in the urine)
• Cystathionine (which is also excreted in the urine) in individuals with
• Note:
• Hyperhomocysteinemia and mixed disulfides (which are also excreted in the urine)
• Cystathionine (which is also excreted in the urine) in individuals with
• For this disorder a multigene panel that also includes deletion/duplication analysis can be considered if sequence analysis has not identified two pathogenic variants in an individual with strong biochemical evidence for a disorder of intracellular cobalamin metabolism.
• For an introduction to multigene panels click
## Suggestive Findings
A disorder of intracellular cobalamin metabolism
Macrocytic anemia with normal B
Hyperammonemia and/or metabolic acidosis in infancy (rare)
Detection by newborn screening (NBS) depends on the C3 and C3/C2 ratio cutoff values used by reference laboratories and the availability of detection of low methionine [
Since NBS potentially allows early detection of certain disorders of intracellular cobalamin metabolism, some affected individuals may be diagnosed before the onset of symptoms.
• Macrocytic anemia with normal B
• Hyperammonemia and/or metabolic acidosis in infancy (rare)
• Detection by newborn screening (NBS) depends on the C3 and C3/C2 ratio cutoff values used by reference laboratories and the availability of detection of low methionine [
• Since NBS potentially allows early detection of certain disorders of intracellular cobalamin metabolism, some affected individuals may be diagnosed before the onset of symptoms.
## Establishing the Diagnosis
The diagnosis of a disorder of intracellular cobalamin metabolism
The identification of disorders of intracellular cobalamin metabolism relies on the following testing (
Note: Delays in separating serum from plasma after obtaining a blood sample can artificially increase total homocysteine by as much as 10% an hour [
Other findings that can be seen on PAA analysis:
Hyperhomocysteinemia and mixed disulfides (which are also excreted in the urine)
Cystathionine (which is also excreted in the urine) in individuals with
Note:
Metabolite Concentrations in Disorders of Intracellular Cobalamin Metabolism
NR = not reported
Standard values have not been exclusively derived from children or neonates. Some laboratories report urine methylmalonic acid (MMA) concentrations in mg/g/Cr (normal: <3 mg/g/Cr) and serum concentrations in nmol/L (normal: <271 nmol/L). The molecular weight of MMA is 118 g/mol.
Authors' experience with >50 affected individuals
Values refer to
Mild elevation uncommon [
Molecular genetic testing approaches can include a combination of
Individuals with the distinctive laboratory findings of a specific disorder of intracellular cobalamin metabolism described in
When the phenotypic and laboratory findings suggest the diagnosis of a disorder of intracellular cobalamin metabolism, molecular genetic testing approaches can include
For this disorder a multigene panel that also includes deletion/duplication analysis can be considered if sequence analysis has not identified two pathogenic variants in an individual with strong biochemical evidence for a disorder of intracellular cobalamin metabolism.
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by the wide of array of possible nonspecific clinical findings or an individual has atypical phenotypic features of a disorder of intracellular cobalamin metabolism,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Disorders of Intracellular Cobalamin Metabolism
Genes are listed in order of complementation group number.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A rare complex variant of
No data on detection rate of gene-targeted deletion/duplication analysis are available.
One consanguineous individual has been found to have biallelic
A deletion spanning exon 2 was reported by
• Note: Delays in separating serum from plasma after obtaining a blood sample can artificially increase total homocysteine by as much as 10% an hour [
• Other findings that can be seen on PAA analysis:
• Hyperhomocysteinemia and mixed disulfides (which are also excreted in the urine)
• Cystathionine (which is also excreted in the urine) in individuals with
• Hyperhomocysteinemia and mixed disulfides (which are also excreted in the urine)
• Cystathionine (which is also excreted in the urine) in individuals with
• Note:
• Hyperhomocysteinemia and mixed disulfides (which are also excreted in the urine)
• Cystathionine (which is also excreted in the urine) in individuals with
• For this disorder a multigene panel that also includes deletion/duplication analysis can be considered if sequence analysis has not identified two pathogenic variants in an individual with strong biochemical evidence for a disorder of intracellular cobalamin metabolism.
• For an introduction to multigene panels click
## Biochemical Testing
The identification of disorders of intracellular cobalamin metabolism relies on the following testing (
Note: Delays in separating serum from plasma after obtaining a blood sample can artificially increase total homocysteine by as much as 10% an hour [
Other findings that can be seen on PAA analysis:
Hyperhomocysteinemia and mixed disulfides (which are also excreted in the urine)
Cystathionine (which is also excreted in the urine) in individuals with
Note:
Metabolite Concentrations in Disorders of Intracellular Cobalamin Metabolism
NR = not reported
Standard values have not been exclusively derived from children or neonates. Some laboratories report urine methylmalonic acid (MMA) concentrations in mg/g/Cr (normal: <3 mg/g/Cr) and serum concentrations in nmol/L (normal: <271 nmol/L). The molecular weight of MMA is 118 g/mol.
Authors' experience with >50 affected individuals
Values refer to
Mild elevation uncommon [
• Note: Delays in separating serum from plasma after obtaining a blood sample can artificially increase total homocysteine by as much as 10% an hour [
• Other findings that can be seen on PAA analysis:
• Hyperhomocysteinemia and mixed disulfides (which are also excreted in the urine)
• Cystathionine (which is also excreted in the urine) in individuals with
• Hyperhomocysteinemia and mixed disulfides (which are also excreted in the urine)
• Cystathionine (which is also excreted in the urine) in individuals with
• Note:
• Hyperhomocysteinemia and mixed disulfides (which are also excreted in the urine)
• Cystathionine (which is also excreted in the urine) in individuals with
## Molecular Genetic Testing
Molecular genetic testing approaches can include a combination of
Individuals with the distinctive laboratory findings of a specific disorder of intracellular cobalamin metabolism described in
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of a disorder of intracellular cobalamin metabolism, molecular genetic testing approaches can include
For this disorder a multigene panel that also includes deletion/duplication analysis can be considered if sequence analysis has not identified two pathogenic variants in an individual with strong biochemical evidence for a disorder of intracellular cobalamin metabolism.
For an introduction to multigene panels click
• For this disorder a multigene panel that also includes deletion/duplication analysis can be considered if sequence analysis has not identified two pathogenic variants in an individual with strong biochemical evidence for a disorder of intracellular cobalamin metabolism.
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by the wide of array of possible nonspecific clinical findings or an individual has atypical phenotypic features of a disorder of intracellular cobalamin metabolism,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Disorders of Intracellular Cobalamin Metabolism
Genes are listed in order of complementation group number.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A rare complex variant of
No data on detection rate of gene-targeted deletion/duplication analysis are available.
One consanguineous individual has been found to have biallelic
A deletion spanning exon 2 was reported by
## Complementation Group Analysis
Complementation analysis is a method used historically to diagnose the specific defects of intracellular cobalamin metabolism using cultured skin fibroblasts [
## Clinical Characteristics
Disorders of intracellular cobalamin metabolism have a variable phenotype (
Clinical Manifestations of Disorders of Intracellular Cobalamin Metabolism
Microcephaly
Congenital heart malformation
Dilated cardiomyopathy
Hydrocephalus
Mild dysmorphic features (long face, high forehead, smooth philtrum, and low-set ears) [
Failure to thrive, poor feeding, and hypotonia in the first weeks of life
An acute metabolic derangement (high anion gap metabolic acidosis, ketonuria, and hyperammonemia)
Hemolytic uremic syndrome (HUS) that may be fatal if treatment with daily hydroxocobalamin (OHCbl) is not initiated promptly [
Untreated infants may have multiorgan involvement, neurologic deterioration, seizures (i.e., infantile spasms), and encephalopathy.
Maculopathy and progressive retinopathy develop in most individuals with infantile
The initial manifestations are "wandering eye movements," ocular fixation difficulties, and nystagmus.
Fundoscopic changes (which can be detected by careful examination as early as the first month of life) are characterized by abnormal macular pigmentation, "bull's-eye" macula, or macular coloboma; the retinal disease evolves over time into pigmentary retinopathy and optic nerve atrophy [
Note: Adolescent and adult (late-onset) presentations of
Neuropsychiatric symptoms (behavioral and personality changes, social withdrawal, visual and auditory hallucinations, delirium, psychosis) [
Progressive cognitive decline (regression, deterioration in school or work performance, impaired dexterity and memory, speech difficulties, dementia, and lethargy) that is frequently described in the absence of other manifestations [
Brain MRI may reveal leukodystrophy ranging from isolated periventricular white matter hyperintensities to diffuse white matter loss [
Subacute combined degeneration of the spinal cord [
Other presenting concerns in adolescents and adults have included renal thromobotic microangiopathy, HUS, pulmonary hypertension, and pulmonary thrombotic events [
Individuals have presented with signs from the prenatal period (IUGR, congenital malformations) to age five months (developmental delay, seizures). The developmental delay has been characterized as severe with significant intellectual disability and is associated with early-onset intractable seizures including infantile spasms. Microcephaly, brain malformations, and dysmorphic features were noted in some individuals. Other clinical features include nonketotic hyperglycinemia [
Some expected metabolite abnormalities were mild enough to be difficult to detect. Abnormal metabolites responded to B
Note:
Methylcobalamin deficiency secondary to methionine synthase reductase deficiency (
Genotype-phenotype correlations observed include the following:
Infantile-presentation (early-onset), severe disease is associated with the
Noninfantile presentation (late onset) is usually associated with
Clear genotype-phenotype correlations have not been described for
The true prevalence of the disorders of intracellular cobalamin metabolism is unknown.
The incidence of
Fewer than 40 cases have been described for
• Microcephaly
• Congenital heart malformation
• Dilated cardiomyopathy
• Hydrocephalus
• Mild dysmorphic features (long face, high forehead, smooth philtrum, and low-set ears) [
• Microcephaly
• Congenital heart malformation
• Dilated cardiomyopathy
• Hydrocephalus
• Mild dysmorphic features (long face, high forehead, smooth philtrum, and low-set ears) [
• Failure to thrive, poor feeding, and hypotonia in the first weeks of life
• An acute metabolic derangement (high anion gap metabolic acidosis, ketonuria, and hyperammonemia)
• Hemolytic uremic syndrome (HUS) that may be fatal if treatment with daily hydroxocobalamin (OHCbl) is not initiated promptly [
• Untreated infants may have multiorgan involvement, neurologic deterioration, seizures (i.e., infantile spasms), and encephalopathy.
• Maculopathy and progressive retinopathy develop in most individuals with infantile
• The initial manifestations are "wandering eye movements," ocular fixation difficulties, and nystagmus.
• Fundoscopic changes (which can be detected by careful examination as early as the first month of life) are characterized by abnormal macular pigmentation, "bull's-eye" macula, or macular coloboma; the retinal disease evolves over time into pigmentary retinopathy and optic nerve atrophy [
• Note: Adolescent and adult (late-onset) presentations of
• Failure to thrive, poor feeding, and hypotonia in the first weeks of life
• An acute metabolic derangement (high anion gap metabolic acidosis, ketonuria, and hyperammonemia)
• Hemolytic uremic syndrome (HUS) that may be fatal if treatment with daily hydroxocobalamin (OHCbl) is not initiated promptly [
• The initial manifestations are "wandering eye movements," ocular fixation difficulties, and nystagmus.
• Fundoscopic changes (which can be detected by careful examination as early as the first month of life) are characterized by abnormal macular pigmentation, "bull's-eye" macula, or macular coloboma; the retinal disease evolves over time into pigmentary retinopathy and optic nerve atrophy [
• Note: Adolescent and adult (late-onset) presentations of
• Neuropsychiatric symptoms (behavioral and personality changes, social withdrawal, visual and auditory hallucinations, delirium, psychosis) [
• Progressive cognitive decline (regression, deterioration in school or work performance, impaired dexterity and memory, speech difficulties, dementia, and lethargy) that is frequently described in the absence of other manifestations [
• Brain MRI may reveal leukodystrophy ranging from isolated periventricular white matter hyperintensities to diffuse white matter loss [
• Subacute combined degeneration of the spinal cord [
• Other presenting concerns in adolescents and adults have included renal thromobotic microangiopathy, HUS, pulmonary hypertension, and pulmonary thrombotic events [
• Neuropsychiatric symptoms (behavioral and personality changes, social withdrawal, visual and auditory hallucinations, delirium, psychosis) [
• Progressive cognitive decline (regression, deterioration in school or work performance, impaired dexterity and memory, speech difficulties, dementia, and lethargy) that is frequently described in the absence of other manifestations [
• Brain MRI may reveal leukodystrophy ranging from isolated periventricular white matter hyperintensities to diffuse white matter loss [
• Subacute combined degeneration of the spinal cord [
• Microcephaly
• Congenital heart malformation
• Dilated cardiomyopathy
• Hydrocephalus
• Mild dysmorphic features (long face, high forehead, smooth philtrum, and low-set ears) [
• Failure to thrive, poor feeding, and hypotonia in the first weeks of life
• An acute metabolic derangement (high anion gap metabolic acidosis, ketonuria, and hyperammonemia)
• Hemolytic uremic syndrome (HUS) that may be fatal if treatment with daily hydroxocobalamin (OHCbl) is not initiated promptly [
• The initial manifestations are "wandering eye movements," ocular fixation difficulties, and nystagmus.
• Fundoscopic changes (which can be detected by careful examination as early as the first month of life) are characterized by abnormal macular pigmentation, "bull's-eye" macula, or macular coloboma; the retinal disease evolves over time into pigmentary retinopathy and optic nerve atrophy [
• Note: Adolescent and adult (late-onset) presentations of
• Neuropsychiatric symptoms (behavioral and personality changes, social withdrawal, visual and auditory hallucinations, delirium, psychosis) [
• Progressive cognitive decline (regression, deterioration in school or work performance, impaired dexterity and memory, speech difficulties, dementia, and lethargy) that is frequently described in the absence of other manifestations [
• Brain MRI may reveal leukodystrophy ranging from isolated periventricular white matter hyperintensities to diffuse white matter loss [
• Subacute combined degeneration of the spinal cord [
• Note:
• Infantile-presentation (early-onset), severe disease is associated with the
• Noninfantile presentation (late onset) is usually associated with
• The incidence of
• Fewer than 40 cases have been described for
## Clinical Description
Disorders of intracellular cobalamin metabolism have a variable phenotype (
Clinical Manifestations of Disorders of Intracellular Cobalamin Metabolism
Microcephaly
Congenital heart malformation
Dilated cardiomyopathy
Hydrocephalus
Mild dysmorphic features (long face, high forehead, smooth philtrum, and low-set ears) [
Failure to thrive, poor feeding, and hypotonia in the first weeks of life
An acute metabolic derangement (high anion gap metabolic acidosis, ketonuria, and hyperammonemia)
Hemolytic uremic syndrome (HUS) that may be fatal if treatment with daily hydroxocobalamin (OHCbl) is not initiated promptly [
Untreated infants may have multiorgan involvement, neurologic deterioration, seizures (i.e., infantile spasms), and encephalopathy.
Maculopathy and progressive retinopathy develop in most individuals with infantile
The initial manifestations are "wandering eye movements," ocular fixation difficulties, and nystagmus.
Fundoscopic changes (which can be detected by careful examination as early as the first month of life) are characterized by abnormal macular pigmentation, "bull's-eye" macula, or macular coloboma; the retinal disease evolves over time into pigmentary retinopathy and optic nerve atrophy [
Note: Adolescent and adult (late-onset) presentations of
Neuropsychiatric symptoms (behavioral and personality changes, social withdrawal, visual and auditory hallucinations, delirium, psychosis) [
Progressive cognitive decline (regression, deterioration in school or work performance, impaired dexterity and memory, speech difficulties, dementia, and lethargy) that is frequently described in the absence of other manifestations [
Brain MRI may reveal leukodystrophy ranging from isolated periventricular white matter hyperintensities to diffuse white matter loss [
Subacute combined degeneration of the spinal cord [
Other presenting concerns in adolescents and adults have included renal thromobotic microangiopathy, HUS, pulmonary hypertension, and pulmonary thrombotic events [
Individuals have presented with signs from the prenatal period (IUGR, congenital malformations) to age five months (developmental delay, seizures). The developmental delay has been characterized as severe with significant intellectual disability and is associated with early-onset intractable seizures including infantile spasms. Microcephaly, brain malformations, and dysmorphic features were noted in some individuals. Other clinical features include nonketotic hyperglycinemia [
Some expected metabolite abnormalities were mild enough to be difficult to detect. Abnormal metabolites responded to B
Note:
Methylcobalamin deficiency secondary to methionine synthase reductase deficiency (
• Microcephaly
• Congenital heart malformation
• Dilated cardiomyopathy
• Hydrocephalus
• Mild dysmorphic features (long face, high forehead, smooth philtrum, and low-set ears) [
• Microcephaly
• Congenital heart malformation
• Dilated cardiomyopathy
• Hydrocephalus
• Mild dysmorphic features (long face, high forehead, smooth philtrum, and low-set ears) [
• Failure to thrive, poor feeding, and hypotonia in the first weeks of life
• An acute metabolic derangement (high anion gap metabolic acidosis, ketonuria, and hyperammonemia)
• Hemolytic uremic syndrome (HUS) that may be fatal if treatment with daily hydroxocobalamin (OHCbl) is not initiated promptly [
• Untreated infants may have multiorgan involvement, neurologic deterioration, seizures (i.e., infantile spasms), and encephalopathy.
• Maculopathy and progressive retinopathy develop in most individuals with infantile
• The initial manifestations are "wandering eye movements," ocular fixation difficulties, and nystagmus.
• Fundoscopic changes (which can be detected by careful examination as early as the first month of life) are characterized by abnormal macular pigmentation, "bull's-eye" macula, or macular coloboma; the retinal disease evolves over time into pigmentary retinopathy and optic nerve atrophy [
• Note: Adolescent and adult (late-onset) presentations of
• Failure to thrive, poor feeding, and hypotonia in the first weeks of life
• An acute metabolic derangement (high anion gap metabolic acidosis, ketonuria, and hyperammonemia)
• Hemolytic uremic syndrome (HUS) that may be fatal if treatment with daily hydroxocobalamin (OHCbl) is not initiated promptly [
• The initial manifestations are "wandering eye movements," ocular fixation difficulties, and nystagmus.
• Fundoscopic changes (which can be detected by careful examination as early as the first month of life) are characterized by abnormal macular pigmentation, "bull's-eye" macula, or macular coloboma; the retinal disease evolves over time into pigmentary retinopathy and optic nerve atrophy [
• Note: Adolescent and adult (late-onset) presentations of
• Neuropsychiatric symptoms (behavioral and personality changes, social withdrawal, visual and auditory hallucinations, delirium, psychosis) [
• Progressive cognitive decline (regression, deterioration in school or work performance, impaired dexterity and memory, speech difficulties, dementia, and lethargy) that is frequently described in the absence of other manifestations [
• Brain MRI may reveal leukodystrophy ranging from isolated periventricular white matter hyperintensities to diffuse white matter loss [
• Subacute combined degeneration of the spinal cord [
• Other presenting concerns in adolescents and adults have included renal thromobotic microangiopathy, HUS, pulmonary hypertension, and pulmonary thrombotic events [
• Neuropsychiatric symptoms (behavioral and personality changes, social withdrawal, visual and auditory hallucinations, delirium, psychosis) [
• Progressive cognitive decline (regression, deterioration in school or work performance, impaired dexterity and memory, speech difficulties, dementia, and lethargy) that is frequently described in the absence of other manifestations [
• Brain MRI may reveal leukodystrophy ranging from isolated periventricular white matter hyperintensities to diffuse white matter loss [
• Subacute combined degeneration of the spinal cord [
• Microcephaly
• Congenital heart malformation
• Dilated cardiomyopathy
• Hydrocephalus
• Mild dysmorphic features (long face, high forehead, smooth philtrum, and low-set ears) [
• Failure to thrive, poor feeding, and hypotonia in the first weeks of life
• An acute metabolic derangement (high anion gap metabolic acidosis, ketonuria, and hyperammonemia)
• Hemolytic uremic syndrome (HUS) that may be fatal if treatment with daily hydroxocobalamin (OHCbl) is not initiated promptly [
• The initial manifestations are "wandering eye movements," ocular fixation difficulties, and nystagmus.
• Fundoscopic changes (which can be detected by careful examination as early as the first month of life) are characterized by abnormal macular pigmentation, "bull's-eye" macula, or macular coloboma; the retinal disease evolves over time into pigmentary retinopathy and optic nerve atrophy [
• Note: Adolescent and adult (late-onset) presentations of
• Neuropsychiatric symptoms (behavioral and personality changes, social withdrawal, visual and auditory hallucinations, delirium, psychosis) [
• Progressive cognitive decline (regression, deterioration in school or work performance, impaired dexterity and memory, speech difficulties, dementia, and lethargy) that is frequently described in the absence of other manifestations [
• Brain MRI may reveal leukodystrophy ranging from isolated periventricular white matter hyperintensities to diffuse white matter loss [
• Subacute combined degeneration of the spinal cord [
• Note:
## Combined Methylmalonic Acidemia and Homocystinuria
Microcephaly
Congenital heart malformation
Dilated cardiomyopathy
Hydrocephalus
Mild dysmorphic features (long face, high forehead, smooth philtrum, and low-set ears) [
Failure to thrive, poor feeding, and hypotonia in the first weeks of life
An acute metabolic derangement (high anion gap metabolic acidosis, ketonuria, and hyperammonemia)
Hemolytic uremic syndrome (HUS) that may be fatal if treatment with daily hydroxocobalamin (OHCbl) is not initiated promptly [
Untreated infants may have multiorgan involvement, neurologic deterioration, seizures (i.e., infantile spasms), and encephalopathy.
Maculopathy and progressive retinopathy develop in most individuals with infantile
The initial manifestations are "wandering eye movements," ocular fixation difficulties, and nystagmus.
Fundoscopic changes (which can be detected by careful examination as early as the first month of life) are characterized by abnormal macular pigmentation, "bull's-eye" macula, or macular coloboma; the retinal disease evolves over time into pigmentary retinopathy and optic nerve atrophy [
Note: Adolescent and adult (late-onset) presentations of
Neuropsychiatric symptoms (behavioral and personality changes, social withdrawal, visual and auditory hallucinations, delirium, psychosis) [
Progressive cognitive decline (regression, deterioration in school or work performance, impaired dexterity and memory, speech difficulties, dementia, and lethargy) that is frequently described in the absence of other manifestations [
Brain MRI may reveal leukodystrophy ranging from isolated periventricular white matter hyperintensities to diffuse white matter loss [
Subacute combined degeneration of the spinal cord [
Other presenting concerns in adolescents and adults have included renal thromobotic microangiopathy, HUS, pulmonary hypertension, and pulmonary thrombotic events [
Individuals have presented with signs from the prenatal period (IUGR, congenital malformations) to age five months (developmental delay, seizures). The developmental delay has been characterized as severe with significant intellectual disability and is associated with early-onset intractable seizures including infantile spasms. Microcephaly, brain malformations, and dysmorphic features were noted in some individuals. Other clinical features include nonketotic hyperglycinemia [
Some expected metabolite abnormalities were mild enough to be difficult to detect. Abnormal metabolites responded to B
Note:
• Microcephaly
• Congenital heart malformation
• Dilated cardiomyopathy
• Hydrocephalus
• Mild dysmorphic features (long face, high forehead, smooth philtrum, and low-set ears) [
• Microcephaly
• Congenital heart malformation
• Dilated cardiomyopathy
• Hydrocephalus
• Mild dysmorphic features (long face, high forehead, smooth philtrum, and low-set ears) [
• Failure to thrive, poor feeding, and hypotonia in the first weeks of life
• An acute metabolic derangement (high anion gap metabolic acidosis, ketonuria, and hyperammonemia)
• Hemolytic uremic syndrome (HUS) that may be fatal if treatment with daily hydroxocobalamin (OHCbl) is not initiated promptly [
• Untreated infants may have multiorgan involvement, neurologic deterioration, seizures (i.e., infantile spasms), and encephalopathy.
• Maculopathy and progressive retinopathy develop in most individuals with infantile
• The initial manifestations are "wandering eye movements," ocular fixation difficulties, and nystagmus.
• Fundoscopic changes (which can be detected by careful examination as early as the first month of life) are characterized by abnormal macular pigmentation, "bull's-eye" macula, or macular coloboma; the retinal disease evolves over time into pigmentary retinopathy and optic nerve atrophy [
• Note: Adolescent and adult (late-onset) presentations of
• Failure to thrive, poor feeding, and hypotonia in the first weeks of life
• An acute metabolic derangement (high anion gap metabolic acidosis, ketonuria, and hyperammonemia)
• Hemolytic uremic syndrome (HUS) that may be fatal if treatment with daily hydroxocobalamin (OHCbl) is not initiated promptly [
• The initial manifestations are "wandering eye movements," ocular fixation difficulties, and nystagmus.
• Fundoscopic changes (which can be detected by careful examination as early as the first month of life) are characterized by abnormal macular pigmentation, "bull's-eye" macula, or macular coloboma; the retinal disease evolves over time into pigmentary retinopathy and optic nerve atrophy [
• Note: Adolescent and adult (late-onset) presentations of
• Neuropsychiatric symptoms (behavioral and personality changes, social withdrawal, visual and auditory hallucinations, delirium, psychosis) [
• Progressive cognitive decline (regression, deterioration in school or work performance, impaired dexterity and memory, speech difficulties, dementia, and lethargy) that is frequently described in the absence of other manifestations [
• Brain MRI may reveal leukodystrophy ranging from isolated periventricular white matter hyperintensities to diffuse white matter loss [
• Subacute combined degeneration of the spinal cord [
• Other presenting concerns in adolescents and adults have included renal thromobotic microangiopathy, HUS, pulmonary hypertension, and pulmonary thrombotic events [
• Neuropsychiatric symptoms (behavioral and personality changes, social withdrawal, visual and auditory hallucinations, delirium, psychosis) [
• Progressive cognitive decline (regression, deterioration in school or work performance, impaired dexterity and memory, speech difficulties, dementia, and lethargy) that is frequently described in the absence of other manifestations [
• Brain MRI may reveal leukodystrophy ranging from isolated periventricular white matter hyperintensities to diffuse white matter loss [
• Subacute combined degeneration of the spinal cord [
• Microcephaly
• Congenital heart malformation
• Dilated cardiomyopathy
• Hydrocephalus
• Mild dysmorphic features (long face, high forehead, smooth philtrum, and low-set ears) [
• Failure to thrive, poor feeding, and hypotonia in the first weeks of life
• An acute metabolic derangement (high anion gap metabolic acidosis, ketonuria, and hyperammonemia)
• Hemolytic uremic syndrome (HUS) that may be fatal if treatment with daily hydroxocobalamin (OHCbl) is not initiated promptly [
• The initial manifestations are "wandering eye movements," ocular fixation difficulties, and nystagmus.
• Fundoscopic changes (which can be detected by careful examination as early as the first month of life) are characterized by abnormal macular pigmentation, "bull's-eye" macula, or macular coloboma; the retinal disease evolves over time into pigmentary retinopathy and optic nerve atrophy [
• Note: Adolescent and adult (late-onset) presentations of
• Neuropsychiatric symptoms (behavioral and personality changes, social withdrawal, visual and auditory hallucinations, delirium, psychosis) [
• Progressive cognitive decline (regression, deterioration in school or work performance, impaired dexterity and memory, speech difficulties, dementia, and lethargy) that is frequently described in the absence of other manifestations [
• Brain MRI may reveal leukodystrophy ranging from isolated periventricular white matter hyperintensities to diffuse white matter loss [
• Subacute combined degeneration of the spinal cord [
• Note:
## Isolated Homocystinuria (
Methylcobalamin deficiency secondary to methionine synthase reductase deficiency (
## Genotype-Phenotype Correlations
Genotype-phenotype correlations observed include the following:
Infantile-presentation (early-onset), severe disease is associated with the
Noninfantile presentation (late onset) is usually associated with
Clear genotype-phenotype correlations have not been described for
• Infantile-presentation (early-onset), severe disease is associated with the
• Noninfantile presentation (late onset) is usually associated with
## Prevalence
The true prevalence of the disorders of intracellular cobalamin metabolism is unknown.
The incidence of
Fewer than 40 cases have been described for
• The incidence of
• Fewer than 40 cases have been described for
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The following disorders may cause clinical manifestations and laboratory abnormalities similar to those seen in disorders of intracellular cobalamin metabolism.
B
Intramuscular replacement therapy to normalize vitamin B
Disorders associated with isolated methylmalonic acidemia include methylmalonic acidemia due to pathogenic variants of methylmalonyl-CoA mutase (
For a more detailed description of other entities with isolated methylmalonic acidemia, see
• B
• Intramuscular replacement therapy to normalize vitamin B
• Disorders associated with isolated methylmalonic acidemia include methylmalonic acidemia due to pathogenic variants of methylmalonyl-CoA mutase (
• For a more detailed description of other entities with isolated methylmalonic acidemia, see
## Management
To establish the extent of disease and needs of an individual diagnosed with a disorder of intracellular cobalamin metabolism, the following evaluations are recommended.
In an unstable individual:
Serial metabolic evaluations of blood gases, electrolytes, glucose, ammonia, liver function, total and direct bilirubin, renal function, lactate dehydrogenase, plasma amino acids (methionine), plasma methylmalonic acid (MMA), and total plasma homocysteine (tHcy) to guide acute management until the individual stabilizes
Complete blood count (CBC) with differential to evaluate for megaloblastic anemia or cytopenias
Peripheral blood smear to evaluate for the presence of schistocytes, in the presence of other manifestations of hemolytic uremic syndrome (HUS)
Once the individual becomes stable:
Clinical assessment of growth parameters, head circumference, ability to feed, developmental status, and neurologic status
Laboratory assessment of nutritional status (electrolytes, albumin, prealbumin, plasma amino acids [with careful attention to methionine levels], vitamin levels [including thiamine and 25-hydroxyvitamin D], and trace minerals) and renal function; complete blood count to monitor for cytopenias
Echocardiogram to screen for cardiac defects and cardiomyopathy [
EEG and brain MRI in symptomatic individuals
Ophthalmologic examination
Consultation with a clinical geneticist and/or genetic counselor
A set of guidelines for the diagnosis and management of
Early treatment with hydroxocobalamin injections improves survival and biochemical, hematologic, and microangiopathic symptoms in individuals with
Institution of therapy during acute illness results in rapid improvement of clinical, biochemical, and hematologic manifestations in individuals with early- and late-onset
Goals of treatment are to reduce toxic metabolites and avoid low methionine levels.
Parenteral hydroxocobalamin (OHCbl) is the mainstay of therapy and should be instituted
Cyanocobalamin should not be used as it will not be effective in individuals with
Avoid treating individuals with a low-protein diet and medical foods designed for the treatment of individuals with isolated MMA because they contain no methionine, which can further reduce methionine level.
Those with elevated total plasma homocysteine (tHcy) should also receive betaine (250 mg/kg/day) and folate or folinic acid. Betaine has a short effective half-life and should be given in divided doses (optimally divided into 3 or 4 doses per day). It can also be titrated to response while monitoring tHcy and plasma methionine.
Although less common in the disorders of intracellular cobalamin metabolism than in isolated
Treatment includes volume replacement with isotonic solutions containing high (10%-12.5%) glucose to reverse catabolism, correction of metabolic acidosis with sodium bicarbonate, and prompt reintroduction of feedings – preferably enterally, but parenterally if enteral route cannot be established. Parenteral hydroxocobalamin should be given immediately in the setting of an acute decompensation.
Thromboembolic complications as a cause of mortality in
The goals of long-term management include improving the metabolic derangement by lowering plasma tHcy and methylmalonic acid (MMA) concentrations and maintaining plasma methionine concentrations within the normal range. These are accomplished by the following.
Weight-appropriate adjustment of OHCbl to 0.3 mg/kg/day to maintain the dosing in infancy is recommended and can be attained by the ability to concentrate OHCbl up to 30 mg/mL [
Low-protein diets and medical foods designed for isolated methylmalonic acidemia are
The use of low-protein diets correlated with lower height-for-age z scores [
Medical foods designed for isolated methylmalonic acidemia do not contain methionine and also have an increased amount of leucine, which may compete with methionine for uptake to the brain and potentially exacerbate cerebral methionine deficiency.
Gastrostomy tube placement may be required in the presence of feeding difficulties and failure to thrive.
The following have not been fully validated:
Treatment of infantile spasms, seizures, congenital heart malformations, and hydrocephalus is done in a routine manner.
Prenatal therapy of an affected fetus by administration of intramuscular OHCbl to the mother may improve neurocognitive outcome; however, the ophthalmologic manifestations are often still present [
The dose and frequency of OHCbl administration to pregnant mothers has not been established.
Favorable outcomes of prenatal treatment have been reported by using dosages between 1 and 10 mg per day, 2-3 times a week, starting as early as 15 weeks' gestational age [
Early institution of injectable hydroxocobalamin improves survival and may reduce but not completely prevent primary manifestations.
To prevent metabolic decompensations, affected individuals should be advised to avoid situations that result in catabolism, such as prolonged fasting and dehydration, and always remain on a weight-appropriate dose of hydroxocobalamin. Of note, during an intercurrent illness individuals may be treated with glucose-containing IV fluid.
Flu prevention (i.e., immunization) should be a routine part of health maintenance.
The following evaluations are performed at different intervals depending on age and disease severity:
During the first year of life, infants may need to be evaluated once or twice a month by a metabolic specialist.
Toddlers and school-age children should be evaluated at least twice a year to adjust medication dosing (hydroxocobalamin, betaine) during growth and to evaluate nutritional status.
Teens and adults may be seen on a yearly basis.
Clinical evaluation should assess the following:
Growth including weight, linear growth, and head circumference
Nutritional status
Feeding ability
Developmental and neurocognitive progress, as age-appropriate
Laboratory evaluation should include the following:
Metabolic studies including urine organic acids, serum methylmalonic acid analysis, plasma amino acids (methionine), plasma tHcy concentration
CBC to monitor for cytopenias
Nutritional studies, if indicated: electrolytes, albumin, prealbumin, plasma amino acids, vitamin levels (including thiamine and 25-hydroxyvitamin D), essential fatty acids, and trace minerals
Routine evaluations should include the following:
Ophthalmologic evaluation for retinal and optic nerve changes in those with
Neurologic evaluations for early signs of developmental delays, behavioral disturbances, seizures, and myelopathy
Brain MRI and/or EEG as clinically indicated
Echocardiogram
Potentially exacerbating circumstances:
Prolonged fasting (longer than overnight without dextrose-containing intravenous fluids)
Dietary protein intake below the recommended dietary allowance (RDA) for age
Dietary protein intake greater than that prescribed by a metabolic specialist especially in individuals with
Medical foods. Medical foods given to infants with isolated methylmalonic acidemia do not contain methionine and should be avoided as the decreased methionine intake may worsen hypomethioninemia and long-term use may contribute to poor head and linear growth [
Nitrous oxide, an anesthetic that is potentially toxic as it depletes the body stores of vitamin B
If the pathogenic variant(s) in the family are known, at-risk sibs may be tested prenatally to allow initiation of treatment in utero or as soon as possible after birth.
If the newborn sib of an affected individual has not undergone prenatal testing, molecular genetic testing can be performed in the first week of life if the pathogenic variant(s) in the family are known. If the pathogneic variant(s) are not known, evaluation of urine organic acids and plasma amino acids, measurement of total plasma homocysteine, serum methylmalonic acid analysis, and acylcarnitine profile analysis can be used for the purpose of early diagnosis and treatment.
See
A good pregnancy outcome was reported in two women with
Search
• Serial metabolic evaluations of blood gases, electrolytes, glucose, ammonia, liver function, total and direct bilirubin, renal function, lactate dehydrogenase, plasma amino acids (methionine), plasma methylmalonic acid (MMA), and total plasma homocysteine (tHcy) to guide acute management until the individual stabilizes
• Complete blood count (CBC) with differential to evaluate for megaloblastic anemia or cytopenias
• Peripheral blood smear to evaluate for the presence of schistocytes, in the presence of other manifestations of hemolytic uremic syndrome (HUS)
• Clinical assessment of growth parameters, head circumference, ability to feed, developmental status, and neurologic status
• Laboratory assessment of nutritional status (electrolytes, albumin, prealbumin, plasma amino acids [with careful attention to methionine levels], vitamin levels [including thiamine and 25-hydroxyvitamin D], and trace minerals) and renal function; complete blood count to monitor for cytopenias
• Echocardiogram to screen for cardiac defects and cardiomyopathy [
• EEG and brain MRI in symptomatic individuals
• Ophthalmologic examination
• Consultation with a clinical geneticist and/or genetic counselor
• Parenteral hydroxocobalamin (OHCbl) is the mainstay of therapy and should be instituted
• Cyanocobalamin should not be used as it will not be effective in individuals with
• Avoid treating individuals with a low-protein diet and medical foods designed for the treatment of individuals with isolated MMA because they contain no methionine, which can further reduce methionine level.
• Those with elevated total plasma homocysteine (tHcy) should also receive betaine (250 mg/kg/day) and folate or folinic acid. Betaine has a short effective half-life and should be given in divided doses (optimally divided into 3 or 4 doses per day). It can also be titrated to response while monitoring tHcy and plasma methionine.
• Low-protein diets and medical foods designed for isolated methylmalonic acidemia are
• The use of low-protein diets correlated with lower height-for-age z scores [
• Medical foods designed for isolated methylmalonic acidemia do not contain methionine and also have an increased amount of leucine, which may compete with methionine for uptake to the brain and potentially exacerbate cerebral methionine deficiency.
• The use of low-protein diets correlated with lower height-for-age z scores [
• Medical foods designed for isolated methylmalonic acidemia do not contain methionine and also have an increased amount of leucine, which may compete with methionine for uptake to the brain and potentially exacerbate cerebral methionine deficiency.
• Gastrostomy tube placement may be required in the presence of feeding difficulties and failure to thrive.
• The use of low-protein diets correlated with lower height-for-age z scores [
• Medical foods designed for isolated methylmalonic acidemia do not contain methionine and also have an increased amount of leucine, which may compete with methionine for uptake to the brain and potentially exacerbate cerebral methionine deficiency.
• The dose and frequency of OHCbl administration to pregnant mothers has not been established.
• Favorable outcomes of prenatal treatment have been reported by using dosages between 1 and 10 mg per day, 2-3 times a week, starting as early as 15 weeks' gestational age [
• During the first year of life, infants may need to be evaluated once or twice a month by a metabolic specialist.
• Toddlers and school-age children should be evaluated at least twice a year to adjust medication dosing (hydroxocobalamin, betaine) during growth and to evaluate nutritional status.
• Teens and adults may be seen on a yearly basis.
• Growth including weight, linear growth, and head circumference
• Nutritional status
• Feeding ability
• Developmental and neurocognitive progress, as age-appropriate
• Metabolic studies including urine organic acids, serum methylmalonic acid analysis, plasma amino acids (methionine), plasma tHcy concentration
• CBC to monitor for cytopenias
• Nutritional studies, if indicated: electrolytes, albumin, prealbumin, plasma amino acids, vitamin levels (including thiamine and 25-hydroxyvitamin D), essential fatty acids, and trace minerals
• Ophthalmologic evaluation for retinal and optic nerve changes in those with
• Neurologic evaluations for early signs of developmental delays, behavioral disturbances, seizures, and myelopathy
• Brain MRI and/or EEG as clinically indicated
• Echocardiogram
• Prolonged fasting (longer than overnight without dextrose-containing intravenous fluids)
• Dietary protein intake below the recommended dietary allowance (RDA) for age
• Dietary protein intake greater than that prescribed by a metabolic specialist especially in individuals with
• Medical foods. Medical foods given to infants with isolated methylmalonic acidemia do not contain methionine and should be avoided as the decreased methionine intake may worsen hypomethioninemia and long-term use may contribute to poor head and linear growth [
• Nitrous oxide, an anesthetic that is potentially toxic as it depletes the body stores of vitamin B
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with a disorder of intracellular cobalamin metabolism, the following evaluations are recommended.
In an unstable individual:
Serial metabolic evaluations of blood gases, electrolytes, glucose, ammonia, liver function, total and direct bilirubin, renal function, lactate dehydrogenase, plasma amino acids (methionine), plasma methylmalonic acid (MMA), and total plasma homocysteine (tHcy) to guide acute management until the individual stabilizes
Complete blood count (CBC) with differential to evaluate for megaloblastic anemia or cytopenias
Peripheral blood smear to evaluate for the presence of schistocytes, in the presence of other manifestations of hemolytic uremic syndrome (HUS)
Once the individual becomes stable:
Clinical assessment of growth parameters, head circumference, ability to feed, developmental status, and neurologic status
Laboratory assessment of nutritional status (electrolytes, albumin, prealbumin, plasma amino acids [with careful attention to methionine levels], vitamin levels [including thiamine and 25-hydroxyvitamin D], and trace minerals) and renal function; complete blood count to monitor for cytopenias
Echocardiogram to screen for cardiac defects and cardiomyopathy [
EEG and brain MRI in symptomatic individuals
Ophthalmologic examination
Consultation with a clinical geneticist and/or genetic counselor
• Serial metabolic evaluations of blood gases, electrolytes, glucose, ammonia, liver function, total and direct bilirubin, renal function, lactate dehydrogenase, plasma amino acids (methionine), plasma methylmalonic acid (MMA), and total plasma homocysteine (tHcy) to guide acute management until the individual stabilizes
• Complete blood count (CBC) with differential to evaluate for megaloblastic anemia or cytopenias
• Peripheral blood smear to evaluate for the presence of schistocytes, in the presence of other manifestations of hemolytic uremic syndrome (HUS)
• Clinical assessment of growth parameters, head circumference, ability to feed, developmental status, and neurologic status
• Laboratory assessment of nutritional status (electrolytes, albumin, prealbumin, plasma amino acids [with careful attention to methionine levels], vitamin levels [including thiamine and 25-hydroxyvitamin D], and trace minerals) and renal function; complete blood count to monitor for cytopenias
• Echocardiogram to screen for cardiac defects and cardiomyopathy [
• EEG and brain MRI in symptomatic individuals
• Ophthalmologic examination
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
A set of guidelines for the diagnosis and management of
Early treatment with hydroxocobalamin injections improves survival and biochemical, hematologic, and microangiopathic symptoms in individuals with
Institution of therapy during acute illness results in rapid improvement of clinical, biochemical, and hematologic manifestations in individuals with early- and late-onset
Goals of treatment are to reduce toxic metabolites and avoid low methionine levels.
Parenteral hydroxocobalamin (OHCbl) is the mainstay of therapy and should be instituted
Cyanocobalamin should not be used as it will not be effective in individuals with
Avoid treating individuals with a low-protein diet and medical foods designed for the treatment of individuals with isolated MMA because they contain no methionine, which can further reduce methionine level.
Those with elevated total plasma homocysteine (tHcy) should also receive betaine (250 mg/kg/day) and folate or folinic acid. Betaine has a short effective half-life and should be given in divided doses (optimally divided into 3 or 4 doses per day). It can also be titrated to response while monitoring tHcy and plasma methionine.
Although less common in the disorders of intracellular cobalamin metabolism than in isolated
Treatment includes volume replacement with isotonic solutions containing high (10%-12.5%) glucose to reverse catabolism, correction of metabolic acidosis with sodium bicarbonate, and prompt reintroduction of feedings – preferably enterally, but parenterally if enteral route cannot be established. Parenteral hydroxocobalamin should be given immediately in the setting of an acute decompensation.
Thromboembolic complications as a cause of mortality in
The goals of long-term management include improving the metabolic derangement by lowering plasma tHcy and methylmalonic acid (MMA) concentrations and maintaining plasma methionine concentrations within the normal range. These are accomplished by the following.
Weight-appropriate adjustment of OHCbl to 0.3 mg/kg/day to maintain the dosing in infancy is recommended and can be attained by the ability to concentrate OHCbl up to 30 mg/mL [
Low-protein diets and medical foods designed for isolated methylmalonic acidemia are
The use of low-protein diets correlated with lower height-for-age z scores [
Medical foods designed for isolated methylmalonic acidemia do not contain methionine and also have an increased amount of leucine, which may compete with methionine for uptake to the brain and potentially exacerbate cerebral methionine deficiency.
Gastrostomy tube placement may be required in the presence of feeding difficulties and failure to thrive.
The following have not been fully validated:
Treatment of infantile spasms, seizures, congenital heart malformations, and hydrocephalus is done in a routine manner.
Prenatal therapy of an affected fetus by administration of intramuscular OHCbl to the mother may improve neurocognitive outcome; however, the ophthalmologic manifestations are often still present [
The dose and frequency of OHCbl administration to pregnant mothers has not been established.
Favorable outcomes of prenatal treatment have been reported by using dosages between 1 and 10 mg per day, 2-3 times a week, starting as early as 15 weeks' gestational age [
• Parenteral hydroxocobalamin (OHCbl) is the mainstay of therapy and should be instituted
• Cyanocobalamin should not be used as it will not be effective in individuals with
• Avoid treating individuals with a low-protein diet and medical foods designed for the treatment of individuals with isolated MMA because they contain no methionine, which can further reduce methionine level.
• Those with elevated total plasma homocysteine (tHcy) should also receive betaine (250 mg/kg/day) and folate or folinic acid. Betaine has a short effective half-life and should be given in divided doses (optimally divided into 3 or 4 doses per day). It can also be titrated to response while monitoring tHcy and plasma methionine.
• Low-protein diets and medical foods designed for isolated methylmalonic acidemia are
• The use of low-protein diets correlated with lower height-for-age z scores [
• Medical foods designed for isolated methylmalonic acidemia do not contain methionine and also have an increased amount of leucine, which may compete with methionine for uptake to the brain and potentially exacerbate cerebral methionine deficiency.
• The use of low-protein diets correlated with lower height-for-age z scores [
• Medical foods designed for isolated methylmalonic acidemia do not contain methionine and also have an increased amount of leucine, which may compete with methionine for uptake to the brain and potentially exacerbate cerebral methionine deficiency.
• Gastrostomy tube placement may be required in the presence of feeding difficulties and failure to thrive.
• The use of low-protein diets correlated with lower height-for-age z scores [
• Medical foods designed for isolated methylmalonic acidemia do not contain methionine and also have an increased amount of leucine, which may compete with methionine for uptake to the brain and potentially exacerbate cerebral methionine deficiency.
• The dose and frequency of OHCbl administration to pregnant mothers has not been established.
• Favorable outcomes of prenatal treatment have been reported by using dosages between 1 and 10 mg per day, 2-3 times a week, starting as early as 15 weeks' gestational age [
## At the Time of Diagnosis
Goals of treatment are to reduce toxic metabolites and avoid low methionine levels.
Parenteral hydroxocobalamin (OHCbl) is the mainstay of therapy and should be instituted
Cyanocobalamin should not be used as it will not be effective in individuals with
Avoid treating individuals with a low-protein diet and medical foods designed for the treatment of individuals with isolated MMA because they contain no methionine, which can further reduce methionine level.
Those with elevated total plasma homocysteine (tHcy) should also receive betaine (250 mg/kg/day) and folate or folinic acid. Betaine has a short effective half-life and should be given in divided doses (optimally divided into 3 or 4 doses per day). It can also be titrated to response while monitoring tHcy and plasma methionine.
• Parenteral hydroxocobalamin (OHCbl) is the mainstay of therapy and should be instituted
• Cyanocobalamin should not be used as it will not be effective in individuals with
• Avoid treating individuals with a low-protein diet and medical foods designed for the treatment of individuals with isolated MMA because they contain no methionine, which can further reduce methionine level.
• Those with elevated total plasma homocysteine (tHcy) should also receive betaine (250 mg/kg/day) and folate or folinic acid. Betaine has a short effective half-life and should be given in divided doses (optimally divided into 3 or 4 doses per day). It can also be titrated to response while monitoring tHcy and plasma methionine.
## Acute Metabolic Decompensation
Although less common in the disorders of intracellular cobalamin metabolism than in isolated
Treatment includes volume replacement with isotonic solutions containing high (10%-12.5%) glucose to reverse catabolism, correction of metabolic acidosis with sodium bicarbonate, and prompt reintroduction of feedings – preferably enterally, but parenterally if enteral route cannot be established. Parenteral hydroxocobalamin should be given immediately in the setting of an acute decompensation.
## Thromboembolic Complications
Thromboembolic complications as a cause of mortality in
## Long-Term Management
The goals of long-term management include improving the metabolic derangement by lowering plasma tHcy and methylmalonic acid (MMA) concentrations and maintaining plasma methionine concentrations within the normal range. These are accomplished by the following.
Weight-appropriate adjustment of OHCbl to 0.3 mg/kg/day to maintain the dosing in infancy is recommended and can be attained by the ability to concentrate OHCbl up to 30 mg/mL [
Low-protein diets and medical foods designed for isolated methylmalonic acidemia are
The use of low-protein diets correlated with lower height-for-age z scores [
Medical foods designed for isolated methylmalonic acidemia do not contain methionine and also have an increased amount of leucine, which may compete with methionine for uptake to the brain and potentially exacerbate cerebral methionine deficiency.
Gastrostomy tube placement may be required in the presence of feeding difficulties and failure to thrive.
• Low-protein diets and medical foods designed for isolated methylmalonic acidemia are
• The use of low-protein diets correlated with lower height-for-age z scores [
• Medical foods designed for isolated methylmalonic acidemia do not contain methionine and also have an increased amount of leucine, which may compete with methionine for uptake to the brain and potentially exacerbate cerebral methionine deficiency.
• The use of low-protein diets correlated with lower height-for-age z scores [
• Medical foods designed for isolated methylmalonic acidemia do not contain methionine and also have an increased amount of leucine, which may compete with methionine for uptake to the brain and potentially exacerbate cerebral methionine deficiency.
• Gastrostomy tube placement may be required in the presence of feeding difficulties and failure to thrive.
• The use of low-protein diets correlated with lower height-for-age z scores [
• Medical foods designed for isolated methylmalonic acidemia do not contain methionine and also have an increased amount of leucine, which may compete with methionine for uptake to the brain and potentially exacerbate cerebral methionine deficiency.
## Other Therapeutic Considerations
The following have not been fully validated:
Treatment of infantile spasms, seizures, congenital heart malformations, and hydrocephalus is done in a routine manner.
## Prenatal Therapy
Prenatal therapy of an affected fetus by administration of intramuscular OHCbl to the mother may improve neurocognitive outcome; however, the ophthalmologic manifestations are often still present [
The dose and frequency of OHCbl administration to pregnant mothers has not been established.
Favorable outcomes of prenatal treatment have been reported by using dosages between 1 and 10 mg per day, 2-3 times a week, starting as early as 15 weeks' gestational age [
• The dose and frequency of OHCbl administration to pregnant mothers has not been established.
• Favorable outcomes of prenatal treatment have been reported by using dosages between 1 and 10 mg per day, 2-3 times a week, starting as early as 15 weeks' gestational age [
## Prevention of Primary Manifestations
Early institution of injectable hydroxocobalamin improves survival and may reduce but not completely prevent primary manifestations.
To prevent metabolic decompensations, affected individuals should be advised to avoid situations that result in catabolism, such as prolonged fasting and dehydration, and always remain on a weight-appropriate dose of hydroxocobalamin. Of note, during an intercurrent illness individuals may be treated with glucose-containing IV fluid.
Flu prevention (i.e., immunization) should be a routine part of health maintenance.
## Surveillance
The following evaluations are performed at different intervals depending on age and disease severity:
During the first year of life, infants may need to be evaluated once or twice a month by a metabolic specialist.
Toddlers and school-age children should be evaluated at least twice a year to adjust medication dosing (hydroxocobalamin, betaine) during growth and to evaluate nutritional status.
Teens and adults may be seen on a yearly basis.
Clinical evaluation should assess the following:
Growth including weight, linear growth, and head circumference
Nutritional status
Feeding ability
Developmental and neurocognitive progress, as age-appropriate
Laboratory evaluation should include the following:
Metabolic studies including urine organic acids, serum methylmalonic acid analysis, plasma amino acids (methionine), plasma tHcy concentration
CBC to monitor for cytopenias
Nutritional studies, if indicated: electrolytes, albumin, prealbumin, plasma amino acids, vitamin levels (including thiamine and 25-hydroxyvitamin D), essential fatty acids, and trace minerals
Routine evaluations should include the following:
Ophthalmologic evaluation for retinal and optic nerve changes in those with
Neurologic evaluations for early signs of developmental delays, behavioral disturbances, seizures, and myelopathy
Brain MRI and/or EEG as clinically indicated
Echocardiogram
• During the first year of life, infants may need to be evaluated once or twice a month by a metabolic specialist.
• Toddlers and school-age children should be evaluated at least twice a year to adjust medication dosing (hydroxocobalamin, betaine) during growth and to evaluate nutritional status.
• Teens and adults may be seen on a yearly basis.
• Growth including weight, linear growth, and head circumference
• Nutritional status
• Feeding ability
• Developmental and neurocognitive progress, as age-appropriate
• Metabolic studies including urine organic acids, serum methylmalonic acid analysis, plasma amino acids (methionine), plasma tHcy concentration
• CBC to monitor for cytopenias
• Nutritional studies, if indicated: electrolytes, albumin, prealbumin, plasma amino acids, vitamin levels (including thiamine and 25-hydroxyvitamin D), essential fatty acids, and trace minerals
• Ophthalmologic evaluation for retinal and optic nerve changes in those with
• Neurologic evaluations for early signs of developmental delays, behavioral disturbances, seizures, and myelopathy
• Brain MRI and/or EEG as clinically indicated
• Echocardiogram
## Agents/Circumstances to Avoid
Potentially exacerbating circumstances:
Prolonged fasting (longer than overnight without dextrose-containing intravenous fluids)
Dietary protein intake below the recommended dietary allowance (RDA) for age
Dietary protein intake greater than that prescribed by a metabolic specialist especially in individuals with
Medical foods. Medical foods given to infants with isolated methylmalonic acidemia do not contain methionine and should be avoided as the decreased methionine intake may worsen hypomethioninemia and long-term use may contribute to poor head and linear growth [
Nitrous oxide, an anesthetic that is potentially toxic as it depletes the body stores of vitamin B
• Prolonged fasting (longer than overnight without dextrose-containing intravenous fluids)
• Dietary protein intake below the recommended dietary allowance (RDA) for age
• Dietary protein intake greater than that prescribed by a metabolic specialist especially in individuals with
• Medical foods. Medical foods given to infants with isolated methylmalonic acidemia do not contain methionine and should be avoided as the decreased methionine intake may worsen hypomethioninemia and long-term use may contribute to poor head and linear growth [
• Nitrous oxide, an anesthetic that is potentially toxic as it depletes the body stores of vitamin B
## Evaluation of Relatives at Risk
If the pathogenic variant(s) in the family are known, at-risk sibs may be tested prenatally to allow initiation of treatment in utero or as soon as possible after birth.
If the newborn sib of an affected individual has not undergone prenatal testing, molecular genetic testing can be performed in the first week of life if the pathogenic variant(s) in the family are known. If the pathogneic variant(s) are not known, evaluation of urine organic acids and plasma amino acids, measurement of total plasma homocysteine, serum methylmalonic acid analysis, and acylcarnitine profile analysis can be used for the purpose of early diagnosis and treatment.
See
## Pregnancy Management
A good pregnancy outcome was reported in two women with
## Therapies Under Investigation
Search
## Genetic Counseling
Disorders of intracellular cobalamin metabolism caused by pathogenic variants in
The disorder of intracellular cobalamin metabolism caused by pathogenic variants in
A single report of a deceased child with a paternally inherited
The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant).
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
Biochemical testing is not reliable for carrier detection.
The father of an affected male will not have the disorder, nor will he be hemizyous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a
If the mother of the proband has an
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
All of their daughters, who will be carriers (heterozygotes) and will usually not be affected; and
None of their sons.
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
Biochemical testing is not reliable for carrier testing.
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Complementation analysis of cultured amniocytes [
Measurement of MMA and tHcy concentrations in amniotic fluid using mass spectrometric techniques [
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The father of an affected male will not have the disorder, nor will he be hemizyous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a
• If the mother of the proband has an
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• All of their daughters, who will be carriers (heterozygotes) and will usually not be affected; and
• None of their sons.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Complementation analysis of cultured amniocytes [
• Measurement of MMA and tHcy concentrations in amniotic fluid using mass spectrometric techniques [
## Mode of Inheritance
Disorders of intracellular cobalamin metabolism caused by pathogenic variants in
The disorder of intracellular cobalamin metabolism caused by pathogenic variants in
A single report of a deceased child with a paternally inherited
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant).
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
Biochemical testing is not reliable for carrier detection.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
Biochemical testing is not reliable for carrier detection.
## X-Linked Inheritance – Risk to Family Members
The father of an affected male will not have the disorder, nor will he be hemizyous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a
If the mother of the proband has an
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
All of their daughters, who will be carriers (heterozygotes) and will usually not be affected; and
None of their sons.
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
Biochemical testing is not reliable for carrier testing.
• The father of an affected male will not have the disorder, nor will he be hemizyous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a
• If the mother of the proband has an
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• All of their daughters, who will be carriers (heterozygotes) and will usually not be affected; and
• None of their sons.
## Heterozygote Detection
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
Biochemical testing is not reliable for carrier testing.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Complementation analysis of cultured amniocytes [
Measurement of MMA and tHcy concentrations in amniotic fluid using mass spectrometric techniques [
• Complementation analysis of cultured amniocytes [
• Measurement of MMA and tHcy concentrations in amniotic fluid using mass spectrometric techniques [
## Resources
623 Creek Lane
Flourtown PA 19031
Health Resources & Services Administration
•
• 623 Creek Lane
• Flourtown PA 19031
•
•
• Health Resources & Services Administration
•
•
•
•
•
## Molecular Genetics
Disorders of Intracellular Cobalamin Metabolism: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Disorders of Intracellular Cobalamin Metabolism (
See
Other
Variants listed in
Variants listed in the table have been provided by the authors.
Variants listed in the table have been provided by the authors.
Variants listed in the table have been provided by the authors.
See
Accounts for approximately 30%-50% of disease alleles in individuals of European ancestry [
Common in people of Cajun and French Canadian ancestry [
Common in people of Indian and Middle Eastern ancestry [
Associated with milder disease, and may be more common in individuals of Hispanic descent [
Common in people of Chinese ancestry [
Recently, three individuals who are double heterozygous for pathogenic variants in
Truncating variants in exons 3 and 4, encoding the N-terminus of the protein, cause AdoCbl deficiency (
Missense variants in exons 6 and 8, encoding the C-terminus, cause MeCbl deficiency (
Truncating variants in exons 5, 7, and 8 and intron 7 cause combined AdoCbl and MeCbl deficiency [
A subset of severe pathogenic variants (including frameshifting deletions and nonsense variants) [
Variants listed in the table have been provided by the authors.
The 38-kd C-terminal domain binds AdoMet.
A domain comprising amino acids 650 to 896 includes the binding domain for the required cofactor methylcobalamin.
The 70-kd N-terminal domain binds homocysteine and methyltetrahydrofolate.
The latter two activities may be on separate domains within this region [
The most common disease-causing variant, accounting for 25% of alleles, is a deep intronic variant in intron 6 (c.903+469T>C) that activates a splice enhancer site in a pseudoexon resulting in its inclusion [
The c.1361C>T variant is common in persons of Iberian ancestry. Reports suggest a milder phenotype with no neurologic involvement [
Other variants have been described [
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Variants listed in the table have been provided by the authors.
Variants listed in the table have been provided by the authors.
• Truncating variants in exons 3 and 4, encoding the N-terminus of the protein, cause AdoCbl deficiency (
• Missense variants in exons 6 and 8, encoding the C-terminus, cause MeCbl deficiency (
• Truncating variants in exons 5, 7, and 8 and intron 7 cause combined AdoCbl and MeCbl deficiency [
• The 38-kd C-terminal domain binds AdoMet.
• A domain comprising amino acids 650 to 896 includes the binding domain for the required cofactor methylcobalamin.
• The 70-kd N-terminal domain binds homocysteine and methyltetrahydrofolate.
• The most common disease-causing variant, accounting for 25% of alleles, is a deep intronic variant in intron 6 (c.903+469T>C) that activates a splice enhancer site in a pseudoexon resulting in its inclusion [
• The c.1361C>T variant is common in persons of Iberian ancestry. Reports suggest a milder phenotype with no neurologic involvement [
##
##
Other
Variants listed in
Variants listed in the table have been provided by the authors.
##
Variants listed in the table have been provided by the authors.
##
Variants listed in the table have been provided by the authors.
See
Accounts for approximately 30%-50% of disease alleles in individuals of European ancestry [
Common in people of Cajun and French Canadian ancestry [
Common in people of Indian and Middle Eastern ancestry [
Associated with milder disease, and may be more common in individuals of Hispanic descent [
Common in people of Chinese ancestry [
Recently, three individuals who are double heterozygous for pathogenic variants in
##
Truncating variants in exons 3 and 4, encoding the N-terminus of the protein, cause AdoCbl deficiency (
Missense variants in exons 6 and 8, encoding the C-terminus, cause MeCbl deficiency (
Truncating variants in exons 5, 7, and 8 and intron 7 cause combined AdoCbl and MeCbl deficiency [
• Truncating variants in exons 3 and 4, encoding the N-terminus of the protein, cause AdoCbl deficiency (
• Missense variants in exons 6 and 8, encoding the C-terminus, cause MeCbl deficiency (
• Truncating variants in exons 5, 7, and 8 and intron 7 cause combined AdoCbl and MeCbl deficiency [
##
A subset of severe pathogenic variants (including frameshifting deletions and nonsense variants) [
Variants listed in the table have been provided by the authors.
The 38-kd C-terminal domain binds AdoMet.
A domain comprising amino acids 650 to 896 includes the binding domain for the required cofactor methylcobalamin.
The 70-kd N-terminal domain binds homocysteine and methyltetrahydrofolate.
The latter two activities may be on separate domains within this region [
• The 38-kd C-terminal domain binds AdoMet.
• A domain comprising amino acids 650 to 896 includes the binding domain for the required cofactor methylcobalamin.
• The 70-kd N-terminal domain binds homocysteine and methyltetrahydrofolate.
##
The most common disease-causing variant, accounting for 25% of alleles, is a deep intronic variant in intron 6 (c.903+469T>C) that activates a splice enhancer site in a pseudoexon resulting in its inclusion [
The c.1361C>T variant is common in persons of Iberian ancestry. Reports suggest a milder phenotype with no neurologic involvement [
Other variants have been described [
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• The most common disease-causing variant, accounting for 25% of alleles, is a deep intronic variant in intron 6 (c.903+469T>C) that activates a splice enhancer site in a pseudoexon resulting in its inclusion [
• The c.1361C>T variant is common in persons of Iberian ancestry. Reports suggest a milder phenotype with no neurologic involvement [
##
Variants listed in the table have been provided by the authors.
##
Variants listed in the table have been provided by the authors.
## Chapter Notes
Dr Sloan is a genetic counselor and researcher at the National Human Genome Research Institute at the National Institutes of Health.
Dr Carrillo is a pediatrician and biochemical geneticist. She is an attending physician at the National Human Genome Research Institute at the National Institutes of Health.
Dr Adams is a pediatrician and biochemical geneticist. He is an attending physician at the National Human Genome Research Institute at the National Institutes of Health.
Dr Venditti is a pediatrician and biochemical geneticist. He is the director of the Organic Acid Disorder Research Unit, a Senior Investigator in the National Human Genome Research Institute, and an attending physician at the National Institutes of Health Clinical Center.
16 December 2021 (js) Revision:
6 September 2018 (ha) Comprehensive update posted live
21 November 2013 (me) Comprehensive update posted live
25 February 2008 (me) Review posted live
22 December 2006 (cpv) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 16 December 2021 (js) Revision:
• 6 September 2018 (ha) Comprehensive update posted live
• 21 November 2013 (me) Comprehensive update posted live
• 25 February 2008 (me) Review posted live
• 22 December 2006 (cpv) Original submission
## Author Notes
Dr Sloan is a genetic counselor and researcher at the National Human Genome Research Institute at the National Institutes of Health.
Dr Carrillo is a pediatrician and biochemical geneticist. She is an attending physician at the National Human Genome Research Institute at the National Institutes of Health.
Dr Adams is a pediatrician and biochemical geneticist. He is an attending physician at the National Human Genome Research Institute at the National Institutes of Health.
Dr Venditti is a pediatrician and biochemical geneticist. He is the director of the Organic Acid Disorder Research Unit, a Senior Investigator in the National Human Genome Research Institute, and an attending physician at the National Institutes of Health Clinical Center.
## Revision History
16 December 2021 (js) Revision:
6 September 2018 (ha) Comprehensive update posted live
21 November 2013 (me) Comprehensive update posted live
25 February 2008 (me) Review posted live
22 December 2006 (cpv) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 16 December 2021 (js) Revision:
• 6 September 2018 (ha) Comprehensive update posted live
• 21 November 2013 (me) Comprehensive update posted live
• 25 February 2008 (me) Review posted live
• 22 December 2006 (cpv) Original submission
## References
## Literature Cited
Intracellular metabolism of cobalamin. The intracellular cobalamin metabolism and related pathways – including the complementation groups and corresponding genes – are shown.
Endocytosis of
Testing algorithm to confirm the diagnosis of a disorder of intracellular cobalamin metabolism in a proband
Footnotes:
1. While diagnostic testing is being performed, contact genetics/metabolic team and initiate treatment
2. The following results on NBS could be due to a cobalamin disorder: ↑C3, ↑C3/C2, ↓Met.
3. The following biochemical testing should be performed: plasma total homocysteine, serum methylmalonic acid, plasma amino acids, plasma acylcarnitine profile, serum vitamin B
4.
5.
6. Variants in
7. Multigene panel should include
|
[] |
25/2/2008
|
6/9/2018
|
16/12/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cc2-leuk
|
cc2-leuk
|
[
"Chloride channel protein 2",
"CLCN2",
"CLCN2-Related Leukoencephalopathy"
] |
Rogier Min, Christel Depienne, Frederic Sedel, Truus EM Abbink, Marjo S van der Knaap
|
Summary The diagnosis of
|
## Diagnosis
Mild ataxia
Mild cognitive impairment
Psychiatric symptoms
Headache
Decreased vision caused by chorioretinopathy or optic atrophy
Auditory symptoms including hearing loss, tinnitus, and vertigo
Male infertility caused by oligo-/azoospermia
Abnormally low signal on T
Posterior limbs of the internal capsules
Midbrain crura cerebri
Middle cerebellar peduncles
Additional findings can include abnormally low signal on T
Pyramidal tracts in the pons
Central tegmental tracts in medulla, pons and midbrain
Superior cerebellar peduncles
Decussation of the superior cerebellar peduncles in the midbrain
Cerebellar white matter
Corpus callosum
Cerebral white matter, either with a signal behavior suggestive of hypomyelination or nonspecific, mild inhomogeneous signal abnormalities
The diagnosis of
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive MRI findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A large deletion in
• Mild ataxia
• Mild cognitive impairment
• Psychiatric symptoms
• Headache
• Decreased vision caused by chorioretinopathy or optic atrophy
• Auditory symptoms including hearing loss, tinnitus, and vertigo
• Male infertility caused by oligo-/azoospermia
• Abnormally low signal on T
• Posterior limbs of the internal capsules
• Midbrain crura cerebri
• Middle cerebellar peduncles
• Posterior limbs of the internal capsules
• Midbrain crura cerebri
• Middle cerebellar peduncles
• Additional findings can include abnormally low signal on T
• Pyramidal tracts in the pons
• Central tegmental tracts in medulla, pons and midbrain
• Superior cerebellar peduncles
• Decussation of the superior cerebellar peduncles in the midbrain
• Cerebellar white matter
• Corpus callosum
• Cerebral white matter, either with a signal behavior suggestive of hypomyelination or nonspecific, mild inhomogeneous signal abnormalities
• Pyramidal tracts in the pons
• Central tegmental tracts in medulla, pons and midbrain
• Superior cerebellar peduncles
• Decussation of the superior cerebellar peduncles in the midbrain
• Cerebellar white matter
• Corpus callosum
• Cerebral white matter, either with a signal behavior suggestive of hypomyelination or nonspecific, mild inhomogeneous signal abnormalities
• Posterior limbs of the internal capsules
• Midbrain crura cerebri
• Middle cerebellar peduncles
• Pyramidal tracts in the pons
• Central tegmental tracts in medulla, pons and midbrain
• Superior cerebellar peduncles
• Decussation of the superior cerebellar peduncles in the midbrain
• Cerebellar white matter
• Corpus callosum
• Cerebral white matter, either with a signal behavior suggestive of hypomyelination or nonspecific, mild inhomogeneous signal abnormalities
## Suggestive Findings
Mild ataxia
Mild cognitive impairment
Psychiatric symptoms
Headache
Decreased vision caused by chorioretinopathy or optic atrophy
Auditory symptoms including hearing loss, tinnitus, and vertigo
Male infertility caused by oligo-/azoospermia
Abnormally low signal on T
Posterior limbs of the internal capsules
Midbrain crura cerebri
Middle cerebellar peduncles
Additional findings can include abnormally low signal on T
Pyramidal tracts in the pons
Central tegmental tracts in medulla, pons and midbrain
Superior cerebellar peduncles
Decussation of the superior cerebellar peduncles in the midbrain
Cerebellar white matter
Corpus callosum
Cerebral white matter, either with a signal behavior suggestive of hypomyelination or nonspecific, mild inhomogeneous signal abnormalities
• Mild ataxia
• Mild cognitive impairment
• Psychiatric symptoms
• Headache
• Decreased vision caused by chorioretinopathy or optic atrophy
• Auditory symptoms including hearing loss, tinnitus, and vertigo
• Male infertility caused by oligo-/azoospermia
• Abnormally low signal on T
• Posterior limbs of the internal capsules
• Midbrain crura cerebri
• Middle cerebellar peduncles
• Posterior limbs of the internal capsules
• Midbrain crura cerebri
• Middle cerebellar peduncles
• Additional findings can include abnormally low signal on T
• Pyramidal tracts in the pons
• Central tegmental tracts in medulla, pons and midbrain
• Superior cerebellar peduncles
• Decussation of the superior cerebellar peduncles in the midbrain
• Cerebellar white matter
• Corpus callosum
• Cerebral white matter, either with a signal behavior suggestive of hypomyelination or nonspecific, mild inhomogeneous signal abnormalities
• Pyramidal tracts in the pons
• Central tegmental tracts in medulla, pons and midbrain
• Superior cerebellar peduncles
• Decussation of the superior cerebellar peduncles in the midbrain
• Cerebellar white matter
• Corpus callosum
• Cerebral white matter, either with a signal behavior suggestive of hypomyelination or nonspecific, mild inhomogeneous signal abnormalities
• Posterior limbs of the internal capsules
• Midbrain crura cerebri
• Middle cerebellar peduncles
• Pyramidal tracts in the pons
• Central tegmental tracts in medulla, pons and midbrain
• Superior cerebellar peduncles
• Decussation of the superior cerebellar peduncles in the midbrain
• Cerebellar white matter
• Corpus callosum
• Cerebral white matter, either with a signal behavior suggestive of hypomyelination or nonspecific, mild inhomogeneous signal abnormalities
## Establishing the Diagnosis
The diagnosis of
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive MRI findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A large deletion in
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A large deletion in
## Clinical Characteristics
The phenotypic spectrum of
To date, 31 individuals have been identified with biallelic pathogenic variants in
Of those assessed for the feature
An infant who presented with frequent generalized tonic-clonic seizures at age three months has been reported. Seizures were effectively controlled by anti-seizure medication (phenobarbital and valproate). A boy age 13 years with the exact same homozygous pathogenic variant as the infant did not have epilepsy [
Two additional individuals with biallelic pathogenic variants in
No genotype-phenotype correlations have been identified.
The prevalence of
## Clinical Description
The phenotypic spectrum of
To date, 31 individuals have been identified with biallelic pathogenic variants in
Of those assessed for the feature
An infant who presented with frequent generalized tonic-clonic seizures at age three months has been reported. Seizures were effectively controlled by anti-seizure medication (phenobarbital and valproate). A boy age 13 years with the exact same homozygous pathogenic variant as the infant did not have epilepsy [
Two additional individuals with biallelic pathogenic variants in
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
Heterozygous
Heterozygous gain-of-function pathogenic variants in
## Differential Diagnosis
The differential diagnosis of the MRI findings of bilateral symmetric signal abnormalities of the middle cerebellar peduncles and variable signal abnormalities in the brain stem and cerebellar and cerebral white matter includes the disorders summarized in
Differential Diagnosis of MRI Findings Seen in
AD = autosomal dominant; AR = autosomal recessive; CLCN2L =
Corticopontine & corticospinal projection fibers are frequently involved.
Signal abnormalities are often present in the corticospinal tracts & medial lemniscus in the brain stem, & slight signal changes are often seen in the periventricular cerebral white matter.
Brain stem signal abnormalities are more variable & rarely involve the middle cerebellar peduncles & crura cerebri.
Brain stem signal abnormalities with a predilection for the medulla may also be present.
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
CLCN2L =
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with
OT = occupational therapy; PT = physical therapy
Recommended Surveillance for Individuals with
It is appropriate to clarify the genetic status of older and younger sibs of a proband in order to identify as early as possible those who would benefit from early diagnosis and routine surveillance for motor, cognitive, vision, and hearing impairment.
See
Search
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
CLCN2L =
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
OT = occupational therapy; PT = physical therapy
## Surveillance
Recommended Surveillance for Individuals with
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of older and younger sibs of a proband in order to identify as early as possible those who would benefit from early diagnosis and routine surveillance for motor, cognitive, vision, and hearing impairment.
See
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
## Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
## Molecular Genetics
CLCN2-Related Leukoencephalopathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CLCN2-Related Leukoencephalopathy (
In the brain, ClC-2 is found in both neurons and glia.
In astrocytes, ClC-2 shows enhanced expression in processes around blood vessels, in the glia limitans, in the ependymal lining, and in astrocyte-astrocyte contacts [
ClC-2 interacts with the glial proteins GlialCAM and MLC1 [
Retinal and testicular degeneration have been described in
## Molecular Pathogenesis
In the brain, ClC-2 is found in both neurons and glia.
In astrocytes, ClC-2 shows enhanced expression in processes around blood vessels, in the glia limitans, in the ependymal lining, and in astrocyte-astrocyte contacts [
ClC-2 interacts with the glial proteins GlialCAM and MLC1 [
Retinal and testicular degeneration have been described in
## Chapter Notes
The Amsterdam Leukodystrophy Center (ALC; Amsterdam UMC, the Netherlands) is headed by Professor Marjo van der Knaap. The purpose of the Center is to optimize diagnostics and care for patients with leukodystrophies, and to perform translational research with the aim to advance insight into disease mechanisms and develop and implement new therapies. Within the center, patient care, clinical studies, and fundamental experimental work on genetics, molecular biology, and neurophysiology are combined. Prof Van der Knaap has pioneered MRI diagnostics, and was the first to describe and genetically define many leukodystrophies. The research team of Dr Rogier Min within the ALC focuses on understanding cellular aspects of ion and water homeostasis in the brain using electrophysiologic and imaging methods.
To obtain a list of known pathogenic variants in
We thank patients with
20 May 2021 (ha) Comprehensive update posted live
5 November 2015 (me) Review posted live
22 April 2015 (mvdk) Original submission
• 20 May 2021 (ha) Comprehensive update posted live
• 5 November 2015 (me) Review posted live
• 22 April 2015 (mvdk) Original submission
## Author Notes
The Amsterdam Leukodystrophy Center (ALC; Amsterdam UMC, the Netherlands) is headed by Professor Marjo van der Knaap. The purpose of the Center is to optimize diagnostics and care for patients with leukodystrophies, and to perform translational research with the aim to advance insight into disease mechanisms and develop and implement new therapies. Within the center, patient care, clinical studies, and fundamental experimental work on genetics, molecular biology, and neurophysiology are combined. Prof Van der Knaap has pioneered MRI diagnostics, and was the first to describe and genetically define many leukodystrophies. The research team of Dr Rogier Min within the ALC focuses on understanding cellular aspects of ion and water homeostasis in the brain using electrophysiologic and imaging methods.
To obtain a list of known pathogenic variants in
## Acknowledgments
We thank patients with
## Revision History
20 May 2021 (ha) Comprehensive update posted live
5 November 2015 (me) Review posted live
22 April 2015 (mvdk) Original submission
• 20 May 2021 (ha) Comprehensive update posted live
• 5 November 2015 (me) Review posted live
• 22 April 2015 (mvdk) Original submission
## References
## Literature Cited
MRI of an individual age 50 years with
|
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"B Parayil Sankaran, M Nagappa, S Chiplunkar, S Kothari, P Govindaraj, S Sinha, AB Taly. Leukodystrophies and genetic leukoencephalopathies in children specified by exome sequencing in an expanded gene panel.. J Child Neurol. 2020;35:433-41",
"R Planells-Cases, TJ Jentsch. Chloride channelopathies.. Biochim Biophys Acta. 2009;1792:173-89",
"S Ratté, SA Prescott. ClC-2 channels regulate neuronal excitability, not intracellular chloride levels.. J Neurosci. 2011;31:15838-43",
"C Saint-Martin, G Gauvain, G Teodorescu, I Gourfinkel-An, E Fedirko, YG Weber, S Maljevic, JP Ernst, J Garcia-Olivares, C Fahlke, R Nabbout, E LeGuern, H Lerche, JC Poncer, C Depienne. Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy.. Hum Mutat. 2009;30:397-405",
"UI Scholl, G Stölting, J Schewe, A Thiel, H Tan, C Nelson-Williams, AA Vichot, SC Jin, E Loring, V Untiet, T Yoo, J Choi, S Xu, A Wu, M Kirchner, P Mertins, LC Rump, AM Onder, C Gamble, D McKenney, RW Lash, DP Jones, G Chune, P Gagliardi, M Choi, R Gordon, M Stowasser, C Fahlke, RP Lifton. CLCN2 chloride channel mutations in familial hyperaldosteronism type II.. Nat Genet. 2018;50:349-54",
"S Sirisi, X Elorza-Vidal, T Arnedo, M Armand-Ugón, G Callejo, X Capdevila-Nortes, T López-Hernández, U Schulte, A Barrallo-Gimeno, V Nunes, X Gasull, R Estévez. Depolarization causes the formation of a ternary complex between GlialCAM, MLC1 and ClC-2 in astrocytes: implications in megalencephalic leukoencephalopathy.. Hum Mol Genet. 2017;26:2436-50",
"E Stogmann, P Lichtner, C Baumgartner, M Schmied, C Hotzy, F Asmus, F Leutmezer, S Bonelli, E Assem-Hilger, K Vass, K Hatala, TM Strom, T Meitinger, F Zimprich, A Zimprich. Mutations in the CLCN2 gene are a rare cause of idiopathic generalized epilepsy syndromes.. Neurogenetics. 2006;7:265-8",
"B Zeydan, U Uygunoglu, A Altintas, S Saip, A Siva, TEM Abbink, MS Van der Knaap, C Yalcinkaya. Identification of 3 novel patients with CLCN2-related leukoencephalopathy due to CLCN2 mutations.. Eur Neurol. 2017;78:125-7"
] |
5/11/2015
|
20/5/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
cca
|
cca
|
[
"Beals-Hecht Syndrome",
"Beals Syndrome",
"Beals Syndrome",
"Beals-Hecht Syndrome",
"Fibrillin-2",
"FBN2",
"Congenital Contractural Arachnodactyly"
] |
Congenital Contractural Arachnodactyly
|
Bert Callewaert
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Summary Congenital contractural arachnodactyly (CCA) appears to comprise a broad phenotypic spectrum. Classic CCA is characterized by arachnodactyly; flexion contractures of multiple joints including elbows, knees, hips, ankles, and/or fingers; kyphoscoliosis (usually progressive); a marfanoid habitus (a long and slender build, dolichostenomelia, pectus deformity, muscular hypoplasia, highly arched palate); and abnormal "crumpled" ears. At the mildest end, parents who are diagnosed retrospectively upon evaluation of their more severely affected child may show a lean body build, mild arachnodactyly, mild contractures without impairment, and minor ear abnormalities. At the most severe end is "severe CCA with cardiovascular and/or gastrointestinal anomalies," a rare phenotype in infants with pronounced features of CCA (severe crumpling of the ears, arachnodactyly, contractures, congenital scoliosis, and/or hypotonia) and severe cardiovascular and/or gastrointestinal anomalies. Phenotypic expression can vary within and between families. The diagnosis of CCA can be established in a proband with suggestive findings and a heterozygous CCA is inherited in an autosomal dominant manner. While many individuals with CCA have an affected parent, as many as 50% may have a
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## Diagnosis
Formal diagnostic criteria for congenital contractural arachnodactyly (CCA) have not been established.
Classic CCA
Arachnodactyly with positive wrist and thumb sign
Flexion contractures of multiple joints including elbows, knees, hips, ankles, and/or fingers
Kyphoscoliosis (usually progressive)
Abnormal pinnae ("crumpled" outer helices)
A marfanoid habitus (a long and slender build, dolichostenomelia, pectus deformity, muscular hypoplasia, highly arched palate)
On rare occasions, infants were reported with the clinical findings of classic CCA as well as the following anomalies [
Although this phenotype has been referred to as "severe/lethal CCA," its molecular basis has not been unequivocally established and a lethal outcome is not certain; the term "severe CCA with cardiovascular and/or gastrointestinal anomalies" more accurately describes this disorder [Author, personal observation].
The diagnosis of CCA
Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of congenital contractural arachnodactyly is broad, individuals with the distinctive findings described in
For an introduction to multigene panels click
When the diagnosis of CCA is not considered because an individual has atypical phenotypic features,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Congenital Contractural Arachnodactyly
See
Because the detection rate for
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of an entire
Five known deletion/duplication pathogenic variants include a mosaic deletion of exons 7-34 [
In the absence of a pathogenic or likely pathogenic
Clinical Scoring System
In neonates: a "crumpled ear" often shows underdevelopment & folding of the upper part of the helix w/a prominent helical crus & inferior crus of the antihelix.
In older children / adults: ear may "unfold" but the prominence of the crura remains, giving a "tram track" appearance to the ear (see
Assessed by evaluating the wrist sign
Both signs should be present before arachnodactyly is confirmed.
↓ US/LS ratio (for white adults <0.85; <0.78 in black adults; no data assessed in Asians); AND
↑ arm-span-to-height ratio (for adults >1.05) w/no significant scoliosis [
Scoliosis can be diagnosed clinically
Kyphosis = exaggerated thoracolumbar kyphosis [
Based on
US/LS = upper segment to lower segment
Positive wrist sign: the tip of the thumb covers the entire fingernail of the fifth finger when wrapped around the contralateral wrist [
Positive thumb sign: the entire distal phalanx of the adducted thumb extends beyond the ulnar border of the palm with or without the assistance of the patient or examiner to achieve maximal adduction [
Clinical diagnosis: on bending forward, a vertical difference of ≥1.5 cm between the ribs of the left and right hemithorax is observed [
Radiographic: a Cobb's angle (angle between a line drawn along the superior-end plate of the superior-end vertebra and a second line drawn along the inferior-end plate of the inferior-end vertebra of the scoliosis measured on anterior-posterior view of the spine) of ≥20° is seen [
• Arachnodactyly with positive wrist and thumb sign
• Flexion contractures of multiple joints including elbows, knees, hips, ankles, and/or fingers
• Kyphoscoliosis (usually progressive)
• Abnormal pinnae ("crumpled" outer helices)
• A marfanoid habitus (a long and slender build, dolichostenomelia, pectus deformity, muscular hypoplasia, highly arched palate)
• In neonates: a "crumpled ear" often shows underdevelopment & folding of the upper part of the helix w/a prominent helical crus & inferior crus of the antihelix.
• In older children / adults: ear may "unfold" but the prominence of the crura remains, giving a "tram track" appearance to the ear (see
• Assessed by evaluating the wrist sign
• Both signs should be present before arachnodactyly is confirmed.
• ↓ US/LS ratio (for white adults <0.85; <0.78 in black adults; no data assessed in Asians); AND
• ↑ arm-span-to-height ratio (for adults >1.05) w/no significant scoliosis [
• Scoliosis can be diagnosed clinically
• Kyphosis = exaggerated thoracolumbar kyphosis [
## Suggestive Findings
Classic CCA
Arachnodactyly with positive wrist and thumb sign
Flexion contractures of multiple joints including elbows, knees, hips, ankles, and/or fingers
Kyphoscoliosis (usually progressive)
Abnormal pinnae ("crumpled" outer helices)
A marfanoid habitus (a long and slender build, dolichostenomelia, pectus deformity, muscular hypoplasia, highly arched palate)
On rare occasions, infants were reported with the clinical findings of classic CCA as well as the following anomalies [
Although this phenotype has been referred to as "severe/lethal CCA," its molecular basis has not been unequivocally established and a lethal outcome is not certain; the term "severe CCA with cardiovascular and/or gastrointestinal anomalies" more accurately describes this disorder [Author, personal observation].
• Arachnodactyly with positive wrist and thumb sign
• Flexion contractures of multiple joints including elbows, knees, hips, ankles, and/or fingers
• Kyphoscoliosis (usually progressive)
• Abnormal pinnae ("crumpled" outer helices)
• A marfanoid habitus (a long and slender build, dolichostenomelia, pectus deformity, muscular hypoplasia, highly arched palate)
## Establishing the Diagnosis
The diagnosis of CCA
Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of congenital contractural arachnodactyly is broad, individuals with the distinctive findings described in
For an introduction to multigene panels click
When the diagnosis of CCA is not considered because an individual has atypical phenotypic features,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Congenital Contractural Arachnodactyly
See
Because the detection rate for
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of an entire
Five known deletion/duplication pathogenic variants include a mosaic deletion of exons 7-34 [
In the absence of a pathogenic or likely pathogenic
Clinical Scoring System
In neonates: a "crumpled ear" often shows underdevelopment & folding of the upper part of the helix w/a prominent helical crus & inferior crus of the antihelix.
In older children / adults: ear may "unfold" but the prominence of the crura remains, giving a "tram track" appearance to the ear (see
Assessed by evaluating the wrist sign
Both signs should be present before arachnodactyly is confirmed.
↓ US/LS ratio (for white adults <0.85; <0.78 in black adults; no data assessed in Asians); AND
↑ arm-span-to-height ratio (for adults >1.05) w/no significant scoliosis [
Scoliosis can be diagnosed clinically
Kyphosis = exaggerated thoracolumbar kyphosis [
Based on
US/LS = upper segment to lower segment
Positive wrist sign: the tip of the thumb covers the entire fingernail of the fifth finger when wrapped around the contralateral wrist [
Positive thumb sign: the entire distal phalanx of the adducted thumb extends beyond the ulnar border of the palm with or without the assistance of the patient or examiner to achieve maximal adduction [
Clinical diagnosis: on bending forward, a vertical difference of ≥1.5 cm between the ribs of the left and right hemithorax is observed [
Radiographic: a Cobb's angle (angle between a line drawn along the superior-end plate of the superior-end vertebra and a second line drawn along the inferior-end plate of the inferior-end vertebra of the scoliosis measured on anterior-posterior view of the spine) of ≥20° is seen [
• In neonates: a "crumpled ear" often shows underdevelopment & folding of the upper part of the helix w/a prominent helical crus & inferior crus of the antihelix.
• In older children / adults: ear may "unfold" but the prominence of the crura remains, giving a "tram track" appearance to the ear (see
• Assessed by evaluating the wrist sign
• Both signs should be present before arachnodactyly is confirmed.
• ↓ US/LS ratio (for white adults <0.85; <0.78 in black adults; no data assessed in Asians); AND
• ↑ arm-span-to-height ratio (for adults >1.05) w/no significant scoliosis [
• Scoliosis can be diagnosed clinically
• Kyphosis = exaggerated thoracolumbar kyphosis [
## Option 1
For an introduction to multigene panels click
## Option 2
When the diagnosis of CCA is not considered because an individual has atypical phenotypic features,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Congenital Contractural Arachnodactyly
See
Because the detection rate for
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of an entire
Five known deletion/duplication pathogenic variants include a mosaic deletion of exons 7-34 [
## Clinical Scoring System
In the absence of a pathogenic or likely pathogenic
Clinical Scoring System
In neonates: a "crumpled ear" often shows underdevelopment & folding of the upper part of the helix w/a prominent helical crus & inferior crus of the antihelix.
In older children / adults: ear may "unfold" but the prominence of the crura remains, giving a "tram track" appearance to the ear (see
Assessed by evaluating the wrist sign
Both signs should be present before arachnodactyly is confirmed.
↓ US/LS ratio (for white adults <0.85; <0.78 in black adults; no data assessed in Asians); AND
↑ arm-span-to-height ratio (for adults >1.05) w/no significant scoliosis [
Scoliosis can be diagnosed clinically
Kyphosis = exaggerated thoracolumbar kyphosis [
Based on
US/LS = upper segment to lower segment
Positive wrist sign: the tip of the thumb covers the entire fingernail of the fifth finger when wrapped around the contralateral wrist [
Positive thumb sign: the entire distal phalanx of the adducted thumb extends beyond the ulnar border of the palm with or without the assistance of the patient or examiner to achieve maximal adduction [
Clinical diagnosis: on bending forward, a vertical difference of ≥1.5 cm between the ribs of the left and right hemithorax is observed [
Radiographic: a Cobb's angle (angle between a line drawn along the superior-end plate of the superior-end vertebra and a second line drawn along the inferior-end plate of the inferior-end vertebra of the scoliosis measured on anterior-posterior view of the spine) of ≥20° is seen [
• In neonates: a "crumpled ear" often shows underdevelopment & folding of the upper part of the helix w/a prominent helical crus & inferior crus of the antihelix.
• In older children / adults: ear may "unfold" but the prominence of the crura remains, giving a "tram track" appearance to the ear (see
• Assessed by evaluating the wrist sign
• Both signs should be present before arachnodactyly is confirmed.
• ↓ US/LS ratio (for white adults <0.85; <0.78 in black adults; no data assessed in Asians); AND
• ↑ arm-span-to-height ratio (for adults >1.05) w/no significant scoliosis [
• Scoliosis can be diagnosed clinically
• Kyphosis = exaggerated thoracolumbar kyphosis [
## Clinical Characteristics
Congenital contractural arachnodactyly (CCA) appears to comprise a broad phenotypic spectrum. Phenotypic expression is variable within and between families. At the mildest end, parents who are diagnosed retrospectively upon evaluation of their more severely affected child may show a lean body build, mild arachnodactyly, prominent anterior crus of the antihelix, and/or mild contractures without impairment. At the most severe end is "severe CCA with cardiovascular and/or gastrointestinal anomalies," a rare phenotype in infants with pronounced features of CCA (severe crumpling of the ears, arachnodactyly, contractures, congenital scoliosis, and/or hypotonia) and severe cardiovascular and/or gastrointestinal anomalies. Only one child with the severe form of CCA has been confirmed to have an
Selected Clinical Features in Classic Congenital Contractural Arachnodactyly by Frequency
Features are ordered by frequency.
%s are based on individuals with a confirmed (likely)
Camptodactyly. Contractures of the small joints (metacarpo/tarsophalangeal, proximal, and distal interphalangeal joints)
Large-joint contractures. Limited movement of hips, knees, ankles (clubfoot), shoulders, elbows, and wrists
Contractures of small and large joints usually improve with time, but some limited restriction often remains. Careful assessment is therefore necessary in (older) children and adults.
Dolichocephaly (long, narrow skull)
Enophthalmia and mildly downslanting palpebral fissures (rare)
Flat midface
Highly arched palate
Micrognathia. Although more often reported in individuals with CCA without a (likely) pathogenic
In addition to the typical skeletal findings in CCA, a few infants with multiple cardiovascular and/or gastrointestinal anomalies requiring surgical correction as early as the first week of life have been reported [
The age of death has ranged from eight days to 11.5 months. Respiratory complications including tracheomalacia and respiratory infections have been the cause of death in most.
Somatic mosaicism has been reported in the following instances:
A mother with somatic mosaicism for an
A likely in-frame mosaic intragenic deletion from exons 7-34 spanning the central region of the gene (exons 24-23) that harbors most pathogenic variants was associated with a severe phenotype [
Somatic and germline mosaicism were reported in the asymptomatic father of two affected children [
No genotype-phenotype correlations have been documented to date.
Some case reports claim a more severe phenotype for deletions [
The penetrance for CCA is likely up to 100%, but some disease manifestations, including the ear and joint manifestations, may become less obvious with age. Nevertheless, upon careful examination, less than 1.2% of the variability of the clinical score (
Clinical manifestations are the same in males and females.
Congenital contractural arachnodactyly (CCA) has been referred to as distal arthrogryposis type 9 (OMIM
The prevalence is not known. To date about 70 probands with CCA have been described. Most described individuals are white, but this likely represents an ascertainment bias [Author, personal observation]. There is no reason to assume that CCA shows any specific geographic or ethnic predilection. Indeed, affected individuals from China [
•
• Camptodactyly. Contractures of the small joints (metacarpo/tarsophalangeal, proximal, and distal interphalangeal joints)
• Large-joint contractures. Limited movement of hips, knees, ankles (clubfoot), shoulders, elbows, and wrists
• Contractures of small and large joints usually improve with time, but some limited restriction often remains. Careful assessment is therefore necessary in (older) children and adults.
• Camptodactyly. Contractures of the small joints (metacarpo/tarsophalangeal, proximal, and distal interphalangeal joints)
• Large-joint contractures. Limited movement of hips, knees, ankles (clubfoot), shoulders, elbows, and wrists
•
• Dolichocephaly (long, narrow skull)
• Enophthalmia and mildly downslanting palpebral fissures (rare)
• Flat midface
• Highly arched palate
• Micrognathia. Although more often reported in individuals with CCA without a (likely) pathogenic
• Dolichocephaly (long, narrow skull)
• Enophthalmia and mildly downslanting palpebral fissures (rare)
• Flat midface
• Highly arched palate
• Micrognathia. Although more often reported in individuals with CCA without a (likely) pathogenic
• Camptodactyly. Contractures of the small joints (metacarpo/tarsophalangeal, proximal, and distal interphalangeal joints)
• Large-joint contractures. Limited movement of hips, knees, ankles (clubfoot), shoulders, elbows, and wrists
• Dolichocephaly (long, narrow skull)
• Enophthalmia and mildly downslanting palpebral fissures (rare)
• Flat midface
• Highly arched palate
• Micrognathia. Although more often reported in individuals with CCA without a (likely) pathogenic
• A mother with somatic mosaicism for an
• A likely in-frame mosaic intragenic deletion from exons 7-34 spanning the central region of the gene (exons 24-23) that harbors most pathogenic variants was associated with a severe phenotype [
• Somatic and germline mosaicism were reported in the asymptomatic father of two affected children [
## Clinical Description
Congenital contractural arachnodactyly (CCA) appears to comprise a broad phenotypic spectrum. Phenotypic expression is variable within and between families. At the mildest end, parents who are diagnosed retrospectively upon evaluation of their more severely affected child may show a lean body build, mild arachnodactyly, prominent anterior crus of the antihelix, and/or mild contractures without impairment. At the most severe end is "severe CCA with cardiovascular and/or gastrointestinal anomalies," a rare phenotype in infants with pronounced features of CCA (severe crumpling of the ears, arachnodactyly, contractures, congenital scoliosis, and/or hypotonia) and severe cardiovascular and/or gastrointestinal anomalies. Only one child with the severe form of CCA has been confirmed to have an
Selected Clinical Features in Classic Congenital Contractural Arachnodactyly by Frequency
Features are ordered by frequency.
%s are based on individuals with a confirmed (likely)
Camptodactyly. Contractures of the small joints (metacarpo/tarsophalangeal, proximal, and distal interphalangeal joints)
Large-joint contractures. Limited movement of hips, knees, ankles (clubfoot), shoulders, elbows, and wrists
Contractures of small and large joints usually improve with time, but some limited restriction often remains. Careful assessment is therefore necessary in (older) children and adults.
Dolichocephaly (long, narrow skull)
Enophthalmia and mildly downslanting palpebral fissures (rare)
Flat midface
Highly arched palate
Micrognathia. Although more often reported in individuals with CCA without a (likely) pathogenic
In addition to the typical skeletal findings in CCA, a few infants with multiple cardiovascular and/or gastrointestinal anomalies requiring surgical correction as early as the first week of life have been reported [
The age of death has ranged from eight days to 11.5 months. Respiratory complications including tracheomalacia and respiratory infections have been the cause of death in most.
Somatic mosaicism has been reported in the following instances:
A mother with somatic mosaicism for an
A likely in-frame mosaic intragenic deletion from exons 7-34 spanning the central region of the gene (exons 24-23) that harbors most pathogenic variants was associated with a severe phenotype [
Somatic and germline mosaicism were reported in the asymptomatic father of two affected children [
•
• Camptodactyly. Contractures of the small joints (metacarpo/tarsophalangeal, proximal, and distal interphalangeal joints)
• Large-joint contractures. Limited movement of hips, knees, ankles (clubfoot), shoulders, elbows, and wrists
• Contractures of small and large joints usually improve with time, but some limited restriction often remains. Careful assessment is therefore necessary in (older) children and adults.
• Camptodactyly. Contractures of the small joints (metacarpo/tarsophalangeal, proximal, and distal interphalangeal joints)
• Large-joint contractures. Limited movement of hips, knees, ankles (clubfoot), shoulders, elbows, and wrists
•
• Dolichocephaly (long, narrow skull)
• Enophthalmia and mildly downslanting palpebral fissures (rare)
• Flat midface
• Highly arched palate
• Micrognathia. Although more often reported in individuals with CCA without a (likely) pathogenic
• Dolichocephaly (long, narrow skull)
• Enophthalmia and mildly downslanting palpebral fissures (rare)
• Flat midface
• Highly arched palate
• Micrognathia. Although more often reported in individuals with CCA without a (likely) pathogenic
• Camptodactyly. Contractures of the small joints (metacarpo/tarsophalangeal, proximal, and distal interphalangeal joints)
• Large-joint contractures. Limited movement of hips, knees, ankles (clubfoot), shoulders, elbows, and wrists
• Dolichocephaly (long, narrow skull)
• Enophthalmia and mildly downslanting palpebral fissures (rare)
• Flat midface
• Highly arched palate
• Micrognathia. Although more often reported in individuals with CCA without a (likely) pathogenic
• A mother with somatic mosaicism for an
• A likely in-frame mosaic intragenic deletion from exons 7-34 spanning the central region of the gene (exons 24-23) that harbors most pathogenic variants was associated with a severe phenotype [
• Somatic and germline mosaicism were reported in the asymptomatic father of two affected children [
## Classic CCA
Selected Clinical Features in Classic Congenital Contractural Arachnodactyly by Frequency
Features are ordered by frequency.
%s are based on individuals with a confirmed (likely)
Camptodactyly. Contractures of the small joints (metacarpo/tarsophalangeal, proximal, and distal interphalangeal joints)
Large-joint contractures. Limited movement of hips, knees, ankles (clubfoot), shoulders, elbows, and wrists
Contractures of small and large joints usually improve with time, but some limited restriction often remains. Careful assessment is therefore necessary in (older) children and adults.
Dolichocephaly (long, narrow skull)
Enophthalmia and mildly downslanting palpebral fissures (rare)
Flat midface
Highly arched palate
Micrognathia. Although more often reported in individuals with CCA without a (likely) pathogenic
•
• Camptodactyly. Contractures of the small joints (metacarpo/tarsophalangeal, proximal, and distal interphalangeal joints)
• Large-joint contractures. Limited movement of hips, knees, ankles (clubfoot), shoulders, elbows, and wrists
• Contractures of small and large joints usually improve with time, but some limited restriction often remains. Careful assessment is therefore necessary in (older) children and adults.
• Camptodactyly. Contractures of the small joints (metacarpo/tarsophalangeal, proximal, and distal interphalangeal joints)
• Large-joint contractures. Limited movement of hips, knees, ankles (clubfoot), shoulders, elbows, and wrists
•
• Dolichocephaly (long, narrow skull)
• Enophthalmia and mildly downslanting palpebral fissures (rare)
• Flat midface
• Highly arched palate
• Micrognathia. Although more often reported in individuals with CCA without a (likely) pathogenic
• Dolichocephaly (long, narrow skull)
• Enophthalmia and mildly downslanting palpebral fissures (rare)
• Flat midface
• Highly arched palate
• Micrognathia. Although more often reported in individuals with CCA without a (likely) pathogenic
• Camptodactyly. Contractures of the small joints (metacarpo/tarsophalangeal, proximal, and distal interphalangeal joints)
• Large-joint contractures. Limited movement of hips, knees, ankles (clubfoot), shoulders, elbows, and wrists
• Dolichocephaly (long, narrow skull)
• Enophthalmia and mildly downslanting palpebral fissures (rare)
• Flat midface
• Highly arched palate
• Micrognathia. Although more often reported in individuals with CCA without a (likely) pathogenic
## Severe CCA with Cardiovascular and/or Gastrointestinal Anomalies
In addition to the typical skeletal findings in CCA, a few infants with multiple cardiovascular and/or gastrointestinal anomalies requiring surgical correction as early as the first week of life have been reported [
The age of death has ranged from eight days to 11.5 months. Respiratory complications including tracheomalacia and respiratory infections have been the cause of death in most.
## Somatic Mosaicism
Somatic mosaicism has been reported in the following instances:
A mother with somatic mosaicism for an
A likely in-frame mosaic intragenic deletion from exons 7-34 spanning the central region of the gene (exons 24-23) that harbors most pathogenic variants was associated with a severe phenotype [
Somatic and germline mosaicism were reported in the asymptomatic father of two affected children [
• A mother with somatic mosaicism for an
• A likely in-frame mosaic intragenic deletion from exons 7-34 spanning the central region of the gene (exons 24-23) that harbors most pathogenic variants was associated with a severe phenotype [
• Somatic and germline mosaicism were reported in the asymptomatic father of two affected children [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been documented to date.
Some case reports claim a more severe phenotype for deletions [
## Penetrance
The penetrance for CCA is likely up to 100%, but some disease manifestations, including the ear and joint manifestations, may become less obvious with age. Nevertheless, upon careful examination, less than 1.2% of the variability of the clinical score (
Clinical manifestations are the same in males and females.
## Nomenclature
Congenital contractural arachnodactyly (CCA) has been referred to as distal arthrogryposis type 9 (OMIM
## Prevalence
The prevalence is not known. To date about 70 probands with CCA have been described. Most described individuals are white, but this likely represents an ascertainment bias [Author, personal observation]. There is no reason to assume that CCA shows any specific geographic or ethnic predilection. Indeed, affected individuals from China [
## Genetically Related (Allelic) Disorders
Rare contiguous gene deletions that include
No other highly penetrant phenotypes are known to be caused by heterozygous
The following association remains to be confirmed: One individual homozygous for the
## Differential Diagnosis
Disorders with features that overlap with those of congenital contractural arachnodactyly (CCA) are summarized in
Disorders to Consider in the Differential Diagnosis of Congenital Contractural Arachnodactyly (CCA)
Marfanoid habitus, dolichostenomelia
Arachnodactyly
Pectus deformity, kyphoscoliosis
Muscle hypoplasia
Large-joint contractures (mainly elbows)
Severe Marfan syndrome
Lens (sub)luxation
High myopia
Progressive aortic root dilatation
Absence of crumpled ears & joint contractures
Neonates w/severe Marfan syndrome are usually very hypotonic & have valvular anomalies ("floppy valves") &/or aortic root dilatation, rather than the septal defects or interrupted aortic arch in severe CCA.
Differentiating Marfan syndrome & CCA is most important given the severe cardiovascular complications & cardiac monitoring essential in individuals w/Marfan syndrome.
Arachnodactyly
Pectus deformity
Joint laxity
Thin skin
Hypertelorism, bifid uvula, cleft palate
Pectus deformity, scoliosis
(Progressive) aortic root dilatation – patent ductus arteriosus
Joint laxity
Early-onset & rapidly progressive myopia w/↑ risk of cataract, & retinal detachment
Hearing loss (both conductive & sensorineural)
Midfacial underdevelopment & cleft palate
Mild spondyloepiphyseal dysplasia &/or precocious arthritis
Limited joint mobility
Dolichostenomelia
Arachnodactyly
Kyphoscoliosis
Lens (sub)luxation
Osteoporosis
DD in some
Predisposition to thromboembolism
Medially overlapping fingers
Clenched fists
Ulnar deviation of fingers
Camptodactyly
Positional foot deformities
Clubfoot
Scoliosis
Absence of marfanoid habitus, arachnodactyly, contractures of knees & elbows, & crumpled ears
Additional features depending on DA subtype
Often pursed lips
Joint contractures
Muscular hypoplasia
Contractures
Arachnodactyly
Pectus excavatum
Femoral bowing
Normal ears
Interdigital webbing
Cleft palate
Craniosynostosis
Contractures
Pectus deformity
Bowed long bones
Clubfeet
Osteopenia – fractures
Absence of arachnodactyly
Pterygia
Contractures
Hypotonia
Micrognathia
Scoliosis
DD
Umbilical hernia
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance
Neonatal Marfan syndrome is at the most severe end of the spectrum of Marfan syndrome.
In neonatal Marfan syndrome, cardiovascular abnormalities include mitral and tricuspid valve anomalies and dilated aorta. In severe/lethal CCA, cardiovascular abnormalities include atrial and/or ventricular septal defects and interrupted aortic arch.
Joint contractures are seen at birth in individuals with CCA.
Stickler syndrome caused by pathogenic variants
Distal arthrogryposes is inherited in an autosomal dominant manner with the exception of
• Marfanoid habitus, dolichostenomelia
• Arachnodactyly
• Pectus deformity, kyphoscoliosis
• Muscle hypoplasia
• Large-joint contractures (mainly elbows)
• Severe Marfan syndrome
• Lens (sub)luxation
• High myopia
• Progressive aortic root dilatation
• Absence of crumpled ears & joint contractures
• Neonates w/severe Marfan syndrome are usually very hypotonic & have valvular anomalies ("floppy valves") &/or aortic root dilatation, rather than the septal defects or interrupted aortic arch in severe CCA.
• Differentiating Marfan syndrome & CCA is most important given the severe cardiovascular complications & cardiac monitoring essential in individuals w/Marfan syndrome.
• Arachnodactyly
• Pectus deformity
• Joint laxity
• Thin skin
• Hypertelorism, bifid uvula, cleft palate
• Pectus deformity, scoliosis
• (Progressive) aortic root dilatation – patent ductus arteriosus
• Joint laxity
• Early-onset & rapidly progressive myopia w/↑ risk of cataract, & retinal detachment
• Hearing loss (both conductive & sensorineural)
• Midfacial underdevelopment & cleft palate
• Mild spondyloepiphyseal dysplasia &/or precocious arthritis
• Limited joint mobility
• Dolichostenomelia
• Arachnodactyly
• Kyphoscoliosis
• Lens (sub)luxation
• Osteoporosis
• DD in some
• Predisposition to thromboembolism
• Medially overlapping fingers
• Clenched fists
• Ulnar deviation of fingers
• Camptodactyly
• Positional foot deformities
• Clubfoot
• Scoliosis
• Absence of marfanoid habitus, arachnodactyly, contractures of knees & elbows, & crumpled ears
• Additional features depending on DA subtype
• Often pursed lips
• Joint contractures
• Muscular hypoplasia
• Contractures
• Arachnodactyly
• Pectus excavatum
• Femoral bowing
• Normal ears
• Interdigital webbing
• Cleft palate
• Craniosynostosis
• Contractures
• Pectus deformity
• Bowed long bones
• Clubfeet
• Osteopenia – fractures
• Absence of arachnodactyly
• Pterygia
• Contractures
• Hypotonia
• Micrognathia
• Scoliosis
• DD
• Umbilical hernia
## Management
To establish the extent of disease in an individual diagnosed with congenital contractural arachnodactyly (CCA), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Classic Congenital Contractural Arachnodactyly
OT = occupational therapy; PT = physical therapy
Recommended Evaluations Following Initial Diagnosis in Infants with Severe Congenital Contractural Arachnodactyly
OT = occupational therapy; PT = physical therapy
Treatment of Manifestations in Individuals with Classic Congenital Contractural Arachnodactyly
Contractures may require surgical release.
Clubfeet may require casting.
Progressive kyphoscoliosis may require bracing &/or surgical intervention.
Early PT in children helps ↑ joint mobility & counteract muscle hypoplasia (usually calf muscles).
Camptodactyly & large-joint contractures may spontaneously improve over time.
Swimming reinforces the musculature w/out taxing joints.
Cycling may benefit those w/patellar hypermobility by ↓ risk for patellar luxation.
Correction of refractive errors
Keratoconus can be treated by scleral contact lenses. It is currently unknown if corneal crosslinking is safe &/or useful in CCA.
Use of palatal expander may be indicated.
Dental crowding may necessitate extraction of molars.
OT = occupational therapy; PT = physical therapy
Treatment of Manifestations in Individuals with Severe/Lethal CCA
Contractures may require surgical release.
Clubfeet may require casting.
Progressive kyphoscoliosis may require bracing &/or surgical intervention.
Severe pectus excavatum may rarely cause restrictive lung disease or cardiac displacement & thus require surgical treatment (Nüss procedure).
Early PT in children helps ↑ joint mobility & improve muscle hypoplasia (usually calf muscles).
Camptodactyly & large-joint contractures may spontaneously improve over time.
Hypoplastic aortic arch or interrupted aortic arch, a ductus-dependent heart defect, requires intervention shortly after birth (incl prostaglandins while awaiting surgery).
For septal defects, treatment is either conservative (by percutaneous closure) or surgical following standard guidelines.
Aortic root dilatation is managed in a standard manner. See
Surgical correction of malrotation if symptomatic (vomiting)
Surgical correction of esophageal or duodenal atresia
Correction of refractive errors
Keratoconus can be treated by contact lenses. It is currently unknown if corneal crosslinking is safe &/or useful in CCA.
Tracheomalacia requires bronchoscopy &/or vascular imaging to determine cause & best treatment options.
Aggressive treatment of pulmonary infections
Respiratory physiotherapy may be necessary in case of severe hypotonia & reduced coughing.
As it is unclear if pulmonary emphysema may develop, positive pressure ventilation should be kept to a minimum.
OT = occupational therapy; PT = physical therapy
Recommended Surveillance for Individuals with Classic Congenital Contractural Arachnodactyly
Avoid contact sports and activities that stress joints. Individuals should remain active but avoid high-intensity aerobic activities.
LASIK eye surgery may increase the risk for keratoconus in individuals with predisposing ocular conditions.
It is appropriate to clarify the genetic status of apparently asymptomatic or self-reportedly asymptomatic at-risk relatives of an affected individual. Some parents have been unaware of their clinical status. In those individuals, evaluation of their status is necessary to reveal a low but potential risk for aortic and/or ocular complications.
Evaluations can include:
Molecular genetic testing if the pathogenic variant in the family is known;
Clinical evaluation if the pathogenic variant in the family is not known.
See
There are no reported complications related to pregnancy or delivery in females with CCA. It is advisable to perform an echocardiography preconceptually and to increase cardiac surveillance during pregnancy in women with dilatation of the aortic root.
Search
• Contractures may require surgical release.
• Clubfeet may require casting.
• Progressive kyphoscoliosis may require bracing &/or surgical intervention.
• Early PT in children helps ↑ joint mobility & counteract muscle hypoplasia (usually calf muscles).
• Camptodactyly & large-joint contractures may spontaneously improve over time.
• Swimming reinforces the musculature w/out taxing joints.
• Cycling may benefit those w/patellar hypermobility by ↓ risk for patellar luxation.
• Correction of refractive errors
• Keratoconus can be treated by scleral contact lenses. It is currently unknown if corneal crosslinking is safe &/or useful in CCA.
• Use of palatal expander may be indicated.
• Dental crowding may necessitate extraction of molars.
• Contractures may require surgical release.
• Clubfeet may require casting.
• Progressive kyphoscoliosis may require bracing &/or surgical intervention.
• Severe pectus excavatum may rarely cause restrictive lung disease or cardiac displacement & thus require surgical treatment (Nüss procedure).
• Early PT in children helps ↑ joint mobility & improve muscle hypoplasia (usually calf muscles).
• Camptodactyly & large-joint contractures may spontaneously improve over time.
• Hypoplastic aortic arch or interrupted aortic arch, a ductus-dependent heart defect, requires intervention shortly after birth (incl prostaglandins while awaiting surgery).
• For septal defects, treatment is either conservative (by percutaneous closure) or surgical following standard guidelines.
• Aortic root dilatation is managed in a standard manner. See
• Surgical correction of malrotation if symptomatic (vomiting)
• Surgical correction of esophageal or duodenal atresia
• Correction of refractive errors
• Keratoconus can be treated by contact lenses. It is currently unknown if corneal crosslinking is safe &/or useful in CCA.
• Tracheomalacia requires bronchoscopy &/or vascular imaging to determine cause & best treatment options.
• Aggressive treatment of pulmonary infections
• Respiratory physiotherapy may be necessary in case of severe hypotonia & reduced coughing.
• As it is unclear if pulmonary emphysema may develop, positive pressure ventilation should be kept to a minimum.
• Molecular genetic testing if the pathogenic variant in the family is known;
• Clinical evaluation if the pathogenic variant in the family is not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with congenital contractural arachnodactyly (CCA), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Classic Congenital Contractural Arachnodactyly
OT = occupational therapy; PT = physical therapy
Recommended Evaluations Following Initial Diagnosis in Infants with Severe Congenital Contractural Arachnodactyly
OT = occupational therapy; PT = physical therapy
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Classic Congenital Contractural Arachnodactyly
Contractures may require surgical release.
Clubfeet may require casting.
Progressive kyphoscoliosis may require bracing &/or surgical intervention.
Early PT in children helps ↑ joint mobility & counteract muscle hypoplasia (usually calf muscles).
Camptodactyly & large-joint contractures may spontaneously improve over time.
Swimming reinforces the musculature w/out taxing joints.
Cycling may benefit those w/patellar hypermobility by ↓ risk for patellar luxation.
Correction of refractive errors
Keratoconus can be treated by scleral contact lenses. It is currently unknown if corneal crosslinking is safe &/or useful in CCA.
Use of palatal expander may be indicated.
Dental crowding may necessitate extraction of molars.
OT = occupational therapy; PT = physical therapy
Treatment of Manifestations in Individuals with Severe/Lethal CCA
Contractures may require surgical release.
Clubfeet may require casting.
Progressive kyphoscoliosis may require bracing &/or surgical intervention.
Severe pectus excavatum may rarely cause restrictive lung disease or cardiac displacement & thus require surgical treatment (Nüss procedure).
Early PT in children helps ↑ joint mobility & improve muscle hypoplasia (usually calf muscles).
Camptodactyly & large-joint contractures may spontaneously improve over time.
Hypoplastic aortic arch or interrupted aortic arch, a ductus-dependent heart defect, requires intervention shortly after birth (incl prostaglandins while awaiting surgery).
For septal defects, treatment is either conservative (by percutaneous closure) or surgical following standard guidelines.
Aortic root dilatation is managed in a standard manner. See
Surgical correction of malrotation if symptomatic (vomiting)
Surgical correction of esophageal or duodenal atresia
Correction of refractive errors
Keratoconus can be treated by contact lenses. It is currently unknown if corneal crosslinking is safe &/or useful in CCA.
Tracheomalacia requires bronchoscopy &/or vascular imaging to determine cause & best treatment options.
Aggressive treatment of pulmonary infections
Respiratory physiotherapy may be necessary in case of severe hypotonia & reduced coughing.
As it is unclear if pulmonary emphysema may develop, positive pressure ventilation should be kept to a minimum.
OT = occupational therapy; PT = physical therapy
• Contractures may require surgical release.
• Clubfeet may require casting.
• Progressive kyphoscoliosis may require bracing &/or surgical intervention.
• Early PT in children helps ↑ joint mobility & counteract muscle hypoplasia (usually calf muscles).
• Camptodactyly & large-joint contractures may spontaneously improve over time.
• Swimming reinforces the musculature w/out taxing joints.
• Cycling may benefit those w/patellar hypermobility by ↓ risk for patellar luxation.
• Correction of refractive errors
• Keratoconus can be treated by scleral contact lenses. It is currently unknown if corneal crosslinking is safe &/or useful in CCA.
• Use of palatal expander may be indicated.
• Dental crowding may necessitate extraction of molars.
• Contractures may require surgical release.
• Clubfeet may require casting.
• Progressive kyphoscoliosis may require bracing &/or surgical intervention.
• Severe pectus excavatum may rarely cause restrictive lung disease or cardiac displacement & thus require surgical treatment (Nüss procedure).
• Early PT in children helps ↑ joint mobility & improve muscle hypoplasia (usually calf muscles).
• Camptodactyly & large-joint contractures may spontaneously improve over time.
• Hypoplastic aortic arch or interrupted aortic arch, a ductus-dependent heart defect, requires intervention shortly after birth (incl prostaglandins while awaiting surgery).
• For septal defects, treatment is either conservative (by percutaneous closure) or surgical following standard guidelines.
• Aortic root dilatation is managed in a standard manner. See
• Surgical correction of malrotation if symptomatic (vomiting)
• Surgical correction of esophageal or duodenal atresia
• Correction of refractive errors
• Keratoconus can be treated by contact lenses. It is currently unknown if corneal crosslinking is safe &/or useful in CCA.
• Tracheomalacia requires bronchoscopy &/or vascular imaging to determine cause & best treatment options.
• Aggressive treatment of pulmonary infections
• Respiratory physiotherapy may be necessary in case of severe hypotonia & reduced coughing.
• As it is unclear if pulmonary emphysema may develop, positive pressure ventilation should be kept to a minimum.
## Surveillance
Recommended Surveillance for Individuals with Classic Congenital Contractural Arachnodactyly
## Agents/Circumstances to Avoid
Avoid contact sports and activities that stress joints. Individuals should remain active but avoid high-intensity aerobic activities.
LASIK eye surgery may increase the risk for keratoconus in individuals with predisposing ocular conditions.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic or self-reportedly asymptomatic at-risk relatives of an affected individual. Some parents have been unaware of their clinical status. In those individuals, evaluation of their status is necessary to reveal a low but potential risk for aortic and/or ocular complications.
Evaluations can include:
Molecular genetic testing if the pathogenic variant in the family is known;
Clinical evaluation if the pathogenic variant in the family is not known.
See
• Molecular genetic testing if the pathogenic variant in the family is known;
• Clinical evaluation if the pathogenic variant in the family is not known.
## Pregnancy Management
There are no reported complications related to pregnancy or delivery in females with CCA. It is advisable to perform an echocardiography preconceptually and to increase cardiac surveillance during pregnancy in women with dilatation of the aortic root.
## Therapies Under Investigation
Search
## Genetic Counseling
Congenital contractural arachnodactyly (CCA) is inherited in an autosomal dominant manner.
Many individuals diagnosed with CCA have an affected parent.
A proband with CCA may have the disorder as the result of a
Molecular genetic testing (if the
If the
The family history of some individuals diagnosed with CCA may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
Note: If the parent is the individual in whom the
If a parent of the proband has clinical features of CCA and/or is known to have the
If neither parent is clinically affected and if the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Many individuals diagnosed with CCA have an affected parent.
• A proband with CCA may have the disorder as the result of a
• Molecular genetic testing (if the
• If the
• The family history of some individuals diagnosed with CCA may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• Note: If the parent is the individual in whom the
• If a parent of the proband has clinical features of CCA and/or is known to have the
• If neither parent is clinically affected and if the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Congenital contractural arachnodactyly (CCA) is inherited in an autosomal dominant manner.
## Risk to Family Members
Many individuals diagnosed with CCA have an affected parent.
A proband with CCA may have the disorder as the result of a
Molecular genetic testing (if the
If the
The family history of some individuals diagnosed with CCA may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
Note: If the parent is the individual in whom the
If a parent of the proband has clinical features of CCA and/or is known to have the
If neither parent is clinically affected and if the
• Many individuals diagnosed with CCA have an affected parent.
• A proband with CCA may have the disorder as the result of a
• Molecular genetic testing (if the
• If the
• The family history of some individuals diagnosed with CCA may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• Note: If the parent is the individual in whom the
• If a parent of the proband has clinical features of CCA and/or is known to have the
• If neither parent is clinically affected and if the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
•
•
•
• Canada
•
•
•
## Molecular Genetics
Congenital Contractural Arachnodactyly: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Congenital Contractural Arachnodactyly (
Fibrillin-2 is homologous to fibrillin-1, encoded by
Of note, disease-associated variants in
Nevertheless, identification of an
Notable
Variants listed in the table have been provided by the author.
## Molecular Pathogenesis
Fibrillin-2 is homologous to fibrillin-1, encoded by
Of note, disease-associated variants in
Nevertheless, identification of an
Notable
Variants listed in the table have been provided by the author.
## Chapter Notes
Dr Bert Callewaert (
Contact Dr Callewaert at
Dr Callewaert (
Bert Callewaert, MD, PhD (2019-present)Maurice Godfrey, PhD; University of Nebraska Medical Center (2001-2019)
14 July 2022 (bc) Revision: contact information for questions about congenital contractural arachnodactyly added to
21 October 2019 (bp) Comprehensive update posted live
23 February 2012 (me) Comprehensive update posted live
4 May 2007 (me) Comprehensive update posted live
5 April 2006 (cd) Revision:
29 December 2004 (me) Comprehensive update posted live
5 February 2003 (me) Comprehensive update posted live
23 January 2001 (me) Review posted live
June 2000 (mg) Original submission
• 14 July 2022 (bc) Revision: contact information for questions about congenital contractural arachnodactyly added to
• 21 October 2019 (bp) Comprehensive update posted live
• 23 February 2012 (me) Comprehensive update posted live
• 4 May 2007 (me) Comprehensive update posted live
• 5 April 2006 (cd) Revision:
• 29 December 2004 (me) Comprehensive update posted live
• 5 February 2003 (me) Comprehensive update posted live
• 23 January 2001 (me) Review posted live
• June 2000 (mg) Original submission
## Author Notes
Dr Bert Callewaert (
Contact Dr Callewaert at
Dr Callewaert (
## Author History
Bert Callewaert, MD, PhD (2019-present)Maurice Godfrey, PhD; University of Nebraska Medical Center (2001-2019)
## Revision History
14 July 2022 (bc) Revision: contact information for questions about congenital contractural arachnodactyly added to
21 October 2019 (bp) Comprehensive update posted live
23 February 2012 (me) Comprehensive update posted live
4 May 2007 (me) Comprehensive update posted live
5 April 2006 (cd) Revision:
29 December 2004 (me) Comprehensive update posted live
5 February 2003 (me) Comprehensive update posted live
23 January 2001 (me) Review posted live
June 2000 (mg) Original submission
• 14 July 2022 (bc) Revision: contact information for questions about congenital contractural arachnodactyly added to
• 21 October 2019 (bp) Comprehensive update posted live
• 23 February 2012 (me) Comprehensive update posted live
• 4 May 2007 (me) Comprehensive update posted live
• 5 April 2006 (cd) Revision:
• 29 December 2004 (me) Comprehensive update posted live
• 5 February 2003 (me) Comprehensive update posted live
• 23 January 2001 (me) Review posted live
• June 2000 (mg) Original submission
## References
## Literature Cited
Features of CCA
A. Facial characteristics in a child age two years: midface hypoplasia and micrognathia
B, C. Facial characteristics in a child age one year (B) and a child age five months (C) showing dolichocephaly, flat midface, micrognathia, and crumpled ear
D. Crumpled ear in a neonate
E, F. External ear anomalies in adults showing that the ear has "unfolded," but the helical crus and inferior crus of the antihelix remain prominent and parallel giving a "tram track" appearance
G, H. Arachnodactyly of the fingers in a child age four years (G) and an adult (H) showing mild contractures of the proximal interphalangeal joints
I. Arachnodactyly of the toes and a long and slender foot in a child age one year
J. Muscular hypoplasia and contractures of the knees in a child age four years
Images published with family consent.
|
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"KM Snape, MC Fahey, G McGillivray, P Gupta, DM Milewicz, MB Delatycki. Long-term survival in a child with severe congenital contractural arachnodactyly, autism and severe intellectual disability.. Clin Dysmorphol 2006;15:95-9",
"N Takeda, H Morita, D Fujita, R Inuzuka, Y Taniguchi, Y Imai, Y Hirata, I Komuro. Congenital contractural arachnodactyly complicated with aortic dilatation and dissection: case report and review of literature.. Am J Med Genet A. 2015;167A:2382-7",
"M Wang, CL Clericuzio, M Godfrey. Familial occurrence of typical and severe lethal congenital contractural arachnodactyly caused by missplicing of exon 34 of fibrillin-2.. Am J Hum Genet 1996;59:1027-34"
] |
23/1/2001
|
21/10/2019
|
14/7/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
ccd
|
ccd
|
[
"Cleidocranial Dysostosis",
"Cleidocranial Dysostosis",
"Runt-related transcription factor 2",
"RUNX2",
"Cleidocranial Dysplasia Spectrum Disorder"
] |
Cleidocranial Dysplasia Spectrum Disorder
|
Keren Machol, Roberto Mendoza-Londono, Brendan Lee
|
Summary Cleidocranial dysplasia (CCD) spectrum disorder is a skeletal dysplasia that represents a clinical continuum ranging from classic CCD (triad of delayed closure of the cranial sutures, hypoplastic or aplastic clavicles, and dental abnormalities), to mild CCD, to isolated dental anomalies without other skeletal features. Individuals with classic CCD spectrum disorder typically have abnormally large, wide-open fontanelles at birth that may remain open throughout life. Clavicular hypoplasia can result in narrow, sloping shoulders that can be opposed at the midline. Moderate short stature may be observed, with most affected individuals being shorter than their unaffected sibs. Dental anomalies may include delayed eruption of secondary dentition, failure to shed the primary teeth, and supernumerary teeth. Individuals with CCD spectrum disorder are at increased risk of developing recurrent sinus infections, recurrent ear infections leading to conductive hearing loss, and upper airway obstruction. Intelligence is typically normal. The diagnosis of CCD spectrum disorder is established in an individual with typical clinical and radiographic findings and/or a heterozygous pathogenic variant in CCD spectrum disorder is inherited in an autosomal dominant manner. The proportion of individuals with CCD spectrum disorder caused by a
|
## Diagnosis
Cleidocranial dysplasia (CCD) spectrum disorder is a skeletal dysplasia that represents a continuum of clinical and radiographic findings ranging from classic CCD (triad of delayed closure of the cranial sutures, hypoplastic or aplastic clavicles, and dental abnormalities), to mild CCD, to isolated dental anomalies without other skeletal features. No formal clinical diagnostic criteria for CCD spectrum disorder have been established.
CCD spectrum disorder
Wide-open sutures, patent fontanelles, presence of Wormian bones
Delayed ossification of the skull
Poor or absent pneumatization of the paranasal, frontal, and mastoid sinuses
Impacted, crowded teeth; supernumerary teeth
Cone-shaped thorax with narrow upper thoracic diameter
Typically bilateral (but not necessarily symmetric) clavicular abnormalities ranging from complete absence to hypoplastic or discontinuous clavicles. The lateral portions are more affected than the medial aspects of the clavicles (see
Hypoplastic scapulae
Delayed ossification of the pubic bone with wide pubic symphysis
Hypoplasia of the iliac wings
Widening of the sacroiliac joints
Elongated femoral head with short femoral neck and elongated epiphyses ("chef-hat" appearance)
Coxa vara
Pseudoepiphyses of the metacarpal and metatarsal bones, which may result in a characteristic lengthening of the second metacarpal (See
Hypoplastic distal phalanges
Deformed and short middle phalanges of the third, fourth, and fifth digits with cone-shaped epiphyses
The clinical diagnosis of a CCD spectrum disorder can be
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic, and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
Molecular Genetic Testing Used in Cleidocranial Dysplasia Spectrum Disorder
NA = not applicable
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Individuals with
Two individuals with translocations involving the
•
•
• Wide-open sutures, patent fontanelles, presence of Wormian bones
• Delayed ossification of the skull
• Poor or absent pneumatization of the paranasal, frontal, and mastoid sinuses
• Impacted, crowded teeth; supernumerary teeth
• Wide-open sutures, patent fontanelles, presence of Wormian bones
• Delayed ossification of the skull
• Poor or absent pneumatization of the paranasal, frontal, and mastoid sinuses
• Impacted, crowded teeth; supernumerary teeth
•
• Cone-shaped thorax with narrow upper thoracic diameter
• Typically bilateral (but not necessarily symmetric) clavicular abnormalities ranging from complete absence to hypoplastic or discontinuous clavicles. The lateral portions are more affected than the medial aspects of the clavicles (see
• Hypoplastic scapulae
• Cone-shaped thorax with narrow upper thoracic diameter
• Typically bilateral (but not necessarily symmetric) clavicular abnormalities ranging from complete absence to hypoplastic or discontinuous clavicles. The lateral portions are more affected than the medial aspects of the clavicles (see
• Hypoplastic scapulae
•
• Delayed ossification of the pubic bone with wide pubic symphysis
• Hypoplasia of the iliac wings
• Widening of the sacroiliac joints
• Elongated femoral head with short femoral neck and elongated epiphyses ("chef-hat" appearance)
• Coxa vara
• Delayed ossification of the pubic bone with wide pubic symphysis
• Hypoplasia of the iliac wings
• Widening of the sacroiliac joints
• Elongated femoral head with short femoral neck and elongated epiphyses ("chef-hat" appearance)
• Coxa vara
•
• Pseudoepiphyses of the metacarpal and metatarsal bones, which may result in a characteristic lengthening of the second metacarpal (See
• Hypoplastic distal phalanges
• Deformed and short middle phalanges of the third, fourth, and fifth digits with cone-shaped epiphyses
• Pseudoepiphyses of the metacarpal and metatarsal bones, which may result in a characteristic lengthening of the second metacarpal (See
• Hypoplastic distal phalanges
• Deformed and short middle phalanges of the third, fourth, and fifth digits with cone-shaped epiphyses
• Wide-open sutures, patent fontanelles, presence of Wormian bones
• Delayed ossification of the skull
• Poor or absent pneumatization of the paranasal, frontal, and mastoid sinuses
• Impacted, crowded teeth; supernumerary teeth
• Cone-shaped thorax with narrow upper thoracic diameter
• Typically bilateral (but not necessarily symmetric) clavicular abnormalities ranging from complete absence to hypoplastic or discontinuous clavicles. The lateral portions are more affected than the medial aspects of the clavicles (see
• Hypoplastic scapulae
• Delayed ossification of the pubic bone with wide pubic symphysis
• Hypoplasia of the iliac wings
• Widening of the sacroiliac joints
• Elongated femoral head with short femoral neck and elongated epiphyses ("chef-hat" appearance)
• Coxa vara
• Pseudoepiphyses of the metacarpal and metatarsal bones, which may result in a characteristic lengthening of the second metacarpal (See
• Hypoplastic distal phalanges
• Deformed and short middle phalanges of the third, fourth, and fifth digits with cone-shaped epiphyses
• For an introduction to multigene panels click
## Suggestive Findings
CCD spectrum disorder
Wide-open sutures, patent fontanelles, presence of Wormian bones
Delayed ossification of the skull
Poor or absent pneumatization of the paranasal, frontal, and mastoid sinuses
Impacted, crowded teeth; supernumerary teeth
Cone-shaped thorax with narrow upper thoracic diameter
Typically bilateral (but not necessarily symmetric) clavicular abnormalities ranging from complete absence to hypoplastic or discontinuous clavicles. The lateral portions are more affected than the medial aspects of the clavicles (see
Hypoplastic scapulae
Delayed ossification of the pubic bone with wide pubic symphysis
Hypoplasia of the iliac wings
Widening of the sacroiliac joints
Elongated femoral head with short femoral neck and elongated epiphyses ("chef-hat" appearance)
Coxa vara
Pseudoepiphyses of the metacarpal and metatarsal bones, which may result in a characteristic lengthening of the second metacarpal (See
Hypoplastic distal phalanges
Deformed and short middle phalanges of the third, fourth, and fifth digits with cone-shaped epiphyses
•
•
• Wide-open sutures, patent fontanelles, presence of Wormian bones
• Delayed ossification of the skull
• Poor or absent pneumatization of the paranasal, frontal, and mastoid sinuses
• Impacted, crowded teeth; supernumerary teeth
• Wide-open sutures, patent fontanelles, presence of Wormian bones
• Delayed ossification of the skull
• Poor or absent pneumatization of the paranasal, frontal, and mastoid sinuses
• Impacted, crowded teeth; supernumerary teeth
•
• Cone-shaped thorax with narrow upper thoracic diameter
• Typically bilateral (but not necessarily symmetric) clavicular abnormalities ranging from complete absence to hypoplastic or discontinuous clavicles. The lateral portions are more affected than the medial aspects of the clavicles (see
• Hypoplastic scapulae
• Cone-shaped thorax with narrow upper thoracic diameter
• Typically bilateral (but not necessarily symmetric) clavicular abnormalities ranging from complete absence to hypoplastic or discontinuous clavicles. The lateral portions are more affected than the medial aspects of the clavicles (see
• Hypoplastic scapulae
•
• Delayed ossification of the pubic bone with wide pubic symphysis
• Hypoplasia of the iliac wings
• Widening of the sacroiliac joints
• Elongated femoral head with short femoral neck and elongated epiphyses ("chef-hat" appearance)
• Coxa vara
• Delayed ossification of the pubic bone with wide pubic symphysis
• Hypoplasia of the iliac wings
• Widening of the sacroiliac joints
• Elongated femoral head with short femoral neck and elongated epiphyses ("chef-hat" appearance)
• Coxa vara
•
• Pseudoepiphyses of the metacarpal and metatarsal bones, which may result in a characteristic lengthening of the second metacarpal (See
• Hypoplastic distal phalanges
• Deformed and short middle phalanges of the third, fourth, and fifth digits with cone-shaped epiphyses
• Pseudoepiphyses of the metacarpal and metatarsal bones, which may result in a characteristic lengthening of the second metacarpal (See
• Hypoplastic distal phalanges
• Deformed and short middle phalanges of the third, fourth, and fifth digits with cone-shaped epiphyses
• Wide-open sutures, patent fontanelles, presence of Wormian bones
• Delayed ossification of the skull
• Poor or absent pneumatization of the paranasal, frontal, and mastoid sinuses
• Impacted, crowded teeth; supernumerary teeth
• Cone-shaped thorax with narrow upper thoracic diameter
• Typically bilateral (but not necessarily symmetric) clavicular abnormalities ranging from complete absence to hypoplastic or discontinuous clavicles. The lateral portions are more affected than the medial aspects of the clavicles (see
• Hypoplastic scapulae
• Delayed ossification of the pubic bone with wide pubic symphysis
• Hypoplasia of the iliac wings
• Widening of the sacroiliac joints
• Elongated femoral head with short femoral neck and elongated epiphyses ("chef-hat" appearance)
• Coxa vara
• Pseudoepiphyses of the metacarpal and metatarsal bones, which may result in a characteristic lengthening of the second metacarpal (See
• Hypoplastic distal phalanges
• Deformed and short middle phalanges of the third, fourth, and fifth digits with cone-shaped epiphyses
## Establishing the Diagnosis
The clinical diagnosis of a CCD spectrum disorder can be
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic, and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
Molecular Genetic Testing Used in Cleidocranial Dysplasia Spectrum Disorder
NA = not applicable
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Individuals with
Two individuals with translocations involving the
• For an introduction to multigene panels click
## Clinical Characteristics
Cleidocranial dysplasia (CCD) spectrum disorder is a skeletal dysplasia representing a clinical continuum ranging from classic CCD (triad of delayed closure of the cranial sutures, hypoplastic or aplastic clavicles, and dental abnormalities), to mild CCD, to isolated dental anomalies without other skeletal features [
Further medical problems identified in individuals with CCD spectrum disorder include short stature, skeletal/orthopedic findings, dental complications, ENT complications, endocrine findings, and mild developmental delay.
Males are on average six inches shorter than their unaffected brothers and have an average height of 165 cm (± 8 cm).
Females are on average three inches shorter than their unaffected sisters and have an average height of 156 cm (± 10 cm) [
Pes planus (flat feet) in 57%
Genu valgum (knock-knee deformity) in 28%
Scoliosis in 18% [
Osteoporosis, found in 8/14 (57%) affected individuals; and osteopenia, identified in 3/14 (21%) individuals [
Other less common orthopedic problems include joint dislocation at the shoulder and elbow [
Some genotype-phenotype correlations have been established for the dental manifestations seen in CCD spectrum disorder. No clear correlation has been established between genotype and clavicular involvement [
Heterozygous
Short stature and dental anomalies were found to be milder in individuals with a classic CCD phenotype who had an intact runt domain and higher residual RUNX2 activity when compared to individuals with a classic CCD phenotype in whom the pathogenic variant affected the runt domain [
A clinical spectrum ranging from isolated dental anomalies without the skeletal features of CCD, to mild CCD, to classic CCD results from hypomorphic pathogenic variants that result in partial loss of protein function (
Osteoporosis leading to recurrent bone fractures and scoliosis has been associated with a heterozygous pathogenic frameshift variant
Pathogenic variants in
Cleidocranial dysplasia spectrum disorder was originally described as dento-osseous dysplasia affecting several individuals in a large pedigree.
While the term "cleidocranial dysostosis" has been used, the disease is more correctly considered a dysplasia given that RUNX2 has important functions both during skeletal formation and in bone maintenance.
• Males are on average six inches shorter than their unaffected brothers and have an average height of 165 cm (± 8 cm).
• Females are on average three inches shorter than their unaffected sisters and have an average height of 156 cm (± 10 cm) [
• Pes planus (flat feet) in 57%
• Genu valgum (knock-knee deformity) in 28%
• Scoliosis in 18% [
• Osteoporosis, found in 8/14 (57%) affected individuals; and osteopenia, identified in 3/14 (21%) individuals [
• Heterozygous
• Short stature and dental anomalies were found to be milder in individuals with a classic CCD phenotype who had an intact runt domain and higher residual RUNX2 activity when compared to individuals with a classic CCD phenotype in whom the pathogenic variant affected the runt domain [
• A clinical spectrum ranging from isolated dental anomalies without the skeletal features of CCD, to mild CCD, to classic CCD results from hypomorphic pathogenic variants that result in partial loss of protein function (
• Osteoporosis leading to recurrent bone fractures and scoliosis has been associated with a heterozygous pathogenic frameshift variant
## Clinical Description
Cleidocranial dysplasia (CCD) spectrum disorder is a skeletal dysplasia representing a clinical continuum ranging from classic CCD (triad of delayed closure of the cranial sutures, hypoplastic or aplastic clavicles, and dental abnormalities), to mild CCD, to isolated dental anomalies without other skeletal features [
Further medical problems identified in individuals with CCD spectrum disorder include short stature, skeletal/orthopedic findings, dental complications, ENT complications, endocrine findings, and mild developmental delay.
Males are on average six inches shorter than their unaffected brothers and have an average height of 165 cm (± 8 cm).
Females are on average three inches shorter than their unaffected sisters and have an average height of 156 cm (± 10 cm) [
Pes planus (flat feet) in 57%
Genu valgum (knock-knee deformity) in 28%
Scoliosis in 18% [
Osteoporosis, found in 8/14 (57%) affected individuals; and osteopenia, identified in 3/14 (21%) individuals [
Other less common orthopedic problems include joint dislocation at the shoulder and elbow [
• Males are on average six inches shorter than their unaffected brothers and have an average height of 165 cm (± 8 cm).
• Females are on average three inches shorter than their unaffected sisters and have an average height of 156 cm (± 10 cm) [
• Pes planus (flat feet) in 57%
• Genu valgum (knock-knee deformity) in 28%
• Scoliosis in 18% [
• Osteoporosis, found in 8/14 (57%) affected individuals; and osteopenia, identified in 3/14 (21%) individuals [
## Genotype-Phenotype Correlations
Some genotype-phenotype correlations have been established for the dental manifestations seen in CCD spectrum disorder. No clear correlation has been established between genotype and clavicular involvement [
Heterozygous
Short stature and dental anomalies were found to be milder in individuals with a classic CCD phenotype who had an intact runt domain and higher residual RUNX2 activity when compared to individuals with a classic CCD phenotype in whom the pathogenic variant affected the runt domain [
A clinical spectrum ranging from isolated dental anomalies without the skeletal features of CCD, to mild CCD, to classic CCD results from hypomorphic pathogenic variants that result in partial loss of protein function (
Osteoporosis leading to recurrent bone fractures and scoliosis has been associated with a heterozygous pathogenic frameshift variant
• Heterozygous
• Short stature and dental anomalies were found to be milder in individuals with a classic CCD phenotype who had an intact runt domain and higher residual RUNX2 activity when compared to individuals with a classic CCD phenotype in whom the pathogenic variant affected the runt domain [
• A clinical spectrum ranging from isolated dental anomalies without the skeletal features of CCD, to mild CCD, to classic CCD results from hypomorphic pathogenic variants that result in partial loss of protein function (
• Osteoporosis leading to recurrent bone fractures and scoliosis has been associated with a heterozygous pathogenic frameshift variant
## Penetrance
Pathogenic variants in
## Nomenclature
Cleidocranial dysplasia spectrum disorder was originally described as dento-osseous dysplasia affecting several individuals in a large pedigree.
While the term "cleidocranial dysostosis" has been used, the disease is more correctly considered a dysplasia given that RUNX2 has important functions both during skeletal formation and in bone maintenance.
## Prevalence
## Genetically Related (Allelic) Disorders
Partial intragenic duplication of
Complete duplications of
## Differential Diagnosis
Other conditions share some characteristics with cleidocranial dysplasia (CCD) spectrum disorder. The fact that similar skeletal elements are affected suggests that some of these conditions may result from mutation of genes (most notably
Genes of Interest in the Differential Diagnosis of Cleidocranial Dysplasia Spectrum Disorder
Children w/infantile form may present w/very poorly mineralized cranium & widened cranial sutures.
Premature deciduous tooth loss
Generalized defect of mineralization w/delayed ossification of multiple skeletal elements
Children w/infantile form may present w/short ribs & narrow thorax.
Clavicles least affected
Rachitic skeletal changes
Very low alkaline phosphatase activity in serum & tissues
Nephrocalcinosis
Hypercalcemia
Delayed closure of fontanelle
Delayed/absent eruption of deciduous teeth
Supernumerary teeth
Hypoplastic or absent clavicles, clavicula bipartita
Metacarpal/metatarsal pseudoepiphyses
Delayed ossification of pubic & carpal bones
Short distal phalanges
Normal stature
DD (mild to moderate)
Short clavicles
Short stature
Short distal phalanges
Delayed ossification of skull
Poor weight gain
DD
Congenital heart defect
Acro-osteolysis
Osteopetrosis; radio-opacity of all bones ↑ due to ↑ density of trabecular bone but not cortices
Short stature w/↑ bone fragility, short terminal phalanges
Wide-open fontanelles & sutures
Unusual mineralization of skull
Hypoplastic clavicles
Absence/hypoplasia of thumbs, halluces, & distal phalanges
Gracile bones
Prenatal growth deficiency
Brain malformations
Delayed closure of cranial sutures
Micrognathia
Early tooth loss
Dysplastic clavicles
Acro-osteodysplasia of fingers & toes w/delayed ossification of carpal bones
Progressively stiff joints
Short stature
Alopecia; scalp hair sparse by 3rd decade
Atrophic skin w/↓ subcutaneous fat
Skin hyperpigmentation
Enlarged parietal foramina
Broad forehead w/frontal bossing
Not assoc w/dental abnormalities
AR = autosomal recessive; AD = autosomal dominant; CCD = cleidocranial dysplasia; DD = developmental delay; MOI = mode of inheritance
In one report, an individual with severe CCD was initially thought to have hypophosphatasia [
Perinatal and infantile hypophosphatasia are typically inherited in an autosomal recessive manner. The milder forms, especially adult hypophosphatasia and odontohypophosphatasia, may be inherited in an autosomal recessive or autosomal dominant manner depending on the effect that the
See
• Children w/infantile form may present w/very poorly mineralized cranium & widened cranial sutures.
• Premature deciduous tooth loss
• Generalized defect of mineralization w/delayed ossification of multiple skeletal elements
• Children w/infantile form may present w/short ribs & narrow thorax.
• Clavicles least affected
• Rachitic skeletal changes
• Very low alkaline phosphatase activity in serum & tissues
• Nephrocalcinosis
• Hypercalcemia
• Delayed closure of fontanelle
• Delayed/absent eruption of deciduous teeth
• Supernumerary teeth
• Hypoplastic or absent clavicles, clavicula bipartita
• Metacarpal/metatarsal pseudoepiphyses
• Delayed ossification of pubic & carpal bones
• Short distal phalanges
• Normal stature
• DD (mild to moderate)
• Short clavicles
• Short stature
• Short distal phalanges
• Delayed ossification of skull
• Poor weight gain
• DD
• Congenital heart defect
• Acro-osteolysis
• Osteopetrosis; radio-opacity of all bones ↑ due to ↑ density of trabecular bone but not cortices
• Short stature w/↑ bone fragility, short terminal phalanges
• Wide-open fontanelles & sutures
• Unusual mineralization of skull
• Hypoplastic clavicles
• Absence/hypoplasia of thumbs, halluces, & distal phalanges
• Gracile bones
• Prenatal growth deficiency
• Brain malformations
• Delayed closure of cranial sutures
• Micrognathia
• Early tooth loss
• Dysplastic clavicles
• Acro-osteodysplasia of fingers & toes w/delayed ossification of carpal bones
• Progressively stiff joints
• Short stature
• Alopecia; scalp hair sparse by 3rd decade
• Atrophic skin w/↓ subcutaneous fat
• Skin hyperpigmentation
• Enlarged parietal foramina
• Broad forehead w/frontal bossing
• Not assoc w/dental abnormalities
## Management
No clinical practice guidelines for cleidocranial dysplasia (CCD) spectrum disorder have been published.
To establish the extent of disease and needs in an individual diagnosed with CCD spectrum disorder, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Cleidocranial Dysplasia Spectrum Disorder
Clinical assessment for skeletal manifestations
Full skeletal survey incl hands & feet
CCD = cleidocranial dysplasia; DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with Cleidocranial Dysplasia Spectrum Disorder
If cranial vault defect is significant, protect head from blunt trauma; helmets may be advised for high-risk activities. In these persons, eval by craniofacial surgeon & rehabilitation services are indicated.
Affected persons may consider correction of metopic groove for cosmetic reasons.
Careful planning for anesthetic mgmt
ENT consult to assist in securing airway
Consider alternative anesthetic approaches, incl neuraxial block, taking into account possible spine abnormalities.
Retention of primary dentition
Presence of supernumerary teeth
Non-eruption of secondary dentition
Improve appearance
Provide functioning masticatory mechanism
Prosthetic replacements, w/ or w/o prior extractions
Removal of supernumerary teeth followed by surgical repositioning of secondary teeth
Combination of surgical & orthodontic measures for actively erupting teeth & aligning impacted secondary teeth
Aggressive & timely treatment
Tympanostomy tubes should be considered when middle ear infections are recurrent.
Regular immunizations incl influenza
Sleep study in those w/manifestations of obstructive sleep apnea
Surgical intervention may be required.
Efficacy of GH therapy in CCD has not been proven.
Possible adverse effects of GH therapy on primary chondrodysplastic growth plate are theoretically possible, as
CCD = cleidocranial dysplasia; DXA = dual-energy x-ray absorptiometry; GH = growth hormone
There have been reports of successful surgical interventions for metopic groove & hypoplastic clavicles in a very small number of affected individuals [
For a detailed review, see
See
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Recommended Surveillance for Individuals with Cleidocranial Dysplasia Spectrum Disorder
Every 6 mos or more frequently as recommended by dentist beginning at age 3 yrs
Assess for recurrent sinus & ear infections.
Assess for manifestations of upper airway obstruction.
DXA = dual-energy x-ray absorptiometry
To avoid head trauma, helmets and protective devices should be worn when participating in high-risk sports and activities.
See
Pregnant women with CCD spectrum disorder should be monitored closely for cephalopelvic disproportion, which may require delivery by cesarean section. The primary cesarean section rate among women with a CCD spectrum disorder is 69%, which is higher than in controls [
Search
• Clinical assessment for skeletal manifestations
• Full skeletal survey incl hands & feet
• If cranial vault defect is significant, protect head from blunt trauma; helmets may be advised for high-risk activities. In these persons, eval by craniofacial surgeon & rehabilitation services are indicated.
• Affected persons may consider correction of metopic groove for cosmetic reasons.
• Careful planning for anesthetic mgmt
• ENT consult to assist in securing airway
• Consider alternative anesthetic approaches, incl neuraxial block, taking into account possible spine abnormalities.
• Retention of primary dentition
• Presence of supernumerary teeth
• Non-eruption of secondary dentition
• Improve appearance
• Provide functioning masticatory mechanism
• Prosthetic replacements, w/ or w/o prior extractions
• Removal of supernumerary teeth followed by surgical repositioning of secondary teeth
• Combination of surgical & orthodontic measures for actively erupting teeth & aligning impacted secondary teeth
• Aggressive & timely treatment
• Tympanostomy tubes should be considered when middle ear infections are recurrent.
• Regular immunizations incl influenza
• Sleep study in those w/manifestations of obstructive sleep apnea
• Surgical intervention may be required.
• Efficacy of GH therapy in CCD has not been proven.
• Possible adverse effects of GH therapy on primary chondrodysplastic growth plate are theoretically possible, as
• Assess for recurrent sinus & ear infections.
• Assess for manifestations of upper airway obstruction.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CCD spectrum disorder, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Cleidocranial Dysplasia Spectrum Disorder
Clinical assessment for skeletal manifestations
Full skeletal survey incl hands & feet
CCD = cleidocranial dysplasia; DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Clinical assessment for skeletal manifestations
• Full skeletal survey incl hands & feet
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Cleidocranial Dysplasia Spectrum Disorder
If cranial vault defect is significant, protect head from blunt trauma; helmets may be advised for high-risk activities. In these persons, eval by craniofacial surgeon & rehabilitation services are indicated.
Affected persons may consider correction of metopic groove for cosmetic reasons.
Careful planning for anesthetic mgmt
ENT consult to assist in securing airway
Consider alternative anesthetic approaches, incl neuraxial block, taking into account possible spine abnormalities.
Retention of primary dentition
Presence of supernumerary teeth
Non-eruption of secondary dentition
Improve appearance
Provide functioning masticatory mechanism
Prosthetic replacements, w/ or w/o prior extractions
Removal of supernumerary teeth followed by surgical repositioning of secondary teeth
Combination of surgical & orthodontic measures for actively erupting teeth & aligning impacted secondary teeth
Aggressive & timely treatment
Tympanostomy tubes should be considered when middle ear infections are recurrent.
Regular immunizations incl influenza
Sleep study in those w/manifestations of obstructive sleep apnea
Surgical intervention may be required.
Efficacy of GH therapy in CCD has not been proven.
Possible adverse effects of GH therapy on primary chondrodysplastic growth plate are theoretically possible, as
CCD = cleidocranial dysplasia; DXA = dual-energy x-ray absorptiometry; GH = growth hormone
There have been reports of successful surgical interventions for metopic groove & hypoplastic clavicles in a very small number of affected individuals [
For a detailed review, see
See
• If cranial vault defect is significant, protect head from blunt trauma; helmets may be advised for high-risk activities. In these persons, eval by craniofacial surgeon & rehabilitation services are indicated.
• Affected persons may consider correction of metopic groove for cosmetic reasons.
• Careful planning for anesthetic mgmt
• ENT consult to assist in securing airway
• Consider alternative anesthetic approaches, incl neuraxial block, taking into account possible spine abnormalities.
• Retention of primary dentition
• Presence of supernumerary teeth
• Non-eruption of secondary dentition
• Improve appearance
• Provide functioning masticatory mechanism
• Prosthetic replacements, w/ or w/o prior extractions
• Removal of supernumerary teeth followed by surgical repositioning of secondary teeth
• Combination of surgical & orthodontic measures for actively erupting teeth & aligning impacted secondary teeth
• Aggressive & timely treatment
• Tympanostomy tubes should be considered when middle ear infections are recurrent.
• Regular immunizations incl influenza
• Sleep study in those w/manifestations of obstructive sleep apnea
• Surgical intervention may be required.
• Efficacy of GH therapy in CCD has not been proven.
• Possible adverse effects of GH therapy on primary chondrodysplastic growth plate are theoretically possible, as
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Recommended Surveillance for Individuals with Cleidocranial Dysplasia Spectrum Disorder
Every 6 mos or more frequently as recommended by dentist beginning at age 3 yrs
Assess for recurrent sinus & ear infections.
Assess for manifestations of upper airway obstruction.
DXA = dual-energy x-ray absorptiometry
• Assess for recurrent sinus & ear infections.
• Assess for manifestations of upper airway obstruction.
## Agents/Circumstances to Avoid
To avoid head trauma, helmets and protective devices should be worn when participating in high-risk sports and activities.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Pregnant women with CCD spectrum disorder should be monitored closely for cephalopelvic disproportion, which may require delivery by cesarean section. The primary cesarean section rate among women with a CCD spectrum disorder is 69%, which is higher than in controls [
## Therapies Under Investigation
Search
## Genetic Counseling
Cleidocranial dysplasia (CCD) spectrum disorder is inherited in an autosomal dominant manner.
Some individuals diagnosed with CCD spectrum disorder have an affected parent.
A proband with CCD spectrum disorder may have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include:
Detailed clinical examination and consideration of craniofacial and skeletal x-rays if there are signs suggestive of dental or bone abnormalities. (Note: The phenotype may vary between parent and child even though they have the same pathogenic variant.)
Molecular genetic testing (if a molecular diagnosis has been established in the proband) to confirm the genetic status of the parents and to allow reliable recurrence risk counseling.
If the proband has a known pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism* [
* A parent with somatic and germline mosaicism for a
The family history of some individuals diagnosed with CCD spectrum disorder may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical examination (with skeletal x-rays) of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
The phenotype may vary among sibs who inherit the same
If the proband has a known
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental germline mosaicism.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Some individuals diagnosed with CCD spectrum disorder have an affected parent.
• A proband with CCD spectrum disorder may have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include:
• Detailed clinical examination and consideration of craniofacial and skeletal x-rays if there are signs suggestive of dental or bone abnormalities. (Note: The phenotype may vary between parent and child even though they have the same pathogenic variant.)
• Molecular genetic testing (if a molecular diagnosis has been established in the proband) to confirm the genetic status of the parents and to allow reliable recurrence risk counseling.
• Detailed clinical examination and consideration of craniofacial and skeletal x-rays if there are signs suggestive of dental or bone abnormalities. (Note: The phenotype may vary between parent and child even though they have the same pathogenic variant.)
• Molecular genetic testing (if a molecular diagnosis has been established in the proband) to confirm the genetic status of the parents and to allow reliable recurrence risk counseling.
• If the proband has a known pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism* [
• * A parent with somatic and germline mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism* [
• * A parent with somatic and germline mosaicism for a
• The family history of some individuals diagnosed with CCD spectrum disorder may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical examination (with skeletal x-rays) of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
• Detailed clinical examination and consideration of craniofacial and skeletal x-rays if there are signs suggestive of dental or bone abnormalities. (Note: The phenotype may vary between parent and child even though they have the same pathogenic variant.)
• Molecular genetic testing (if a molecular diagnosis has been established in the proband) to confirm the genetic status of the parents and to allow reliable recurrence risk counseling.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism* [
• * A parent with somatic and germline mosaicism for a
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• The phenotype may vary among sibs who inherit the same
• If the proband has a known
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental germline mosaicism.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
## Mode of Inheritance
Cleidocranial dysplasia (CCD) spectrum disorder is inherited in an autosomal dominant manner.
## Risk to Family Members
Some individuals diagnosed with CCD spectrum disorder have an affected parent.
A proband with CCD spectrum disorder may have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include:
Detailed clinical examination and consideration of craniofacial and skeletal x-rays if there are signs suggestive of dental or bone abnormalities. (Note: The phenotype may vary between parent and child even though they have the same pathogenic variant.)
Molecular genetic testing (if a molecular diagnosis has been established in the proband) to confirm the genetic status of the parents and to allow reliable recurrence risk counseling.
If the proband has a known pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism* [
* A parent with somatic and germline mosaicism for a
The family history of some individuals diagnosed with CCD spectrum disorder may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical examination (with skeletal x-rays) of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
The phenotype may vary among sibs who inherit the same
If the proband has a known
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental germline mosaicism.
• Some individuals diagnosed with CCD spectrum disorder have an affected parent.
• A proband with CCD spectrum disorder may have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include:
• Detailed clinical examination and consideration of craniofacial and skeletal x-rays if there are signs suggestive of dental or bone abnormalities. (Note: The phenotype may vary between parent and child even though they have the same pathogenic variant.)
• Molecular genetic testing (if a molecular diagnosis has been established in the proband) to confirm the genetic status of the parents and to allow reliable recurrence risk counseling.
• Detailed clinical examination and consideration of craniofacial and skeletal x-rays if there are signs suggestive of dental or bone abnormalities. (Note: The phenotype may vary between parent and child even though they have the same pathogenic variant.)
• Molecular genetic testing (if a molecular diagnosis has been established in the proband) to confirm the genetic status of the parents and to allow reliable recurrence risk counseling.
• If the proband has a known pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism* [
• * A parent with somatic and germline mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism* [
• * A parent with somatic and germline mosaicism for a
• The family history of some individuals diagnosed with CCD spectrum disorder may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical examination (with skeletal x-rays) of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
• Detailed clinical examination and consideration of craniofacial and skeletal x-rays if there are signs suggestive of dental or bone abnormalities. (Note: The phenotype may vary between parent and child even though they have the same pathogenic variant.)
• Molecular genetic testing (if a molecular diagnosis has been established in the proband) to confirm the genetic status of the parents and to allow reliable recurrence risk counseling.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism* [
• * A parent with somatic and germline mosaicism for a
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• The phenotype may vary among sibs who inherit the same
• If the proband has a known
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental germline mosaicism.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
## Prenatal Testing and Preimplantation Genetic Testing
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
•
• Canada
•
•
•
•
•
•
•
•
•
•
•
## Molecular Genetics
Cleidocranial Dysplasia Spectrum Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Cleidocranial Dysplasia Spectrum Disorder (
The majority of
Hypomorphic
Notable
Variants listed in the table have been provided by the authors.
Published as frameshift variant in codon Pro402 [
## Molecular Pathogenesis
The majority of
Hypomorphic
Notable
Variants listed in the table have been provided by the authors.
Published as frameshift variant in codon Pro402 [
## Chapter Notes
Dr Keren Machol's web pages:
Dr Mendoza-Londono's
Dr Lee's web pages:
13 April 2023 (sw) Comprehensive update posted live
16 November 2017 (ma) Comprehensive update posted live
29 August 2013 (me) Comprehensive update posted live
25 June 2009 (me) Comprehensive update posted live
3 January 2006 (me) Review posted live
28 June 2005 (rml) Original submission
• 13 April 2023 (sw) Comprehensive update posted live
• 16 November 2017 (ma) Comprehensive update posted live
• 29 August 2013 (me) Comprehensive update posted live
• 25 June 2009 (me) Comprehensive update posted live
• 3 January 2006 (me) Review posted live
• 28 June 2005 (rml) Original submission
## Author Notes
Dr Keren Machol's web pages:
Dr Mendoza-Londono's
Dr Lee's web pages:
## Revision History
13 April 2023 (sw) Comprehensive update posted live
16 November 2017 (ma) Comprehensive update posted live
29 August 2013 (me) Comprehensive update posted live
25 June 2009 (me) Comprehensive update posted live
3 January 2006 (me) Review posted live
28 June 2005 (rml) Original submission
• 13 April 2023 (sw) Comprehensive update posted live
• 16 November 2017 (ma) Comprehensive update posted live
• 29 August 2013 (me) Comprehensive update posted live
• 25 June 2009 (me) Comprehensive update posted live
• 3 January 2006 (me) Review posted live
• 28 June 2005 (rml) Original submission
## References
## Literature Cited
Shoulders in an individual with clavicular hypoplasia may be brought to the midline.
Chest x-ray demonstrates clavicular hypoplasia.
Hand x-ray of a male age 2.5 years with cleidocranial dysplasia spectrum disorder
a. Note pseudoepiphyses at the bases of the second and third metacarpals with accessory physes seen at the base of the fourth and fifth metacarpals.
b. Cone-shaped epiphyses are seen involving most predominantly the third and fourth middle phalanges. The phalanges appear abnormally formed, particularly the middle phalanges of the second through fifth digits.
|
[
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"T Goto, M Aramaki, H Yoshihashi, G Nishimura, Y Hasegawa, T Takahashi, T Ishii, Y Fukushima, K Kosaki. Large fontanels are a shared feature of haploinsufficiency of RUNX2 and its co-activator CBFB.. Congenit Anom (Kyoto) 2004;44:225-9",
"MR Greives, EA Odessey, DJ Waggoner, DS Shenaq, S Aradhya, A Mitchell, E Whitcomb, N Warshawsky, TC He, RR Reid. RUNX2 quadruplication: additional evidence toward a new form of syndromic craniosynostosis.. J Craniofac Surg. 2013;24:126-9",
"NV Hermann, HD Hove, C Jørgensen, P Larsen, TA Darvann, S Kreiborg, K Sundberg. Prenatal 3D ultrasound diagnostics in cleidocranial dysplasia.. Fetal Diagn Ther. 2009;25:36-9",
"SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97",
"A Ioscovich, D Barth, A Samueloff, S Grisaru-Granovsky, S Halpern. Anesthetic management of a patient with cleidocranial dysplasia undergoing various obstetric procedures.. Int J Obstet Anesth. 2010;19:106-8",
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"N Kang, SZ Kim, SN Jung. Correction of depressed forehead with BoneSource in cleidocranial dysplasia.. J Craniofac Surg. 2009;20:564-6",
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"JK Northup, R Matalon, LH Lockhart, JC Hawkins, GV Velagaleti. A complex chromosome rearrangement, der(6)ins(6)(p21.1q25.3q27)inv(6)(p25.3q27), in a child with cleidocranial dysplasia.. Eur J Med Genet. 2011;54:e394-8",
"M Muurinen, F Taylan, S Tournis, J Eisfeldt, A Balanika, H Vastardis, S Ala-Mello, O Mäkitie, A. Costantini. Mosaic Deletions of Known Genes Explain Skeletal Dysplasias With High and Low Bone Mass.. JBMR Plus. 2022;6",
"CE Ott, H Hein, S Lohan, J Hoogeboom, N Foulds, J Grünhagen, S Stricker, P Villavicencio-Lorini, E Klopocki, S Mundlos. Microduplications upstream of MSX2 are associated with a phenocopy of cleidocranial dysplasia.. J Med Genet. 2012;49:437-41",
"CE Ott, G Leschik, F Trotier, L Brueton, HG Brunner, W Brussel, E Guillen-Navarro, C Haase, J Kohlhase, D Kotzot, A Lane, MA Lee-Kirsch, S Morlot, ME Simon, E Steichen-Gersdorf, DH Tegay, H Peters, S Mundlos, E Klopocki. Deletions of the RUNX2 gene are present in about 10% of individuals with cleidocranial dysplasia.. Hum Mutat. 2010;31:E1587-93",
"F Otto, H Kanegane, S Mundlos. Mutations in the RUNX2 gene in patients with cleidocranial dysplasia.. Hum Mutat 2002;19:209-16",
"T Pal, D Napierala, TA Becker, M Loscalzo, D Baldridge, B Lee, R Sutphen. The presence of germ line mosaicism in cleidocranial dysplasia.. Clin Genet. 2007;71:589-91",
"SM Purandare, R Mendoza-Londono, SA Yatsenko, D Napierala, DA Scott, T Sibai, K Casas, P Wilson, J Lee, R Muneer, JC Leonard, FG Ramji, R Lachman, S Li, P Stankiewicz, B Lee, JJ Mulvihill. De novo three-way chromosome translocation 46,XY,t(4;6;21)(p16;p21.1;q21) in a male with cleidocranial dysplasia.. Am J Med Genet A. 2008;146A:453-8",
"S Puvabanditsin, M February, J Mayne, J McConnell, R. Mehta. Cleidocranial Dysplasia with 6p21.1-p12.3 Microdeletion: A Case Report and Literature Review.. Cleft Palate Craniofac J. 2018;55:891-4",
"Y Qian, Y Zhang, B Wei, M Zhang, J Yang, C Leng, Z Ge, X Xu, M. Sun. A novel Alu-mediated microdeletion in the RUNX2 gene in a Chinese patient with cleidocranial dysplasia.. J Genet. 2018;97:137-43",
"I Quack, B Vonderstrass, M Stock, AS Aylsworth, A Becker, L Brueton, PJ Lee, F Majewski, JB Mulliken, M Suri, M Zenker, S Mundlos, F Otto. Mutation analysis of core binding factor A1 in patients with cleidocranial dysplasia.. Am J Hum Genet 1999;65:1268-78",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"T Roberts, L Stephen, P. Beighton. Cleidocranial dysplasia: a review of the dental, historical, and practical implications with an overview of the South African experience.. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;115:46-55",
"MD Sewell, DS Higgs, SM Lambert. Clavicle lengthening by distraction osteogenesis for congenital clavicular hypoplasia: case series and description of technique.. J Pediatr Orthop. 2013;33:314-20",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"DA Stevenson, JC Carey, JL Byrne, S Srisukhumbowornchai, ML Feldkamp. Analysis of skeletal dysplasias in the Utah population.. Am J Med Genet A. 2012;158A:1046-54",
"PA Stewart, R Wallerstein, E Moran, MJ Lee. Early prenatal ultrasound diagnosis of cleidocranial dysplasia.. Ultrasound Obstet Gynecol 2000;15:154-6",
"S Unger, E Mornet, S Mundlos, S Blaser, DE Cole. Severe cleidocranial dysplasia can mimic hypophosphatasia.. Eur J Pediatr 2002;161:623-6",
"AM Visosky, J Johnson, B Bingea, T Gurney, AK Lalwani. Otolaryngological manifestations of cleidocranial dysplasia, concentrating on audiological findings.. Laryngoscope 2003;113:1508-14",
"C Xing, M Kanchwala, JJ Rios, T Hyatt, RC Wang, A Tran, I Dougherty, A Tovar-Garza, C Purnadi, MG Kumar, D Berk, M Shinawi, AD Irvine, M Toledo-Bahena, NG Agim, DA Glass. Biallelic variants in RNU12 cause CDAGS syndrome.. Hum Mutat. 2021;42:1042-52",
"T Yoshida, H Kanegane, M Osato, M Yanagida, T Miyawaki, Y Ito, K Shigesada. Functional analysis of RUNX2 mutations in Japanese patients with cleidocranial dysplasia demonstrates novel genotype-phenotype correlations.. Am J Hum Genet 2002;71:724-38",
"Q Zheng, E Sebald, G Zhou, Y Chen, W Wilcox, B Lee, D Krakow. Dysregulation of chondrogenesis in human cleidocranial dysplasia.. Am J Hum Genet 2005;77:305-12",
"G Zhou, Y Chen, L Zhou, K Thirunavukkarasu, J Hecht, D Chitayat, BD Gelb, S Pirinen, SA Berry, CR Greenberg, G Karsenty, B Lee. CBFA1 mutation analysis and functional correlation with phenotypic variability in cleidocranial dysplasia.. Hum Mol Genet 1999;8:2311-6"
] |
3/1/2006
|
13/4/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
ccfdn
|
ccfdn
|
[
"CTDP1-CCFDN",
"CTDP1-CCFDN",
"RNA polymerase II subunit A C-terminal domain phosphatase",
"CTDP1",
"CTDP1-Related Congenital Cataracts, Facial Dysmorphism, and Neuropathy"
] |
Luba Kalaydjieva, Teodora Chamova
|
Summary The diagnosis of
|
## Diagnosis
Bilateral congenital cataracts, microcornea, and micropupils
Mildly dysmorphic facial features apparent from late childhood (prominent midface with a well-developed nose, thickening of the perioral tissues, forwardly directed anterior dentition, and micrognathia)
Hypo-/demyelinating peripheral neuropathy
Mild nonprogressive intellectual deficit
Intrauterine growth restriction with subsequent small stature and subnormal weight in adulthood
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include
Note: (1) Although other
Molecular Genetic Testing Used in
See
See
Romani founder variant
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequence analysis should include detection of deep intronic variants including
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Bilateral congenital cataracts, microcornea, and micropupils
• Mildly dysmorphic facial features apparent from late childhood (prominent midface with a well-developed nose, thickening of the perioral tissues, forwardly directed anterior dentition, and micrognathia)
• Hypo-/demyelinating peripheral neuropathy
• Mild nonprogressive intellectual deficit
• Intrauterine growth restriction with subsequent small stature and subnormal weight in adulthood
## Suggestive Findings
Bilateral congenital cataracts, microcornea, and micropupils
Mildly dysmorphic facial features apparent from late childhood (prominent midface with a well-developed nose, thickening of the perioral tissues, forwardly directed anterior dentition, and micrognathia)
Hypo-/demyelinating peripheral neuropathy
Mild nonprogressive intellectual deficit
Intrauterine growth restriction with subsequent small stature and subnormal weight in adulthood
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
• Bilateral congenital cataracts, microcornea, and micropupils
• Mildly dysmorphic facial features apparent from late childhood (prominent midface with a well-developed nose, thickening of the perioral tissues, forwardly directed anterior dentition, and micrognathia)
• Hypo-/demyelinating peripheral neuropathy
• Mild nonprogressive intellectual deficit
• Intrauterine growth restriction with subsequent small stature and subnormal weight in adulthood
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include
Note: (1) Although other
Molecular Genetic Testing Used in
See
See
Romani founder variant
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequence analysis should include detection of deep intronic variants including
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
Congenital cataracts are the invariable first manifestation of
Other ocular manifestations include microcornea, microphthalmia (documented by axial length measurements), and micropupils with fibrotic margins, showing sluggish constriction to light and dilation to mydriatics [
Horizontal pendular nystagmus is very common [
No fundus abnormalities are present.
Dysmorphic facial features become apparent in late childhood and are particularly evident in adult males. They include a prominent midface with a well-developed nose, thickening of the perioral tissues, forwardly directed anterior dentition, and micrognathia [
Skeletal deformities, especially of the feet and hands (pes cavus, pes equinovarus, flexion contractures in the interphalangeal joints), develop in the course of the disease as a result of the peripheral neuropathy and are present in all affected adults. As muscle weakness progresses, spine deformities (e.g., scoliosis, kyphosis) may also develop and lead to reduction in respiratory capacity [
Sensory abnormalities (numbness) in the lower limbs develop in persons older than age ten years.
Nerve conduction velocity is normal in infancy at the onset of myelination and subsequently (age >18 months) begins to decline, stabilizing at approximately 20 m/s at around age four to ten years [
Sensory nerve action potentials are of normal amplitude, suggesting a relatively uniform degree of slowing of nerve conduction across nerve fibers, consistent with congenital hypomyelination. As disease progresses, reduction in amplitudes is seen in sensory and motor nerves; some (e.g., in sural nerve) can become unobtainable after age ten years, indicating secondary axonal loss [
In distal muscles of the upper and lower extremities, neurogenic changes compatible with the underlying neuropathy are seen in all tested individuals [
Neuropathologic studies of sural nerve biopsies provide evidence of primary hypomyelination in the absence of morphologic abnormalities in the Schwann cell or axon [
Formal assessment of cognitive ability reveals variable results, the interpretation of which should take into account visual impairment, poor educational status, and language barriers (i.e., cognitive testing performed in a language other than the individual's primary language). According to available test results, around 10% of affected individuals have normal or borderline cognitive performance, and the rest have mild nonprogressive intellectual deficit. Verbal memory, executive functions, and language skills are similarly affected [
Pyramidal signs without spasticity and extrapyramidal hyperkinesis are observed in some affected individuals [
Individuals with
Cerebral, cerebellar, and cervical spine hypotrophy in childhood; cerebral atrophy with enlargement of the lateral ventricles; and occasionally thin corpus callosum and cerebellar atrophy [
Diffusion tensor MRI results suggestive of axonal loss in the vermis and medulla oblongata [
Myelin immaturity [
Multifocal white matter hyperintensity on T
Affected aduIts are of small stature and most are also of subnormal weight [
Sexual development appears unimpaired, with normal secondary characteristics after puberty and normal menarche. However, most adult females report irregular menstrual cycles and early secondary amenorrhea at ages 25-35 years.
More than half of affected adults of both sexes show evidence of hypogonadotropic hypogonadism, with low testosterone and subnormal follicle stimulating hormone levels in males and low estradiol and subnormal luteinizing hormone levels in females [
Muscle biopsies have shown mild myopathic features with scattered necrotic fibers, normal histochemical reactions for myophosphorylase and phosphofructokinase, and no evidence of mitochondrial pathology [
The
Congenital cataracts, facial dysmorphism, and neuropathy (CCFDN) was also referred to as Marinesco-Sjögren syndrome with rhabdomyolysis [
The title of this
The prevalence of
No affected individuals or carriers in other ethnic groups have been identified to date.
• Pyramidal signs without spasticity and extrapyramidal hyperkinesis are observed in some affected individuals [
• Individuals with
• Cerebral, cerebellar, and cervical spine hypotrophy in childhood; cerebral atrophy with enlargement of the lateral ventricles; and occasionally thin corpus callosum and cerebellar atrophy [
• Diffusion tensor MRI results suggestive of axonal loss in the vermis and medulla oblongata [
• Myelin immaturity [
• Multifocal white matter hyperintensity on T
## Clinical Description
Congenital cataracts are the invariable first manifestation of
Other ocular manifestations include microcornea, microphthalmia (documented by axial length measurements), and micropupils with fibrotic margins, showing sluggish constriction to light and dilation to mydriatics [
Horizontal pendular nystagmus is very common [
No fundus abnormalities are present.
Dysmorphic facial features become apparent in late childhood and are particularly evident in adult males. They include a prominent midface with a well-developed nose, thickening of the perioral tissues, forwardly directed anterior dentition, and micrognathia [
Skeletal deformities, especially of the feet and hands (pes cavus, pes equinovarus, flexion contractures in the interphalangeal joints), develop in the course of the disease as a result of the peripheral neuropathy and are present in all affected adults. As muscle weakness progresses, spine deformities (e.g., scoliosis, kyphosis) may also develop and lead to reduction in respiratory capacity [
Sensory abnormalities (numbness) in the lower limbs develop in persons older than age ten years.
Nerve conduction velocity is normal in infancy at the onset of myelination and subsequently (age >18 months) begins to decline, stabilizing at approximately 20 m/s at around age four to ten years [
Sensory nerve action potentials are of normal amplitude, suggesting a relatively uniform degree of slowing of nerve conduction across nerve fibers, consistent with congenital hypomyelination. As disease progresses, reduction in amplitudes is seen in sensory and motor nerves; some (e.g., in sural nerve) can become unobtainable after age ten years, indicating secondary axonal loss [
In distal muscles of the upper and lower extremities, neurogenic changes compatible with the underlying neuropathy are seen in all tested individuals [
Neuropathologic studies of sural nerve biopsies provide evidence of primary hypomyelination in the absence of morphologic abnormalities in the Schwann cell or axon [
Formal assessment of cognitive ability reveals variable results, the interpretation of which should take into account visual impairment, poor educational status, and language barriers (i.e., cognitive testing performed in a language other than the individual's primary language). According to available test results, around 10% of affected individuals have normal or borderline cognitive performance, and the rest have mild nonprogressive intellectual deficit. Verbal memory, executive functions, and language skills are similarly affected [
Pyramidal signs without spasticity and extrapyramidal hyperkinesis are observed in some affected individuals [
Individuals with
Cerebral, cerebellar, and cervical spine hypotrophy in childhood; cerebral atrophy with enlargement of the lateral ventricles; and occasionally thin corpus callosum and cerebellar atrophy [
Diffusion tensor MRI results suggestive of axonal loss in the vermis and medulla oblongata [
Myelin immaturity [
Multifocal white matter hyperintensity on T
Affected aduIts are of small stature and most are also of subnormal weight [
Sexual development appears unimpaired, with normal secondary characteristics after puberty and normal menarche. However, most adult females report irregular menstrual cycles and early secondary amenorrhea at ages 25-35 years.
More than half of affected adults of both sexes show evidence of hypogonadotropic hypogonadism, with low testosterone and subnormal follicle stimulating hormone levels in males and low estradiol and subnormal luteinizing hormone levels in females [
Muscle biopsies have shown mild myopathic features with scattered necrotic fibers, normal histochemical reactions for myophosphorylase and phosphofructokinase, and no evidence of mitochondrial pathology [
• Pyramidal signs without spasticity and extrapyramidal hyperkinesis are observed in some affected individuals [
• Individuals with
• Cerebral, cerebellar, and cervical spine hypotrophy in childhood; cerebral atrophy with enlargement of the lateral ventricles; and occasionally thin corpus callosum and cerebellar atrophy [
• Diffusion tensor MRI results suggestive of axonal loss in the vermis and medulla oblongata [
• Myelin immaturity [
• Multifocal white matter hyperintensity on T
## Ocular Manifestations
Congenital cataracts are the invariable first manifestation of
Other ocular manifestations include microcornea, microphthalmia (documented by axial length measurements), and micropupils with fibrotic margins, showing sluggish constriction to light and dilation to mydriatics [
Horizontal pendular nystagmus is very common [
No fundus abnormalities are present.
## Facial Features
Dysmorphic facial features become apparent in late childhood and are particularly evident in adult males. They include a prominent midface with a well-developed nose, thickening of the perioral tissues, forwardly directed anterior dentition, and micrognathia [
## Nervous System
Skeletal deformities, especially of the feet and hands (pes cavus, pes equinovarus, flexion contractures in the interphalangeal joints), develop in the course of the disease as a result of the peripheral neuropathy and are present in all affected adults. As muscle weakness progresses, spine deformities (e.g., scoliosis, kyphosis) may also develop and lead to reduction in respiratory capacity [
Sensory abnormalities (numbness) in the lower limbs develop in persons older than age ten years.
Nerve conduction velocity is normal in infancy at the onset of myelination and subsequently (age >18 months) begins to decline, stabilizing at approximately 20 m/s at around age four to ten years [
Sensory nerve action potentials are of normal amplitude, suggesting a relatively uniform degree of slowing of nerve conduction across nerve fibers, consistent with congenital hypomyelination. As disease progresses, reduction in amplitudes is seen in sensory and motor nerves; some (e.g., in sural nerve) can become unobtainable after age ten years, indicating secondary axonal loss [
In distal muscles of the upper and lower extremities, neurogenic changes compatible with the underlying neuropathy are seen in all tested individuals [
Neuropathologic studies of sural nerve biopsies provide evidence of primary hypomyelination in the absence of morphologic abnormalities in the Schwann cell or axon [
## Central Nervous System Manifestations
Formal assessment of cognitive ability reveals variable results, the interpretation of which should take into account visual impairment, poor educational status, and language barriers (i.e., cognitive testing performed in a language other than the individual's primary language). According to available test results, around 10% of affected individuals have normal or borderline cognitive performance, and the rest have mild nonprogressive intellectual deficit. Verbal memory, executive functions, and language skills are similarly affected [
Pyramidal signs without spasticity and extrapyramidal hyperkinesis are observed in some affected individuals [
Individuals with
Cerebral, cerebellar, and cervical spine hypotrophy in childhood; cerebral atrophy with enlargement of the lateral ventricles; and occasionally thin corpus callosum and cerebellar atrophy [
Diffusion tensor MRI results suggestive of axonal loss in the vermis and medulla oblongata [
Myelin immaturity [
Multifocal white matter hyperintensity on T
• Pyramidal signs without spasticity and extrapyramidal hyperkinesis are observed in some affected individuals [
• Individuals with
• Cerebral, cerebellar, and cervical spine hypotrophy in childhood; cerebral atrophy with enlargement of the lateral ventricles; and occasionally thin corpus callosum and cerebellar atrophy [
• Diffusion tensor MRI results suggestive of axonal loss in the vermis and medulla oblongata [
• Myelin immaturity [
• Multifocal white matter hyperintensity on T
## Other
Affected aduIts are of small stature and most are also of subnormal weight [
Sexual development appears unimpaired, with normal secondary characteristics after puberty and normal menarche. However, most adult females report irregular menstrual cycles and early secondary amenorrhea at ages 25-35 years.
More than half of affected adults of both sexes show evidence of hypogonadotropic hypogonadism, with low testosterone and subnormal follicle stimulating hormone levels in males and low estradiol and subnormal luteinizing hormone levels in females [
Muscle biopsies have shown mild myopathic features with scattered necrotic fibers, normal histochemical reactions for myophosphorylase and phosphofructokinase, and no evidence of mitochondrial pathology [
## Genotype-Phenotype Correlations
The
## Nomenclature
Congenital cataracts, facial dysmorphism, and neuropathy (CCFDN) was also referred to as Marinesco-Sjögren syndrome with rhabdomyolysis [
The title of this
## Prevalence
The prevalence of
No affected individuals or carriers in other ethnic groups have been identified to date.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
In early infancy, when bilateral congenital cataracts are the only manifestation, the diagnosis of
The differential diagnosis with other conditions presenting in the first year of life with congenital cataracts, microcornea, and microphthalmia is narrowed by the delayed developmental milestones in children with
Disorders of Interest in the Differential Diagnosis of
AR = autosomal recessive; CNS = central nervous system; MOI = mode of inheritance; NDD = neurodevelopmental disorder
See
See also OMIM Phenotypic Series:
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
ADL = activities of daily living;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with
Surgical removal of cataracts may be complicated by micropupils & fibrotic pupillary margins, requiring alternative mechanical methods of dilation.
Intraocular lenses are generally better tolerated than contact lenses.
Mgmt per physical medicine & rehab
Corrective surgery per orthopedics for secondary bone deformities
Urgent assessment w/onset of any signs/symptoms of rhabdomyolysis (e.g., muscle weakness, myoglobinuria)
Oral corticosteroid treatment for 2-3 wks can result in full recovery w/in 2-6 mos.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended.
Recommended Surveillance for Individuals with
OT = occupational therapy; PT = physical therapy
General anesthesia in individuals with
Prolonged exercise was reported to provoke myalgia in one individual with
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual in order to identify as early as possible those who would benefit from early initiation of treatment of ophthalmologic, neurologic, and endocrine manifestations.
See
Experience is very limited, as only three females with
Search
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Surgical removal of cataracts may be complicated by micropupils & fibrotic pupillary margins, requiring alternative mechanical methods of dilation.
• Intraocular lenses are generally better tolerated than contact lenses.
• Mgmt per physical medicine & rehab
• Corrective surgery per orthopedics for secondary bone deformities
• Urgent assessment w/onset of any signs/symptoms of rhabdomyolysis (e.g., muscle weakness, myoglobinuria)
• Oral corticosteroid treatment for 2-3 wks can result in full recovery w/in 2-6 mos.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
ADL = activities of daily living;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
Surgical removal of cataracts may be complicated by micropupils & fibrotic pupillary margins, requiring alternative mechanical methods of dilation.
Intraocular lenses are generally better tolerated than contact lenses.
Mgmt per physical medicine & rehab
Corrective surgery per orthopedics for secondary bone deformities
Urgent assessment w/onset of any signs/symptoms of rhabdomyolysis (e.g., muscle weakness, myoglobinuria)
Oral corticosteroid treatment for 2-3 wks can result in full recovery w/in 2-6 mos.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Surgical removal of cataracts may be complicated by micropupils & fibrotic pupillary margins, requiring alternative mechanical methods of dilation.
• Intraocular lenses are generally better tolerated than contact lenses.
• Mgmt per physical medicine & rehab
• Corrective surgery per orthopedics for secondary bone deformities
• Urgent assessment w/onset of any signs/symptoms of rhabdomyolysis (e.g., muscle weakness, myoglobinuria)
• Oral corticosteroid treatment for 2-3 wks can result in full recovery w/in 2-6 mos.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended.
Recommended Surveillance for Individuals with
OT = occupational therapy; PT = physical therapy
## Agents/Circumstances to Avoid
General anesthesia in individuals with
Prolonged exercise was reported to provoke myalgia in one individual with
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual in order to identify as early as possible those who would benefit from early initiation of treatment of ophthalmologic, neurologic, and endocrine manifestations.
See
## Pregnancy Management
Experience is very limited, as only three females with
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of an affected child are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
Because of the endogamous nature of Romani communities and the increased frequency of consanguineous marriages, carrier testing should be considered for the extended families of both parents and future reproductive partners of individuals already determined to be carriers.
See Management,
Carrier testing and genetic counseling should be offered to relatives, especially in view of the endogamous nature of many Romani communities. Even though
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Carrier testing and genetic counseling should be offered to relatives, especially in view of the endogamous nature of many Romani communities. Even though
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
Because of the endogamous nature of Romani communities and the increased frequency of consanguineous marriages, carrier testing should be considered for the extended families of both parents and future reproductive partners of individuals already determined to be carriers.
## Related Genetic Counseling Issues
See Management,
Carrier testing and genetic counseling should be offered to relatives, especially in view of the endogamous nature of many Romani communities. Even though
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing and genetic counseling should be offered to relatives, especially in view of the endogamous nature of many Romani communities. Even though
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
## Molecular Genetics
CTDP1-Related Congenital Cataracts, Facial Dysmorphism, and Neuropathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CTDP1-Related Congenital Cataracts, Facial Dysmorphism, and Neuropathy (
The carboxy-terminal domain phosphatase 1 (CTDP1), also known as transcription factor IIF-associating CTD phosphatase 1 (FCP1), is a widely expressed nuclear protein with a catalytic N-terminal part, a phospho-protein-binding BRCT domain common to cell cycle checkpoint proteins and involved in protein-protein interactions, and a C-terminal nuclear localization signal [
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Nucleotide change (c.863+389C>T) triggers an unusual mechanism of aberrant splicing [
## Molecular Pathogenesis
The carboxy-terminal domain phosphatase 1 (CTDP1), also known as transcription factor IIF-associating CTD phosphatase 1 (FCP1), is a widely expressed nuclear protein with a catalytic N-terminal part, a phospho-protein-binding BRCT domain common to cell cycle checkpoint proteins and involved in protein-protein interactions, and a C-terminal nuclear localization signal [
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Nucleotide change (c.863+389C>T) triggers an unusual mechanism of aberrant splicing [
## Chapter Notes
13 October 2022 (sw) Comprehensive update posted live
6 April 2017 (ha/bp) Comprehensive update posted live
2 October 2014 (me) Comprehensive update posted live
16 August 2012 (me) Comprehensive update posted live
2 March 2010 (me) Review posted live
29 October 2009 (lk) Original submission
• 13 October 2022 (sw) Comprehensive update posted live
• 6 April 2017 (ha/bp) Comprehensive update posted live
• 2 October 2014 (me) Comprehensive update posted live
• 16 August 2012 (me) Comprehensive update posted live
• 2 March 2010 (me) Review posted live
• 29 October 2009 (lk) Original submission
## Revision History
13 October 2022 (sw) Comprehensive update posted live
6 April 2017 (ha/bp) Comprehensive update posted live
2 October 2014 (me) Comprehensive update posted live
16 August 2012 (me) Comprehensive update posted live
2 March 2010 (me) Review posted live
29 October 2009 (lk) Original submission
• 13 October 2022 (sw) Comprehensive update posted live
• 6 April 2017 (ha/bp) Comprehensive update posted live
• 2 October 2014 (me) Comprehensive update posted live
• 16 August 2012 (me) Comprehensive update posted live
• 2 March 2010 (me) Review posted live
• 29 October 2009 (lk) Original submission
## References
## Literature Cited
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"J Archambault, RD Chambers, MS Kobor, Y Ho, M Cartier, D Bolotin, B Andrews, CM Kane, J Greenblatt. An essential component of a C-terminal domain phosphatase that interacts with transcription factor IIF in S. cerevisiae.. Proc Natl Acad Sci USA. 1997;94:14300-5",
"LG Biesecker, MP Adam, FS Alkuraya, AR Amemiya, MJ Bamshad, AE Beck, JT Bennett, LM Bird, JC Carey, B Chung, RD Clark, TC Cox, C Curry, MBP Dinulos, WB Dobyns, PF Giampietro, KM Girisha, IA Glass, JM Graham, KW Gripp, CR Haldeman-Englert, BD Hall, AM Innes, JM Kalish, KM Keppler-Noreuil, K Kosaki, BA Kozel, GM Mirzaa, JJ Mulvihill, MJM Nowaczyk, RA Pagon, K Retterer, AF Rope, PA Sanchez-Lara, LH Seaver, JT Shieh, AM Slavotinek, AK Sobering, CA Stevens, DA Stevenson, TY Tan, WH Tan, AC Tsai, DD Weaver, MS Williams, E Zackai, YA Zarate. A dyadic approach to the delineation of diagnostic entities in clinical genomics.. Am J Hum Genet. 2021;108:8-15",
"T Chamova, D Zlatareva, M Raycheva, S Bichev, L Kalaydjieva, I Tournev. Cognitive impairment and brain imaging characteristics of patients with congenital cataracts, facial dysmorphism, neuropathy syndrome.. Behav Neurol. 2015;2015",
"H Cho, TK Kim, H Mancebo, WS Lane, O Flores, D Reinberg. A protein phosphatase functions to recycle RNA polymerase II.. Genes & Dev. 1999;13:1540-52",
"DM Cordelli, C Garone, V Marchiani, R Lodi, C Tonon, S Ferrari, M Seri, E Franzoni. Progressive cerebral white matter involvement in a patient with congenital cataracts facial dysmorphisms neuropathy (CCFDN).. Neuromuscul Disord. 2010;20:343-5",
"K Haugarvoll, S Johansson, CE Rodriguez, H Boman, BI Haukanes, O Bruland, F Roque, I Jonassen, M Blomqvist, W Telstad, JE Månsson, PM Knappskog, LA Bindoff. GBA2 mutations cause a Marinesco-Sjögren-like syndrome: genetic and biochemical studies.. PLoS One. 2017;12",
"J Hudec, M Kosinova, T Prokopova, M Filipovic, M Repko, P Stourac. Anesthesia of a patient with congenital cataract, facial dysmorphism, and neuropathy syndrome for posterior scoliosis: a case report.. World J Clin Cases. 2022;10:4207-13",
"L Kalaydjieva, H Lochmüller, I Tournev, F Baas, J Beres, J Colomer, V Guergueltcheva, R Herrmann, V Karcagi, R King, T Miyata, A Müllner-Eidenböck, T Okuda, V Milic Rasic, M Santos, B Talim, J Vilchez, M Walter, A Urtizberea, L. Merlini. 125th ENMC International Workshop: neuromuscular disorders in the Roma (Gypsy) population, 23-25 April 2004, Naarden, the Netherlands.. Neuromuscul Disord. 2005;15:65-71",
"MS Kobor, J Archambault, W Lester, FC Holstege, O Gieladi, DB Jausma, EG Jennings, F Kouyoumdjan, AR Davidson, RA Young, J Greenblatt. An unusual eukaryotic protein phosphatase required for transcription by RNA polymerase II and CTD dephosphorylation in S. cerevisiae.. Mol Cell. 1999;4:55-62",
"P Lassuthova, D Sišková, J Haberlová, I Sakmaryová, A Filouš, P Seeman. Congenital cataract, facial dysmorphism and demyelinating neuropathy (CCFDN) in 10 Czech Gypsy children--frequent and underestimated cause of disability among Czech Gypsies.. Orphanet J Rare Dis. 2014;9:46",
"P Licciardo, S Amente, L Ruggiero, M Monti, P Pucci, L Lania, B. Majello. The FCP1 phosphatase interacts with RNA polymerase II and with MEP50 a component of the methylosome complex involved in the assembly of snRNP.. Nucl Acids Res. 2003;31:999-1005",
"T Maniatis, R Reed. An extensive network of coupling among gene expression machines.. Nature. 2002;416:499-506",
"OW Masters, E Bergmans, KC Thies. Anaesthesia and orphan disease: a child with Congenital Cataract Facial Dysmorphism neuropathy (CCFDN) syndrome: a case report.. Eur J Anaesthesiol. 2017;34:178-80",
"SD Mastroyianni, A Garoufi, K Voudris, A Skardoutsou, R Gooding, L Kalaydjieva. Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome: a rare cause of parainfectious rhabdomyolysis.. Eur J Pediatr. 2007;166:747-9",
"L Merlini, R Gooding, H Lochmueller, MC Walter, D Angelicheva, B Talim, J Hallmayer, L Kalaydjieva. Genetic identity of Marinesco-Sjögren/ myoglobinuria and CCFDN syndromes.. Neurology. 2002;58:231-6",
"B Morar, D Gresham, D Angelicheva, I Tournev, R Gooding, V Guergueltcheva, C Schmidt, A Abicht, H Lochmüller, A Tordai, L Kalmar, M Nagy, V Karcagi, M Jeanpierre, A Herczegfalvi, R de Pablo, V Kucinskas, L. Kalaydjieva. Mutation history of the Roma/Gypsies.. Am J Hum Genet. 2004;75:596-609",
"W Müller-Felber, D Zafiriou, R Scheck, I Pätzke, M Toepfer, DE Pongratz, U Walther. Marinesco-Sjögren syndrome with rhabdomyolysis. A new subtype of the disease.. Neuropediatrics. 1998;29:97-101",
"A Müllner-Eidenböck, E Moser, N Klebermass, M Amon, G Mernert, M Walther, H Lochmueller, L Kalaydjieva. Ocular features of the CCFDN syndrome (congenital cataracts facial dysmorphism neuropathy).. Ophthalmology. 2004;111:1415-23",
"B Palancade, MF Dubois, ME Dahmus, O Bensaude. Transcription-independent RNA polymerase II dephosphorylation by the FCP1 carboxy-terminal domain phosphatase in Xenopus laevis early embryos.. Mol Cell Biol. 2001;21:6359-68",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"I Tournev, L Kalaydjieva, B Youl, B Ishpekova, V Guerguelcheva, O Kamenov, M Katzarova, Z Kamenov, M Raicheva-Ternzieva, RHM King, R Petkov, A Shmarov, G Dimitrova, N Popova, M Uzunova, S Milanov, J Petrova, Y Petkov, G Kolarov, L Anev, O Radeva, PK Thomas. Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome, a novel complex genetic disease in Balkan Gypsies: clinical and electrophysiological observations.. Ann Neurol. 1999a;45:742-50",
"I Tournev, RH King, J Workman, M Nourallah, JR Muddle, L Kalaydjieva, K Romanski, PK Thomas. Peripheral nerve abnormalities in the congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome.. Acta Neuropathol. 1999b;98:165-70",
"I Tournev, P Thomas, R Gooding, D Angelicheva, R King, B Youl, V Guerueltcheva, B Ishpekova, K Blechsmidt, K Swoboda, R Petkov, M Molnar, Z Kamenov, E Siska, N Taneva, P Borisova, C Lupu, M Raycheva, N Trifonova, A Popova, A Corches, I Litvinenko, L Merlini, M Katzarova, B Tzankov, G Popa, A Akkari, A Rosenthal, O Donzelli, L. Kalaydjieva. Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome – clinical, neuropathological and genetic investigation.. Acta Myologica. 2001;20:210-9",
"R Varon, R Gooding, C Steglich, L Marns, H Tang, D Angelicheva, KK Yong, P Ambrugger, A Reinhold, B Morar, F Baas, M Kwa, I Tournev, V Guerguelcheva, I Kremensky, H Lochmüller, A Müllner-Eidenböck, L Merlini, L Neumann, J Bürger, M Walter, K Swoboda, PK Thomas, A von Moers, N Risch, L Kalaydjieva. Partial deficiency of the C-terminal domain phosphatase of RNA polymerase II is associated with congenital cataracts facial dysmorphism neuropathy syndrome.. Nat Genet. 2003;35:185-9",
"MC Walter, G Bernert, U Zimmermann, A Müllner-Eidenböck, E Moser, L Kalaydjieva, H Lochmüller, W Müller-Felber. Long-term follow-up in patients with CCFDN syndrome.. Neurology. 2014;83:1337-44"
] |
2/3/2010
|
13/10/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
ccm
|
ccm
|
[
"Familial Cavernous Hemangioma",
"Familial Cerebral Cavernous Angioma",
"Familial Cerebral Cavernous Malformation Syndrome",
"Familial Cavernous Hemangioma",
"Familial Cerebral Cavernous Angioma",
"Familial Cerebral Cavernous Malformation Syndrome",
"Cerebral cavernous malformations 2 protein",
"Krev interaction trapped protein 1",
"Programmed cell death protein 10",
"CCM2",
"KRIT1",
"PDCD10",
"Familial Cerebral Cavernous Malformations"
] |
Familial Cerebral Cavernous Malformations
|
Kelly D Flemming, Edward Smith, Douglas Marchuk, W Brent Derry
|
Summary Familial cerebral cavernous malformations (FCCM) is a disorder characterized by multiple vascular lesions in the brain and spinal cord that consist of clustered, endothelial-lined caverns ranging in diameter from a few millimeters to several centimeters. Cerebral and/or spinal cavernous malformations may increase in number over time, and individual lesions may increase or decrease in size. The number of cerebral cavernous malformations (CCMs) identified in an individual ranges from one or two to hundreds of lesions (typical number 6-20 CCMs) depending on the individual's age and the quality and type of brain imaging used. Although CCMs have been reported in infants and children, the majority become evident between the second and fifth decades of life either incidentally or associated with seizures, focal neurologic deficits, headaches, and/or cerebral hemorrhage. Cutaneous vascular lesions are found in 9% and retinal vascular lesions in almost 5% of affected individuals. Up to 50% of individuals with FCCM remain symptom free throughout their lives. The diagnosis of familial cerebral cavernous malformations (FCCM) is established in a proband with multiple CCMs, one CCM and at least one other family member with one or more CCMs, or a heterozygous germline pathogenic variant in FCCM is inherited in an autosomal dominant manner. Many individuals diagnosed with FCCM have a symptomatic parent. The proportion of individuals with FCCM caused by a
|
## Diagnosis
No consensus clinical diagnostic criteria for familial cerebral cavernous malformations (FCCM) have been published.
FCCM
Seizures
Focal neurologic deficits
Headaches
Systemic vascular lesions
Vascular skin lesions. Three main types of cutaneous vascular malformations (CVMs) have been associated with FCCM: hyperkeratotic cutaneous capillary-venous malformations (HCCVMs), punctate capillary malformations (PCMs), and deep blue nodules (DBNs).
Retinal cavernomas and rare choroidal hemangiomas
Liver cavernous hemangiomas
Renal angiomas
Atypical vertebral hemangiomas (capillary-venous malformations within the bone that can rarely result in pathologic fractures)
Other
Brain tumors (e.g., meningioma, acoustic neuroma, cerebellar astrocytoma)
Adrenal gland calcifications
The characteristic, Zabramski type 2 lesion is comprised of mixed signal intensity with a central reticulated core surrounded by a dark hemosiderin ring. A Zabramski type 3 lesion is hypointense on T
A hemorrhagic cerebral cavernous malformation (CCM) may demonstrate acute or subacute blood (high T
Zabramski type 4 lesions appear as hypointense lesions on gradient echo or susceptibility-weighted imaging (SWI) only [
Note: Brain MRI with SWI on a 3 Tesla or higher-magnet MRI is preferred [
Note: A family member with a pathogenic variant in one of the FCCM-associated genes may or may not be clinically symptomatic (asymptomatic vascular lesions are fairly common in families segregating an FCCM-related pathogenic variant); therefore, the presence of a single CCM in an individual with no known family history of CCM does not exclude the diagnosis of FCCM.
The clinical diagnosis of FCCM can be
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Note: Targeted analysis can be considered first in individuals of Ashkenazi Jewish and Hispanic ancestry due to recurrent and/or founder variants in
For an introduction to multigene panels click
When the diagnosis of FCCM has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Familial Cerebral Cavernous Malformations
FCCM = familial cerebral cavernous malformations; NA = not applicable
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Variability in the detection rate of deletion/duplication testing results from the high prevalence of a founder
Following stringent inclusion criteria for FCCM (multiple lesions and/or family history consistent with FCCM), a heterozygous pathogenic variant in either
• Seizures
• Focal neurologic deficits
• Headaches
• Systemic vascular lesions
• Vascular skin lesions. Three main types of cutaneous vascular malformations (CVMs) have been associated with FCCM: hyperkeratotic cutaneous capillary-venous malformations (HCCVMs), punctate capillary malformations (PCMs), and deep blue nodules (DBNs).
• Retinal cavernomas and rare choroidal hemangiomas
• Liver cavernous hemangiomas
• Renal angiomas
• Atypical vertebral hemangiomas (capillary-venous malformations within the bone that can rarely result in pathologic fractures)
• Vascular skin lesions. Three main types of cutaneous vascular malformations (CVMs) have been associated with FCCM: hyperkeratotic cutaneous capillary-venous malformations (HCCVMs), punctate capillary malformations (PCMs), and deep blue nodules (DBNs).
• Retinal cavernomas and rare choroidal hemangiomas
• Liver cavernous hemangiomas
• Renal angiomas
• Atypical vertebral hemangiomas (capillary-venous malformations within the bone that can rarely result in pathologic fractures)
• Other
• Brain tumors (e.g., meningioma, acoustic neuroma, cerebellar astrocytoma)
• Adrenal gland calcifications
• Brain tumors (e.g., meningioma, acoustic neuroma, cerebellar astrocytoma)
• Adrenal gland calcifications
• Vascular skin lesions. Three main types of cutaneous vascular malformations (CVMs) have been associated with FCCM: hyperkeratotic cutaneous capillary-venous malformations (HCCVMs), punctate capillary malformations (PCMs), and deep blue nodules (DBNs).
• Retinal cavernomas and rare choroidal hemangiomas
• Liver cavernous hemangiomas
• Renal angiomas
• Atypical vertebral hemangiomas (capillary-venous malformations within the bone that can rarely result in pathologic fractures)
• Brain tumors (e.g., meningioma, acoustic neuroma, cerebellar astrocytoma)
• Adrenal gland calcifications
• The characteristic, Zabramski type 2 lesion is comprised of mixed signal intensity with a central reticulated core surrounded by a dark hemosiderin ring. A Zabramski type 3 lesion is hypointense on T
• A hemorrhagic cerebral cavernous malformation (CCM) may demonstrate acute or subacute blood (high T
• Zabramski type 4 lesions appear as hypointense lesions on gradient echo or susceptibility-weighted imaging (SWI) only [
## Suggestive Findings
FCCM
Seizures
Focal neurologic deficits
Headaches
Systemic vascular lesions
Vascular skin lesions. Three main types of cutaneous vascular malformations (CVMs) have been associated with FCCM: hyperkeratotic cutaneous capillary-venous malformations (HCCVMs), punctate capillary malformations (PCMs), and deep blue nodules (DBNs).
Retinal cavernomas and rare choroidal hemangiomas
Liver cavernous hemangiomas
Renal angiomas
Atypical vertebral hemangiomas (capillary-venous malformations within the bone that can rarely result in pathologic fractures)
Other
Brain tumors (e.g., meningioma, acoustic neuroma, cerebellar astrocytoma)
Adrenal gland calcifications
The characteristic, Zabramski type 2 lesion is comprised of mixed signal intensity with a central reticulated core surrounded by a dark hemosiderin ring. A Zabramski type 3 lesion is hypointense on T
A hemorrhagic cerebral cavernous malformation (CCM) may demonstrate acute or subacute blood (high T
Zabramski type 4 lesions appear as hypointense lesions on gradient echo or susceptibility-weighted imaging (SWI) only [
Note: Brain MRI with SWI on a 3 Tesla or higher-magnet MRI is preferred [
Note: A family member with a pathogenic variant in one of the FCCM-associated genes may or may not be clinically symptomatic (asymptomatic vascular lesions are fairly common in families segregating an FCCM-related pathogenic variant); therefore, the presence of a single CCM in an individual with no known family history of CCM does not exclude the diagnosis of FCCM.
• Seizures
• Focal neurologic deficits
• Headaches
• Systemic vascular lesions
• Vascular skin lesions. Three main types of cutaneous vascular malformations (CVMs) have been associated with FCCM: hyperkeratotic cutaneous capillary-venous malformations (HCCVMs), punctate capillary malformations (PCMs), and deep blue nodules (DBNs).
• Retinal cavernomas and rare choroidal hemangiomas
• Liver cavernous hemangiomas
• Renal angiomas
• Atypical vertebral hemangiomas (capillary-venous malformations within the bone that can rarely result in pathologic fractures)
• Vascular skin lesions. Three main types of cutaneous vascular malformations (CVMs) have been associated with FCCM: hyperkeratotic cutaneous capillary-venous malformations (HCCVMs), punctate capillary malformations (PCMs), and deep blue nodules (DBNs).
• Retinal cavernomas and rare choroidal hemangiomas
• Liver cavernous hemangiomas
• Renal angiomas
• Atypical vertebral hemangiomas (capillary-venous malformations within the bone that can rarely result in pathologic fractures)
• Other
• Brain tumors (e.g., meningioma, acoustic neuroma, cerebellar astrocytoma)
• Adrenal gland calcifications
• Brain tumors (e.g., meningioma, acoustic neuroma, cerebellar astrocytoma)
• Adrenal gland calcifications
• Vascular skin lesions. Three main types of cutaneous vascular malformations (CVMs) have been associated with FCCM: hyperkeratotic cutaneous capillary-venous malformations (HCCVMs), punctate capillary malformations (PCMs), and deep blue nodules (DBNs).
• Retinal cavernomas and rare choroidal hemangiomas
• Liver cavernous hemangiomas
• Renal angiomas
• Atypical vertebral hemangiomas (capillary-venous malformations within the bone that can rarely result in pathologic fractures)
• Brain tumors (e.g., meningioma, acoustic neuroma, cerebellar astrocytoma)
• Adrenal gland calcifications
• The characteristic, Zabramski type 2 lesion is comprised of mixed signal intensity with a central reticulated core surrounded by a dark hemosiderin ring. A Zabramski type 3 lesion is hypointense on T
• A hemorrhagic cerebral cavernous malformation (CCM) may demonstrate acute or subacute blood (high T
• Zabramski type 4 lesions appear as hypointense lesions on gradient echo or susceptibility-weighted imaging (SWI) only [
## Establishing the Diagnosis
The clinical diagnosis of FCCM can be
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Note: Targeted analysis can be considered first in individuals of Ashkenazi Jewish and Hispanic ancestry due to recurrent and/or founder variants in
For an introduction to multigene panels click
When the diagnosis of FCCM has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Familial Cerebral Cavernous Malformations
FCCM = familial cerebral cavernous malformations; NA = not applicable
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Variability in the detection rate of deletion/duplication testing results from the high prevalence of a founder
Following stringent inclusion criteria for FCCM (multiple lesions and/or family history consistent with FCCM), a heterozygous pathogenic variant in either
## Option 1
Note: Targeted analysis can be considered first in individuals of Ashkenazi Jewish and Hispanic ancestry due to recurrent and/or founder variants in
For an introduction to multigene panels click
## Option 2
When the diagnosis of FCCM has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Familial Cerebral Cavernous Malformations
FCCM = familial cerebral cavernous malformations; NA = not applicable
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Variability in the detection rate of deletion/duplication testing results from the high prevalence of a founder
Following stringent inclusion criteria for FCCM (multiple lesions and/or family history consistent with FCCM), a heterozygous pathogenic variant in either
## Clinical Characteristics
Familial cerebral cavernous malformations (FCCM) is a disorder characterized by multiple cerebral cavernous malformations (CCMs) without a developmental venous anomaly. Individuals with FCCM may present with seizure, headaches, or focal neurologic deficits with or without associated cerebral hemorrhage. In some instances, individuals present for screening or evaluation of unrelated concerns and the cavernous malformation(s) are asymptomatic [
To date, it is estimated that more than 1,000 families have been reported with FCCM and a pathogenic variant in one of the FCCM-associated genes. The following is a description of the phenotypic features associated with this disorder.
Familial Cerebral Cavernous Malformations: Frequency of Select Features
Hyperkeratotic cutaneous capillary-venous malformations (HCCVMs)
Punctate capillary malformations (PCMs)
Deep blue nodules (DBNs)
CCM = cerebral cavernous malformation; CVM = cutaneous vascular malformation; FCCM = familial cerebral cavernous malformations
Up to 40%-50% of individuals with FCMM are asymptomatic.
Data reflect percentage of individuals with the feature at the time of initial presentation.
Clinically affected individuals may present with seizures (20%-40%), focal neurologic deficits (35%-50%), and nonspecific headaches (10%-30%). These symptoms may or may not be associated with symptomatic hemorrhage in the brain or the spinal cord [
In large natural history studies, the risk of prospective, symptomatic hemorrhage does not seem to differ between familial and sporadic CCMs [
Seizures are common in FCCM during an individual's lifetime. One large study of individuals with FCCM (n=479) reported that by age 80 years, 60.4% of individuals had at least one seizure [
Four characteristic types of lesions have been described [
The clinical significance of small lesions (classified as Zabramski type 4) seen on MRI (sometimes referred to as cerebral dot-like cavernous malformations) is unclear. For these lesions, a mean hemorrhage rate of 1.3% per year was found over a period of 5.5 years in 18 children with either an inherited or a
FCCM is a dynamic disease based on neuroimaging. Several studies suggest that new lesions appear at a rate between 0.2 to one lesion per person year [
In FCCM, 70%-86% of lesions are supratentorial and 16%-24% infratentorial in location [
Cutaneous vascular malformations were found in 38 out of 417 individuals with FCCM [
Bluish nodules and other subcutaneous nodules have been described as subtypes of venous malformations.
Some affected individuals have skin lesions removed secondary to bleeding, pain, protrusion, cosmetic concerns, or concern for malignancy.
Scoliosis. In a series of 18 affected individuals with pathogenic variants in
Brain tumors. In a series of 18 affected individuals with pathogenic variants in
Adrenal gland calcifications have been rarely reported and are suspected to represent small vascular lesions, with limited histologic confirmation [
Closely clustered enlarged capillary channels (caverns) ranging from two to 55 mm (mean: 8 mm) with a single layer of endothelium without normal mature vessel wall elements or intervening brain parenchyma;
Thrombosis and intra- and extralesional hemorrhage. Edema may surround lesions with recent hemorrhage.
Several FCCM manifestations have been reported in association with specific genes.
One study of children with FCCM found a higher risk of hemorrhage in individuals with pathogenic
One small study suggested that individuals with pathogenic variants in
Individuals with a heterozygous pathogenic variant in
Individuals with pathogenic variants in
Sixty-two percent were symptomatic;
Fifty-eight percent of those who were at least age 50 years had symptoms related to CCM;
Forty-five of 53 symptom-free individuals had lesions on MRI (three had indications of a type 4 lesion; see
Note: SWI MRI, the most sensitive imaging technique for identifying CCMs, was not performed in this study.
Penetrance in individuals with pathogenic variants in
It is estimated that 0.4%-0.9% of the general population has a CCM. Population-based studies estimate the incidence of CCMs to be 0.56 in 100,000 individuals older than age 16 years [
The estimated population-based prevalence of FCCM is 0.07% [
The
• Hyperkeratotic cutaneous capillary-venous malformations (HCCVMs)
• Punctate capillary malformations (PCMs)
• Deep blue nodules (DBNs)
• Cutaneous vascular malformations were found in 38 out of 417 individuals with FCCM [
• Bluish nodules and other subcutaneous nodules have been described as subtypes of venous malformations.
• Some affected individuals have skin lesions removed secondary to bleeding, pain, protrusion, cosmetic concerns, or concern for malignancy.
• Cutaneous vascular malformations were found in 38 out of 417 individuals with FCCM [
• Bluish nodules and other subcutaneous nodules have been described as subtypes of venous malformations.
• Some affected individuals have skin lesions removed secondary to bleeding, pain, protrusion, cosmetic concerns, or concern for malignancy.
• Cutaneous vascular malformations were found in 38 out of 417 individuals with FCCM [
• Bluish nodules and other subcutaneous nodules have been described as subtypes of venous malformations.
• Some affected individuals have skin lesions removed secondary to bleeding, pain, protrusion, cosmetic concerns, or concern for malignancy.
• Scoliosis. In a series of 18 affected individuals with pathogenic variants in
• Brain tumors. In a series of 18 affected individuals with pathogenic variants in
• Adrenal gland calcifications have been rarely reported and are suspected to represent small vascular lesions, with limited histologic confirmation [
• Closely clustered enlarged capillary channels (caverns) ranging from two to 55 mm (mean: 8 mm) with a single layer of endothelium without normal mature vessel wall elements or intervening brain parenchyma;
• Thrombosis and intra- and extralesional hemorrhage. Edema may surround lesions with recent hemorrhage.
• One study of children with FCCM found a higher risk of hemorrhage in individuals with pathogenic
• One small study suggested that individuals with pathogenic variants in
• Individuals with a heterozygous pathogenic variant in
• Individuals with pathogenic variants in
• Sixty-two percent were symptomatic;
• Fifty-eight percent of those who were at least age 50 years had symptoms related to CCM;
• Forty-five of 53 symptom-free individuals had lesions on MRI (three had indications of a type 4 lesion; see
• Note: SWI MRI, the most sensitive imaging technique for identifying CCMs, was not performed in this study.
## Clinical Description
Familial cerebral cavernous malformations (FCCM) is a disorder characterized by multiple cerebral cavernous malformations (CCMs) without a developmental venous anomaly. Individuals with FCCM may present with seizure, headaches, or focal neurologic deficits with or without associated cerebral hemorrhage. In some instances, individuals present for screening or evaluation of unrelated concerns and the cavernous malformation(s) are asymptomatic [
To date, it is estimated that more than 1,000 families have been reported with FCCM and a pathogenic variant in one of the FCCM-associated genes. The following is a description of the phenotypic features associated with this disorder.
Familial Cerebral Cavernous Malformations: Frequency of Select Features
Hyperkeratotic cutaneous capillary-venous malformations (HCCVMs)
Punctate capillary malformations (PCMs)
Deep blue nodules (DBNs)
CCM = cerebral cavernous malformation; CVM = cutaneous vascular malformation; FCCM = familial cerebral cavernous malformations
Up to 40%-50% of individuals with FCMM are asymptomatic.
Data reflect percentage of individuals with the feature at the time of initial presentation.
Clinically affected individuals may present with seizures (20%-40%), focal neurologic deficits (35%-50%), and nonspecific headaches (10%-30%). These symptoms may or may not be associated with symptomatic hemorrhage in the brain or the spinal cord [
In large natural history studies, the risk of prospective, symptomatic hemorrhage does not seem to differ between familial and sporadic CCMs [
Seizures are common in FCCM during an individual's lifetime. One large study of individuals with FCCM (n=479) reported that by age 80 years, 60.4% of individuals had at least one seizure [
Four characteristic types of lesions have been described [
The clinical significance of small lesions (classified as Zabramski type 4) seen on MRI (sometimes referred to as cerebral dot-like cavernous malformations) is unclear. For these lesions, a mean hemorrhage rate of 1.3% per year was found over a period of 5.5 years in 18 children with either an inherited or a
FCCM is a dynamic disease based on neuroimaging. Several studies suggest that new lesions appear at a rate between 0.2 to one lesion per person year [
In FCCM, 70%-86% of lesions are supratentorial and 16%-24% infratentorial in location [
Cutaneous vascular malformations were found in 38 out of 417 individuals with FCCM [
Bluish nodules and other subcutaneous nodules have been described as subtypes of venous malformations.
Some affected individuals have skin lesions removed secondary to bleeding, pain, protrusion, cosmetic concerns, or concern for malignancy.
Scoliosis. In a series of 18 affected individuals with pathogenic variants in
Brain tumors. In a series of 18 affected individuals with pathogenic variants in
Adrenal gland calcifications have been rarely reported and are suspected to represent small vascular lesions, with limited histologic confirmation [
Closely clustered enlarged capillary channels (caverns) ranging from two to 55 mm (mean: 8 mm) with a single layer of endothelium without normal mature vessel wall elements or intervening brain parenchyma;
Thrombosis and intra- and extralesional hemorrhage. Edema may surround lesions with recent hemorrhage.
• Hyperkeratotic cutaneous capillary-venous malformations (HCCVMs)
• Punctate capillary malformations (PCMs)
• Deep blue nodules (DBNs)
• Cutaneous vascular malformations were found in 38 out of 417 individuals with FCCM [
• Bluish nodules and other subcutaneous nodules have been described as subtypes of venous malformations.
• Some affected individuals have skin lesions removed secondary to bleeding, pain, protrusion, cosmetic concerns, or concern for malignancy.
• Cutaneous vascular malformations were found in 38 out of 417 individuals with FCCM [
• Bluish nodules and other subcutaneous nodules have been described as subtypes of venous malformations.
• Some affected individuals have skin lesions removed secondary to bleeding, pain, protrusion, cosmetic concerns, or concern for malignancy.
• Cutaneous vascular malformations were found in 38 out of 417 individuals with FCCM [
• Bluish nodules and other subcutaneous nodules have been described as subtypes of venous malformations.
• Some affected individuals have skin lesions removed secondary to bleeding, pain, protrusion, cosmetic concerns, or concern for malignancy.
• Scoliosis. In a series of 18 affected individuals with pathogenic variants in
• Brain tumors. In a series of 18 affected individuals with pathogenic variants in
• Adrenal gland calcifications have been rarely reported and are suspected to represent small vascular lesions, with limited histologic confirmation [
• Closely clustered enlarged capillary channels (caverns) ranging from two to 55 mm (mean: 8 mm) with a single layer of endothelium without normal mature vessel wall elements or intervening brain parenchyma;
• Thrombosis and intra- and extralesional hemorrhage. Edema may surround lesions with recent hemorrhage.
## Phenotype Correlations by Gene
Several FCCM manifestations have been reported in association with specific genes.
One study of children with FCCM found a higher risk of hemorrhage in individuals with pathogenic
One small study suggested that individuals with pathogenic variants in
Individuals with a heterozygous pathogenic variant in
Individuals with pathogenic variants in
• One study of children with FCCM found a higher risk of hemorrhage in individuals with pathogenic
• One small study suggested that individuals with pathogenic variants in
• Individuals with a heterozygous pathogenic variant in
• Individuals with pathogenic variants in
## Genotype-Phenotype Correlations
## Penetrance
Sixty-two percent were symptomatic;
Fifty-eight percent of those who were at least age 50 years had symptoms related to CCM;
Forty-five of 53 symptom-free individuals had lesions on MRI (three had indications of a type 4 lesion; see
Note: SWI MRI, the most sensitive imaging technique for identifying CCMs, was not performed in this study.
Penetrance in individuals with pathogenic variants in
• Sixty-two percent were symptomatic;
• Fifty-eight percent of those who were at least age 50 years had symptoms related to CCM;
• Forty-five of 53 symptom-free individuals had lesions on MRI (three had indications of a type 4 lesion; see
• Note: SWI MRI, the most sensitive imaging technique for identifying CCMs, was not performed in this study.
## Prevalence
It is estimated that 0.4%-0.9% of the general population has a CCM. Population-based studies estimate the incidence of CCMs to be 0.56 in 100,000 individuals older than age 16 years [
The estimated population-based prevalence of FCCM is 0.07% [
The
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Somatic activating variants in
Somatic pathogenic variants in
Putting all recent somatic variant data together, it appears that (1) CCMs can develop as the result of biallelic loss of any of the three FCCM-related genes or as a result of somatic pathogenic variants in
Hemorrhagic metastases. Renal cell, melanoma, papillary thyroid, lung, breast, and choriocarcinoma can create multiple hemorrhagic lesions of the brain that can be mistaken for FCCM. In general, metastases are more likely to enhance with contrast and more likely to have significant edema as compared to CCMs.
Primary brain tumors, often with calcification (ganglioglioma)
CAPNON (calcified pseudoneoplasm or the neuroaxis). The mixed density and susceptibility-weighted imaging (SWI) changes associated with this lesion are due to calcium rather than hemosiderin. These are usually singular lesions; thus, they are more likely to mimic sporadic CCM than FCCM.
Infectious or inflammatory nodules
Myxomatous emboli. An atrial myxoma embolizing to the brain can be confused with FCCM. However, these lesions typically have significant edema and a more complex appearance than CCMs.
Arteriovenous malformations (AVMs). Most AVMs are readily distinguishable from cavernous malformations by the multiple T
Hemorrhagic metastases (suggestive features include an older individual with a known primary malignancy and areas of enhancement using gadolinium as well as persistent edema)
Cerebral microbleeds due to amyloid angiopathy, hypertension, vasculitis
Amyloid angiopathy typically occurs in individuals older than age 60 years, and lesions are predominantly in the superficial cortex and sometimes associated with sulcal subarachnoid hemorrhage. If in doubt, a spinal fluid evaluation including tau and amyloid levels can be helpful in addition to apolipoprotein E testing.
Hypertensive angiopathy has a pattern of SWI abnormalities in the deep subcortical structures as well as the brain stem and typically occurs in older individuals with a history of uncontrolled or poorly controlled hypertension.
Vasculitis can be associated with superficial SWI changes, but is usually associated with leptomeningeal enhancement and areas of cerebral ischemia as well.
Head trauma. Classically, the microhemorrhages associated with trauma are located at the gray-white matter junction where microvasculature is susceptible to the effects of shearing trauma.
Calcium deposits. Calcium may appear in the brain for many reasons and will appear dark on SWI. A pattern in the bilateral basal ganglia may suggest benign calcification of the basal ganglia. If uncertain, a head CT scan can be helpful along with an MRI to diagnose calcium deposits.
Neurocysticercosis. The SWI signal abnormality in these individuals arises due to calcification rather than hemosiderin deposition. Neurocysticercosis is more likely than FCCM to have areas of enhancement and edema.
Brain irradiation. Two to 20 years after brain irradiation (whole brain or focused), exposed individuals may develop multiple cavernous malformations and/or capillary telangiectasias that may mimic the appearance of FCCM. History of radiation helps make the distinction between this entity and FCCM.
Capillary telangiectasias. Capillary telangiectasias can generally be distinguished from cavernous malformations by their small size and enhancement. These are commonly singular, are often located in the pons, appear dark on SWI and uniformly enhanced on contrasted studies, and do not typically appear on the standard T
• Somatic activating variants in
• Somatic pathogenic variants in
• Putting all recent somatic variant data together, it appears that (1) CCMs can develop as the result of biallelic loss of any of the three FCCM-related genes or as a result of somatic pathogenic variants in
• Hemorrhagic metastases. Renal cell, melanoma, papillary thyroid, lung, breast, and choriocarcinoma can create multiple hemorrhagic lesions of the brain that can be mistaken for FCCM. In general, metastases are more likely to enhance with contrast and more likely to have significant edema as compared to CCMs.
• Primary brain tumors, often with calcification (ganglioglioma)
• CAPNON (calcified pseudoneoplasm or the neuroaxis). The mixed density and susceptibility-weighted imaging (SWI) changes associated with this lesion are due to calcium rather than hemosiderin. These are usually singular lesions; thus, they are more likely to mimic sporadic CCM than FCCM.
• Infectious or inflammatory nodules
• Myxomatous emboli. An atrial myxoma embolizing to the brain can be confused with FCCM. However, these lesions typically have significant edema and a more complex appearance than CCMs.
• Arteriovenous malformations (AVMs). Most AVMs are readily distinguishable from cavernous malformations by the multiple T
• Hemorrhagic metastases (suggestive features include an older individual with a known primary malignancy and areas of enhancement using gadolinium as well as persistent edema)
• Cerebral microbleeds due to amyloid angiopathy, hypertension, vasculitis
• Amyloid angiopathy typically occurs in individuals older than age 60 years, and lesions are predominantly in the superficial cortex and sometimes associated with sulcal subarachnoid hemorrhage. If in doubt, a spinal fluid evaluation including tau and amyloid levels can be helpful in addition to apolipoprotein E testing.
• Hypertensive angiopathy has a pattern of SWI abnormalities in the deep subcortical structures as well as the brain stem and typically occurs in older individuals with a history of uncontrolled or poorly controlled hypertension.
• Vasculitis can be associated with superficial SWI changes, but is usually associated with leptomeningeal enhancement and areas of cerebral ischemia as well.
• Amyloid angiopathy typically occurs in individuals older than age 60 years, and lesions are predominantly in the superficial cortex and sometimes associated with sulcal subarachnoid hemorrhage. If in doubt, a spinal fluid evaluation including tau and amyloid levels can be helpful in addition to apolipoprotein E testing.
• Hypertensive angiopathy has a pattern of SWI abnormalities in the deep subcortical structures as well as the brain stem and typically occurs in older individuals with a history of uncontrolled or poorly controlled hypertension.
• Vasculitis can be associated with superficial SWI changes, but is usually associated with leptomeningeal enhancement and areas of cerebral ischemia as well.
• Head trauma. Classically, the microhemorrhages associated with trauma are located at the gray-white matter junction where microvasculature is susceptible to the effects of shearing trauma.
• Calcium deposits. Calcium may appear in the brain for many reasons and will appear dark on SWI. A pattern in the bilateral basal ganglia may suggest benign calcification of the basal ganglia. If uncertain, a head CT scan can be helpful along with an MRI to diagnose calcium deposits.
• Neurocysticercosis. The SWI signal abnormality in these individuals arises due to calcification rather than hemosiderin deposition. Neurocysticercosis is more likely than FCCM to have areas of enhancement and edema.
• Brain irradiation. Two to 20 years after brain irradiation (whole brain or focused), exposed individuals may develop multiple cavernous malformations and/or capillary telangiectasias that may mimic the appearance of FCCM. History of radiation helps make the distinction between this entity and FCCM.
• Capillary telangiectasias. Capillary telangiectasias can generally be distinguished from cavernous malformations by their small size and enhancement. These are commonly singular, are often located in the pons, appear dark on SWI and uniformly enhanced on contrasted studies, and do not typically appear on the standard T
• Amyloid angiopathy typically occurs in individuals older than age 60 years, and lesions are predominantly in the superficial cortex and sometimes associated with sulcal subarachnoid hemorrhage. If in doubt, a spinal fluid evaluation including tau and amyloid levels can be helpful in addition to apolipoprotein E testing.
• Hypertensive angiopathy has a pattern of SWI abnormalities in the deep subcortical structures as well as the brain stem and typically occurs in older individuals with a history of uncontrolled or poorly controlled hypertension.
• Vasculitis can be associated with superficial SWI changes, but is usually associated with leptomeningeal enhancement and areas of cerebral ischemia as well.
## Management
The management of cerebral cavernous malformations (CCMs) is largely based on epidemiologic, non-randomized surgical and radiosurgical studies, as well as expert opinion. In 2017, The Alliance to Cure Cavernous Malformation (Formerly Angioma Alliance) Scientific Committee published guidelines for the management of CCMs including familial CCM (FCCM) [
To establish the extent of disease and needs in an individual diagnosed with FCCM, the evaluations summarized in
Familial Cerebral Cavernous Malformations: Recommended Evaluations Following Initial Diagnosis
MRI w/standard sequences (T
For initial diagnosis, contrast is helpful to distinguish from other entities.
Afterward, contrast is not necessary to detect hemorrhage but may be useful for preoperative planning.
Community or
Social work involvement for parental support;
Home nursing referral.
CCM = cerebral cavernous malformation; FCCM = familial cerebral cavernous malformations; MOI = mode of inheritance; SCCM = spinal cord cavernous malformations; SWI = susceptibility-weighted imaging
CCMs were previously called "angiographically occult vascular lesions" due to their relatively poor visualization on catheter angiograms. Cerebral arteriography is rarely necessary unless there is concern for an underlying arteriovenous malformation.
Guidelines on the frequency of surveillance have not been established to date.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Familial Cerebral Cavernous Malformations: Treatment of Manifestations
May be assoc w/↑ risk of short-term neurologic disability, new focal deficits, &/or seizures
Complete resection can cure a single lesion; postoperative serial imaging can be helpful to assure there was complete resection.
Persons w/hydrocephalus may require shunting or ETV.
ASM = anti-seizure medication; ETV = endoscopic third ventriculocisternostomy
Of note, stereotactic radiosurgery maybe associated with risk of radiation injury or, rarely, radiation-induced cavernous malformation; it is not generally recommended in FCCM [
Individuals with hydrocephalus may require treatment with shunting or endoscopic third ventriculocisternostomy in those with unresectable midbrain lesions compressing the cerebral aqueduct or those with ventricular compression.
Laser interstitial thermal therapy is an evolving tool for the treatment of CCMs. Small, single-institution series suggest potential benefit in individuals with epilepsy, but further larger studies are needed.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Familial Cerebral Cavernous Malformations: Recommended Surveillance
Brain MRI imaging w/standard sequences (T
It is debatable whether routine surveillance in the absence of symptoms is helpful.
Neurologic & neurosurgical eval
EEG
Brain imaging
If seizures are under control on ASMs, annual follow up w/neurologist is recommended.
If the affected person has an exacerbation of a previously quiescent seizure disorder, brain MRI, EEG, & possibly neurosurgical eval should be considered.
If epilepsy is intractable despite multiple ASM trials, a neurosurgical eval should be considered.
Neurologic eval
PT & rehab
If the affected person has a stable focal neurologic deficit, PT & rehab should be considered.
For persistent lower motor neuron facial weakness or double vision, facial reanimation &/or ophthalmologic surgeries to restore function can be considered.
Spinal imaging should be repeated if the affected person has recurrent or worsening symptoms.
Debate exists regarding routine surveillance in the absence of new symptoms.
CCM = cerebral cavernous malformation; PT = physical therapy; SCCM = spinal cord cavernous malformations; SWI = susceptibility-weighted imaging
There is limited data regarding the use of non-aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs). One study reported a reduction in hemorrhage risk in individuals with sporadic or familial CCM taking NSAIDs [
The use of narcotic pain medications is discouraged in chronic pain conditions because of the potential for addiction and because of their association with rebound headaches.
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of
Molecular genetic testing if the pathogenic variant in the family is known;
Brain and/or spinal cord MR imaging including susceptibility-weighted imaging (SWI) or gradient echo (GRE) if the pathogenic variant in the family is not known.
See
Pregnant women with FCCM who have had recent brain or spinal cord hemorrhage, epilepsy, or migraine require close observation during pregnancy.
Pregnant women with suspected FCCM should undergo counseling regarding the risk for the fetus and genetic testing options.
In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASM may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and stage of pregnancy during which the medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from medication exposure is often less than that associated with an untreated maternal seizure disorder. Neurologists should be involved in the care of pregnant women with CCMs and seizures in the preplanning period or early pregnancy. ASMs should be reviewed to make sure the least teratogenic medication is being used and that women receive folate supplementation. ASM levels may need to be monitored during pregnancy. If a pregnant woman has a breakthrough seizure after a time of stability without an obvious provoking factor (e.g., fever or low ASM level), a brain MRI without contrast is safe and should be considered.
Focal neurologic deficits or significant or severe headaches during pregnancy should be evaluated. In addition to the concern of CCM hemorrhage, other neurologic causes should be ruled out (e.g., ischemic stroke, cerebral venous thrombosis). Three large studies have suggested that the risk of symptomatic hemorrhage does not differ between pregnant and non-pregnant women. These studies are somewhat limited by the number of women who become pregnant after a diagnosis of CCM [
Affected women and obstetricians are frequently concerned that the risk of increased blood pressure and intrathoracic pressure during labor could lead to CCM hemorrhage. However, review of the literature finds clinical events during labor to be extremely rare [
See
As radiation may induce CCM formation, the 2017 Synopsis of Guidelines for the Clinical Management of Cerebral Cavernous Malformations [
Search
• MRI w/standard sequences (T
• For initial diagnosis, contrast is helpful to distinguish from other entities.
• Afterward, contrast is not necessary to detect hemorrhage but may be useful for preoperative planning.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• May be assoc w/↑ risk of short-term neurologic disability, new focal deficits, &/or seizures
• Complete resection can cure a single lesion; postoperative serial imaging can be helpful to assure there was complete resection.
• Persons w/hydrocephalus may require shunting or ETV.
• Brain MRI imaging w/standard sequences (T
• It is debatable whether routine surveillance in the absence of symptoms is helpful.
• Neurologic & neurosurgical eval
• EEG
• Brain imaging
• If seizures are under control on ASMs, annual follow up w/neurologist is recommended.
• If the affected person has an exacerbation of a previously quiescent seizure disorder, brain MRI, EEG, & possibly neurosurgical eval should be considered.
• If epilepsy is intractable despite multiple ASM trials, a neurosurgical eval should be considered.
• Neurologic eval
• PT & rehab
• If the affected person has a stable focal neurologic deficit, PT & rehab should be considered.
• For persistent lower motor neuron facial weakness or double vision, facial reanimation &/or ophthalmologic surgeries to restore function can be considered.
• Spinal imaging should be repeated if the affected person has recurrent or worsening symptoms.
• Debate exists regarding routine surveillance in the absence of new symptoms.
• There is limited data regarding the use of non-aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs). One study reported a reduction in hemorrhage risk in individuals with sporadic or familial CCM taking NSAIDs [
• The use of narcotic pain medications is discouraged in chronic pain conditions because of the potential for addiction and because of their association with rebound headaches.
• Molecular genetic testing if the pathogenic variant in the family is known;
• Brain and/or spinal cord MR imaging including susceptibility-weighted imaging (SWI) or gradient echo (GRE) if the pathogenic variant in the family is not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with FCCM, the evaluations summarized in
Familial Cerebral Cavernous Malformations: Recommended Evaluations Following Initial Diagnosis
MRI w/standard sequences (T
For initial diagnosis, contrast is helpful to distinguish from other entities.
Afterward, contrast is not necessary to detect hemorrhage but may be useful for preoperative planning.
Community or
Social work involvement for parental support;
Home nursing referral.
CCM = cerebral cavernous malformation; FCCM = familial cerebral cavernous malformations; MOI = mode of inheritance; SCCM = spinal cord cavernous malformations; SWI = susceptibility-weighted imaging
CCMs were previously called "angiographically occult vascular lesions" due to their relatively poor visualization on catheter angiograms. Cerebral arteriography is rarely necessary unless there is concern for an underlying arteriovenous malformation.
Guidelines on the frequency of surveillance have not been established to date.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• MRI w/standard sequences (T
• For initial diagnosis, contrast is helpful to distinguish from other entities.
• Afterward, contrast is not necessary to detect hemorrhage but may be useful for preoperative planning.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Familial Cerebral Cavernous Malformations: Treatment of Manifestations
May be assoc w/↑ risk of short-term neurologic disability, new focal deficits, &/or seizures
Complete resection can cure a single lesion; postoperative serial imaging can be helpful to assure there was complete resection.
Persons w/hydrocephalus may require shunting or ETV.
ASM = anti-seizure medication; ETV = endoscopic third ventriculocisternostomy
Of note, stereotactic radiosurgery maybe associated with risk of radiation injury or, rarely, radiation-induced cavernous malformation; it is not generally recommended in FCCM [
Individuals with hydrocephalus may require treatment with shunting or endoscopic third ventriculocisternostomy in those with unresectable midbrain lesions compressing the cerebral aqueduct or those with ventricular compression.
Laser interstitial thermal therapy is an evolving tool for the treatment of CCMs. Small, single-institution series suggest potential benefit in individuals with epilepsy, but further larger studies are needed.
• May be assoc w/↑ risk of short-term neurologic disability, new focal deficits, &/or seizures
• Complete resection can cure a single lesion; postoperative serial imaging can be helpful to assure there was complete resection.
• Persons w/hydrocephalus may require shunting or ETV.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Familial Cerebral Cavernous Malformations: Recommended Surveillance
Brain MRI imaging w/standard sequences (T
It is debatable whether routine surveillance in the absence of symptoms is helpful.
Neurologic & neurosurgical eval
EEG
Brain imaging
If seizures are under control on ASMs, annual follow up w/neurologist is recommended.
If the affected person has an exacerbation of a previously quiescent seizure disorder, brain MRI, EEG, & possibly neurosurgical eval should be considered.
If epilepsy is intractable despite multiple ASM trials, a neurosurgical eval should be considered.
Neurologic eval
PT & rehab
If the affected person has a stable focal neurologic deficit, PT & rehab should be considered.
For persistent lower motor neuron facial weakness or double vision, facial reanimation &/or ophthalmologic surgeries to restore function can be considered.
Spinal imaging should be repeated if the affected person has recurrent or worsening symptoms.
Debate exists regarding routine surveillance in the absence of new symptoms.
CCM = cerebral cavernous malformation; PT = physical therapy; SCCM = spinal cord cavernous malformations; SWI = susceptibility-weighted imaging
• Brain MRI imaging w/standard sequences (T
• It is debatable whether routine surveillance in the absence of symptoms is helpful.
• Neurologic & neurosurgical eval
• EEG
• Brain imaging
• If seizures are under control on ASMs, annual follow up w/neurologist is recommended.
• If the affected person has an exacerbation of a previously quiescent seizure disorder, brain MRI, EEG, & possibly neurosurgical eval should be considered.
• If epilepsy is intractable despite multiple ASM trials, a neurosurgical eval should be considered.
• Neurologic eval
• PT & rehab
• If the affected person has a stable focal neurologic deficit, PT & rehab should be considered.
• For persistent lower motor neuron facial weakness or double vision, facial reanimation &/or ophthalmologic surgeries to restore function can be considered.
• Spinal imaging should be repeated if the affected person has recurrent or worsening symptoms.
• Debate exists regarding routine surveillance in the absence of new symptoms.
## Agents/Circumstances to Avoid
There is limited data regarding the use of non-aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs). One study reported a reduction in hemorrhage risk in individuals with sporadic or familial CCM taking NSAIDs [
The use of narcotic pain medications is discouraged in chronic pain conditions because of the potential for addiction and because of their association with rebound headaches.
• There is limited data regarding the use of non-aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs). One study reported a reduction in hemorrhage risk in individuals with sporadic or familial CCM taking NSAIDs [
• The use of narcotic pain medications is discouraged in chronic pain conditions because of the potential for addiction and because of their association with rebound headaches.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of
Molecular genetic testing if the pathogenic variant in the family is known;
Brain and/or spinal cord MR imaging including susceptibility-weighted imaging (SWI) or gradient echo (GRE) if the pathogenic variant in the family is not known.
See
• Molecular genetic testing if the pathogenic variant in the family is known;
• Brain and/or spinal cord MR imaging including susceptibility-weighted imaging (SWI) or gradient echo (GRE) if the pathogenic variant in the family is not known.
## Pregnancy Management
Pregnant women with FCCM who have had recent brain or spinal cord hemorrhage, epilepsy, or migraine require close observation during pregnancy.
Pregnant women with suspected FCCM should undergo counseling regarding the risk for the fetus and genetic testing options.
In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASM may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and stage of pregnancy during which the medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from medication exposure is often less than that associated with an untreated maternal seizure disorder. Neurologists should be involved in the care of pregnant women with CCMs and seizures in the preplanning period or early pregnancy. ASMs should be reviewed to make sure the least teratogenic medication is being used and that women receive folate supplementation. ASM levels may need to be monitored during pregnancy. If a pregnant woman has a breakthrough seizure after a time of stability without an obvious provoking factor (e.g., fever or low ASM level), a brain MRI without contrast is safe and should be considered.
Focal neurologic deficits or significant or severe headaches during pregnancy should be evaluated. In addition to the concern of CCM hemorrhage, other neurologic causes should be ruled out (e.g., ischemic stroke, cerebral venous thrombosis). Three large studies have suggested that the risk of symptomatic hemorrhage does not differ between pregnant and non-pregnant women. These studies are somewhat limited by the number of women who become pregnant after a diagnosis of CCM [
Affected women and obstetricians are frequently concerned that the risk of increased blood pressure and intrathoracic pressure during labor could lead to CCM hemorrhage. However, review of the literature finds clinical events during labor to be extremely rare [
See
## Therapies Under Investigation
As radiation may induce CCM formation, the 2017 Synopsis of Guidelines for the Clinical Management of Cerebral Cavernous Malformations [
Search
## Genetic Counseling
Familial cerebral cavernous malformations (FCCM) is inherited in an autosomal dominant manner.
The fairly common occurrence of asymptomatic vascular lesions may prevent recognition of an autosomal dominant pattern of inheritance in a family [
Because a clinical diagnosis of FCCM can be established in an individual by the presence of multiple lesions (independent of family history), an individual with a clinical diagnosis of FCCM may represent an apparent simplex case (i.e., the only affected family member). Likewise, an individual with a molecular diagnosis of FCCM (established by the identification of a heterozygous, germline FCCM-related genetic alteration involving
More than 5% of individuals with multiple lesions and/or a family history of CCMs do not have an identifiable pathogenic variant involving any of the three genes known to be associated with FCCM.
Sporadic cerebral cavernous malformations (CCMs) (i.e., CCMs caused by somatic pathogenic variants and not expected to recur in other family members) are not addressed in this section (see
Many individuals diagnosed with FCCM have a symptomatic parent.
A proband with FCCM may have the disorder as the result of a
If the proband is the only family member known to have FCCM, the following evaluations are recommended for the parents to confirm their status and to allow reliable recurrence risk counseling:
Molecular genetic testing (if a molecular diagnosis has been established in the proband); and/or
Brain MRI including gradient echo (GRE) or susceptibility-weighted imaging (SWI).
Family history (e.g., history of seizures, focal neurologic deficits, or brain bleeds) may be helpful in determining which parent is most likely to require a diagnostic evaluation.
If the proband has a known pathogenic variant that cannot be identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with FCCM may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or reduced penetrance in the parent with the pathogenic variant. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (i.e., molecular genetic testing if the pathogenic variant has been identified in the proband and/or brain MRI including GRE or SWI) has been performed on the parents of the proband.
If a parent of the proband is affected and/or a parent is known to have the pathogenic variant identified in the proband (regardless of the parent's clinical status), the risk to sibs is 50%.
If the proband has a known
If parents are clinically unaffected but their genetic status is unknown (because either the parents have not been tested for the pathogenic variant identified in the proband or the proband does not have a genetic alternation involving any of the three genes known to be associated with FCCM), the assumption of a familial form must be made and sibs and parents offered brain MRI with GRE and/or SWI in order to identify those who would benefit from prompt initiation of
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
If an FCCM-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The fairly common occurrence of asymptomatic vascular lesions may prevent recognition of an autosomal dominant pattern of inheritance in a family [
• Because a clinical diagnosis of FCCM can be established in an individual by the presence of multiple lesions (independent of family history), an individual with a clinical diagnosis of FCCM may represent an apparent simplex case (i.e., the only affected family member). Likewise, an individual with a molecular diagnosis of FCCM (established by the identification of a heterozygous, germline FCCM-related genetic alteration involving
• More than 5% of individuals with multiple lesions and/or a family history of CCMs do not have an identifiable pathogenic variant involving any of the three genes known to be associated with FCCM.
• Sporadic cerebral cavernous malformations (CCMs) (i.e., CCMs caused by somatic pathogenic variants and not expected to recur in other family members) are not addressed in this section (see
• Many individuals diagnosed with FCCM have a symptomatic parent.
• A proband with FCCM may have the disorder as the result of a
• If the proband is the only family member known to have FCCM, the following evaluations are recommended for the parents to confirm their status and to allow reliable recurrence risk counseling:
• Molecular genetic testing (if a molecular diagnosis has been established in the proband); and/or
• Brain MRI including gradient echo (GRE) or susceptibility-weighted imaging (SWI).
• Family history (e.g., history of seizures, focal neurologic deficits, or brain bleeds) may be helpful in determining which parent is most likely to require a diagnostic evaluation.
• Molecular genetic testing (if a molecular diagnosis has been established in the proband); and/or
• Brain MRI including gradient echo (GRE) or susceptibility-weighted imaging (SWI).
• If the proband has a known pathogenic variant that cannot be identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with FCCM may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or reduced penetrance in the parent with the pathogenic variant. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (i.e., molecular genetic testing if the pathogenic variant has been identified in the proband and/or brain MRI including GRE or SWI) has been performed on the parents of the proband.
• Molecular genetic testing (if a molecular diagnosis has been established in the proband); and/or
• Brain MRI including gradient echo (GRE) or susceptibility-weighted imaging (SWI).
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or a parent is known to have the pathogenic variant identified in the proband (regardless of the parent's clinical status), the risk to sibs is 50%.
• If the proband has a known
• If parents are clinically unaffected but their genetic status is unknown (because either the parents have not been tested for the pathogenic variant identified in the proband or the proband does not have a genetic alternation involving any of the three genes known to be associated with FCCM), the assumption of a familial form must be made and sibs and parents offered brain MRI with GRE and/or SWI in order to identify those who would benefit from prompt initiation of
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Familial cerebral cavernous malformations (FCCM) is inherited in an autosomal dominant manner.
The fairly common occurrence of asymptomatic vascular lesions may prevent recognition of an autosomal dominant pattern of inheritance in a family [
Because a clinical diagnosis of FCCM can be established in an individual by the presence of multiple lesions (independent of family history), an individual with a clinical diagnosis of FCCM may represent an apparent simplex case (i.e., the only affected family member). Likewise, an individual with a molecular diagnosis of FCCM (established by the identification of a heterozygous, germline FCCM-related genetic alteration involving
More than 5% of individuals with multiple lesions and/or a family history of CCMs do not have an identifiable pathogenic variant involving any of the three genes known to be associated with FCCM.
Sporadic cerebral cavernous malformations (CCMs) (i.e., CCMs caused by somatic pathogenic variants and not expected to recur in other family members) are not addressed in this section (see
• The fairly common occurrence of asymptomatic vascular lesions may prevent recognition of an autosomal dominant pattern of inheritance in a family [
• Because a clinical diagnosis of FCCM can be established in an individual by the presence of multiple lesions (independent of family history), an individual with a clinical diagnosis of FCCM may represent an apparent simplex case (i.e., the only affected family member). Likewise, an individual with a molecular diagnosis of FCCM (established by the identification of a heterozygous, germline FCCM-related genetic alteration involving
• More than 5% of individuals with multiple lesions and/or a family history of CCMs do not have an identifiable pathogenic variant involving any of the three genes known to be associated with FCCM.
• Sporadic cerebral cavernous malformations (CCMs) (i.e., CCMs caused by somatic pathogenic variants and not expected to recur in other family members) are not addressed in this section (see
## Risk to Family Members
Many individuals diagnosed with FCCM have a symptomatic parent.
A proband with FCCM may have the disorder as the result of a
If the proband is the only family member known to have FCCM, the following evaluations are recommended for the parents to confirm their status and to allow reliable recurrence risk counseling:
Molecular genetic testing (if a molecular diagnosis has been established in the proband); and/or
Brain MRI including gradient echo (GRE) or susceptibility-weighted imaging (SWI).
Family history (e.g., history of seizures, focal neurologic deficits, or brain bleeds) may be helpful in determining which parent is most likely to require a diagnostic evaluation.
If the proband has a known pathogenic variant that cannot be identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with FCCM may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or reduced penetrance in the parent with the pathogenic variant. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (i.e., molecular genetic testing if the pathogenic variant has been identified in the proband and/or brain MRI including GRE or SWI) has been performed on the parents of the proband.
If a parent of the proband is affected and/or a parent is known to have the pathogenic variant identified in the proband (regardless of the parent's clinical status), the risk to sibs is 50%.
If the proband has a known
If parents are clinically unaffected but their genetic status is unknown (because either the parents have not been tested for the pathogenic variant identified in the proband or the proband does not have a genetic alternation involving any of the three genes known to be associated with FCCM), the assumption of a familial form must be made and sibs and parents offered brain MRI with GRE and/or SWI in order to identify those who would benefit from prompt initiation of
• Many individuals diagnosed with FCCM have a symptomatic parent.
• A proband with FCCM may have the disorder as the result of a
• If the proband is the only family member known to have FCCM, the following evaluations are recommended for the parents to confirm their status and to allow reliable recurrence risk counseling:
• Molecular genetic testing (if a molecular diagnosis has been established in the proband); and/or
• Brain MRI including gradient echo (GRE) or susceptibility-weighted imaging (SWI).
• Family history (e.g., history of seizures, focal neurologic deficits, or brain bleeds) may be helpful in determining which parent is most likely to require a diagnostic evaluation.
• Molecular genetic testing (if a molecular diagnosis has been established in the proband); and/or
• Brain MRI including gradient echo (GRE) or susceptibility-weighted imaging (SWI).
• If the proband has a known pathogenic variant that cannot be identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with FCCM may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or reduced penetrance in the parent with the pathogenic variant. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (i.e., molecular genetic testing if the pathogenic variant has been identified in the proband and/or brain MRI including GRE or SWI) has been performed on the parents of the proband.
• Molecular genetic testing (if a molecular diagnosis has been established in the proband); and/or
• Brain MRI including gradient echo (GRE) or susceptibility-weighted imaging (SWI).
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or a parent is known to have the pathogenic variant identified in the proband (regardless of the parent's clinical status), the risk to sibs is 50%.
• If the proband has a known
• If parents are clinically unaffected but their genetic status is unknown (because either the parents have not been tested for the pathogenic variant identified in the proband or the proband does not have a genetic alternation involving any of the three genes known to be associated with FCCM), the assumption of a familial form must be made and sibs and parents offered brain MRI with GRE and/or SWI in order to identify those who would benefit from prompt initiation of
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
If an FCCM-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
•
•
•
•
•
•
•
## Molecular Genetics
Familial Cerebral Cavernous Malformation: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Familial Cerebral Cavernous Malformation (
All three cerebral cavernous malformation (CCM) genes (
Molecular genetic analysis of CCMs from individuals with familial CCM (FCCM) identified a second somatic pathogenic variant on the other allele of the same gene with the germline pathogenic variant [
In some (but not all) sporadic cases, lesions can contain two somatic pathogenic variants that inactivate both copies of the gene [
Familial Cerebral Cavernous Malformations: Gene-Specific Laboratory Considerations
A large 77.6-kb deletion that includes exons 2-10 is a common founder deletion in the US population; it is not detectable by sequencing and requires deletion/duplication or CMA analysis, which may be performed as a first-tier test in this population [
Genes from
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the authors.
Genes from
• A large 77.6-kb deletion that includes exons 2-10 is a common founder deletion in the US population; it is not detectable by sequencing and requires deletion/duplication or CMA analysis, which may be performed as a first-tier test in this population [
## Molecular Pathogenesis
All three cerebral cavernous malformation (CCM) genes (
Molecular genetic analysis of CCMs from individuals with familial CCM (FCCM) identified a second somatic pathogenic variant on the other allele of the same gene with the germline pathogenic variant [
In some (but not all) sporadic cases, lesions can contain two somatic pathogenic variants that inactivate both copies of the gene [
Familial Cerebral Cavernous Malformations: Gene-Specific Laboratory Considerations
A large 77.6-kb deletion that includes exons 2-10 is a common founder deletion in the US population; it is not detectable by sequencing and requires deletion/duplication or CMA analysis, which may be performed as a first-tier test in this population [
Genes from
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the authors.
Genes from
• A large 77.6-kb deletion that includes exons 2-10 is a common founder deletion in the US population; it is not detectable by sequencing and requires deletion/duplication or CMA analysis, which may be performed as a first-tier test in this population [
## Chapter Notes
NIH Funding – 454RD
Scientific Advisory Board, Angioma Alliance
WBD holds the Canada Research Chair in Animal Models of Human Disease and is supported by a project grant from the Canadian Institutes of Health Research (PJT-153000).
Amy Akers, PhD; Angioma Alliance (2011-2023)
W Brent Derry, PhD (2023-present)
Kelly D Flemming, MD (2023-present)
Eric W Johnson, PhD; Barrow Neurological Institute (2003-2011)
Douglas Marchuk, PhD (2023-present)
Leslie Morrison, MD; University of New Mexico (2011-2023)
Edward Smith, MD (2023-present)
27 July 2023 (gm) Comprehensive update posted live
4 August 2016 (ma) Comprehensive update posted live
31 May 2011 (me) Comprehensive update posted live
31 May 2005 (me) Comprehensive update posted live
24 February 2003 (me) Review posted live
5 February 2002 (ej) Original submission
• 27 July 2023 (gm) Comprehensive update posted live
• 4 August 2016 (ma) Comprehensive update posted live
• 31 May 2011 (me) Comprehensive update posted live
• 31 May 2005 (me) Comprehensive update posted live
• 24 February 2003 (me) Review posted live
• 5 February 2002 (ej) Original submission
## Author Notes
NIH Funding – 454RD
Scientific Advisory Board, Angioma Alliance
## Acknowledgments
WBD holds the Canada Research Chair in Animal Models of Human Disease and is supported by a project grant from the Canadian Institutes of Health Research (PJT-153000).
## Author History
Amy Akers, PhD; Angioma Alliance (2011-2023)
W Brent Derry, PhD (2023-present)
Kelly D Flemming, MD (2023-present)
Eric W Johnson, PhD; Barrow Neurological Institute (2003-2011)
Douglas Marchuk, PhD (2023-present)
Leslie Morrison, MD; University of New Mexico (2011-2023)
Edward Smith, MD (2023-present)
## Revision History
27 July 2023 (gm) Comprehensive update posted live
4 August 2016 (ma) Comprehensive update posted live
31 May 2011 (me) Comprehensive update posted live
31 May 2005 (me) Comprehensive update posted live
24 February 2003 (me) Review posted live
5 February 2002 (ej) Original submission
• 27 July 2023 (gm) Comprehensive update posted live
• 4 August 2016 (ma) Comprehensive update posted live
• 31 May 2011 (me) Comprehensive update posted live
• 31 May 2005 (me) Comprehensive update posted live
• 24 February 2003 (me) Review posted live
• 5 February 2002 (ej) Original submission
## References
## Literature Cited
Zabramski classification of cavernous malformations
A type 1 cavernous malformation is one with acute or subacute hemorrhage characterized radiographically by hyperintense T
Differential diagnosis of cavernous malformations
The left panel lists the differential diagnosis for "large lesion" cavernous malformations. The right panel lists the differential diagnosis for cavernous malformations not visible on standard MRI sequences (gradient echo or susceptibility-weighted imaging [SWI] only).
|
[] |
24/2/2003
|
27/7/2023
|
13/7/2006
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cco
|
cco
|
[
"Ryanodine receptor 1",
"RYR1",
"Central Core Disease"
] |
Central Core Disease – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
May Christine V Malicdan, Ichizo Nishino
|
Summary Central core disease (CCD) is characterized by muscle weakness ranging from mild to severe. Most affected individuals have mild disease with symmetric proximal muscle weakness and variable involvement of facial and neck muscles. The extraocular muscles are often spared. Motor development is usually delayed, but in general, most affected individuals acquire independent ambulation. Life span is usually normal. Severe disease is early in onset with profound hypotonia often accompanied by poor fetal movement, spinal deformities, hip dislocation, joint contractures, poor suck, and respiratory insufficiency requiring assisted ventilation. The outcome ranges from death in infancy to survival beyond age five years. The weakness in CCD is not typically progressive. The diagnosis of CCD is based on clinical findings of muscle weakness, the histopathologic findings of characteristic cores on muscle biopsy, and molecular genetic testing. Most CCD is associated with pathogenic variants in Central core disease (CCD) is usually inherited in an autosomal dominant (AD) manner but can be inherited in an autosomal recessive (AR) manner. Most individuals diagnosed with AD central core disease have an affected parent or an asymptomatic parent who has a pathogenic variant. The proportion of AD CCD caused by
|
## Diagnosis
Diagnosis of central core disease
In early-onset disease:
Hypotonia and generalized weakness, often accompanied by perinatal complications including poor fetal movement, respiratory insufficiency, and poor suck
Delayed motor milestones (Independent ambulation is commonly achieved between ages three and four years, but varies depending on the severity of the disease.)
Spinal deformities, congenital hip dislocation, high-arched palate, foot deformities, and joint contractures. Rarely, patients may show severe skeletal malformations such as those seen in
In later-onset disease (rare):
Mild symmetric myopathy, predominantly involving the proximal muscles
Mildly affected facial muscles
Occasional involvement of the extraocular muscles (Ophthalmoplegia is relatively common in the autosomal recessive forms.)
The diagnosis of central core disease
In the event that molecular testing is done first:
In a patient with classic clinical presentation of CCD, if the identified
In a patient without visible clinical involvement, muscle biopsy will be of importance if there is a need to interpret
Often well demarcated
May be centrally or peripherally located in the fibers
Run down an appreciable length of the fiber on longitudinal sections
Devoid of mitochondria
Do not stain with oxidative enzyme stains (e.g., NADH-tetrazolium reductase, succinate dehydrogenase, cytochrome
Deficient in phosphorylase activity and glycogen
Sometimes surrounded by a thin rim of high oxidative enzyme activity, giving the appearance of "rimmed cores"
On immunohistochemistry studies, distinct staining patterns that are restricted to the cores: RyR1 protein was focally depleted within the cores, while other proteins including DHPR[alpha]
Less common but nonetheless important pathologic findings in the spectrum of cores include the following [
More than one core can be observed within a single muscle fiber.
The number of type 1 fibers with cores varies.
The diameter of cores can vary.
Foci of multiple minicores in focal areas can occur.
Other pathologic characteristics of muscle:
Type 1 fiber predominance or uniformity
Mild to moderate fiber size variation
Minimal to moderate endomysial fibrosis. Marked fibrosis and increase in adipose tissue have been noted in several cases.
Occasional increase in internal and central nuclei
Note: (1) Nemaline bodies occurring together with cores have been seen in genetically confirmed cases of CCD. When rods are numerous this has sometimes been referred to as core-rod disease. In a large French pedigree demonstrating autosomal dominant inheritance, the association of this disease with
Virtual absence of mitochondria and sarcoplasmic reticulum (SR) in the core region. SR accumulation within the cores has been described on EM.
Irregular zigzag pattern or complete disruption of the Z-lines but often preservation of the striation pattern
Reduction in the intermyofibrillar space
One genetic testing strategy is
An alternative genetic testing strategy is use of a
For an introduction to multigene panels click
Note: Although in the majority of patients CCD results from a single pathogenic variant in
If only one pathogenic variant is identified in a simplex case (i.e., a single occurrence in a family), it is difficult to distinguish between the following:
A
Autosomal recessive inheritance with a known
To resolve this issue, the following can be considered:
Testing both parents for the pathogenic variant (when possible) to confirm or exclude a
If autosomal recessive inheritance is suspected, deletion/duplication analysis or next generation sequencing to identify the pathogenic variant on the second allele
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Central Core Disease
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Exons sequenced vary by laboratory.
In autosomal dominant CCD [
Results from
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
No other locus heterogeneity has been identified. It is possible that other disorders with EC uncoupling could be within the spectrum of CCD, but more studies are warranted. Other candidate genes to be considered include those that code for proteins involved or associated with the triadin, which is the anatomic site of EC uncoupling, and include triadin, junctin, histidine-rich calcium-binding protein, calsequestrin, JP-45, and mitsugamin-29 [
• In early-onset disease:
• Hypotonia and generalized weakness, often accompanied by perinatal complications including poor fetal movement, respiratory insufficiency, and poor suck
• Delayed motor milestones (Independent ambulation is commonly achieved between ages three and four years, but varies depending on the severity of the disease.)
• Spinal deformities, congenital hip dislocation, high-arched palate, foot deformities, and joint contractures. Rarely, patients may show severe skeletal malformations such as those seen in
• Hypotonia and generalized weakness, often accompanied by perinatal complications including poor fetal movement, respiratory insufficiency, and poor suck
• Delayed motor milestones (Independent ambulation is commonly achieved between ages three and four years, but varies depending on the severity of the disease.)
• Spinal deformities, congenital hip dislocation, high-arched palate, foot deformities, and joint contractures. Rarely, patients may show severe skeletal malformations such as those seen in
• In later-onset disease (rare):
• Mild symmetric myopathy, predominantly involving the proximal muscles
• Mildly affected facial muscles
• Occasional involvement of the extraocular muscles (Ophthalmoplegia is relatively common in the autosomal recessive forms.)
• Mild symmetric myopathy, predominantly involving the proximal muscles
• Mildly affected facial muscles
• Occasional involvement of the extraocular muscles (Ophthalmoplegia is relatively common in the autosomal recessive forms.)
• Hypotonia and generalized weakness, often accompanied by perinatal complications including poor fetal movement, respiratory insufficiency, and poor suck
• Delayed motor milestones (Independent ambulation is commonly achieved between ages three and four years, but varies depending on the severity of the disease.)
• Spinal deformities, congenital hip dislocation, high-arched palate, foot deformities, and joint contractures. Rarely, patients may show severe skeletal malformations such as those seen in
• Mild symmetric myopathy, predominantly involving the proximal muscles
• Mildly affected facial muscles
• Occasional involvement of the extraocular muscles (Ophthalmoplegia is relatively common in the autosomal recessive forms.)
• In a patient with classic clinical presentation of CCD, if the identified
• In a patient without visible clinical involvement, muscle biopsy will be of importance if there is a need to interpret
• Often well demarcated
• May be centrally or peripherally located in the fibers
• Run down an appreciable length of the fiber on longitudinal sections
• Devoid of mitochondria
• Do not stain with oxidative enzyme stains (e.g., NADH-tetrazolium reductase, succinate dehydrogenase, cytochrome
• Deficient in phosphorylase activity and glycogen
• Sometimes surrounded by a thin rim of high oxidative enzyme activity, giving the appearance of "rimmed cores"
• On immunohistochemistry studies, distinct staining patterns that are restricted to the cores: RyR1 protein was focally depleted within the cores, while other proteins including DHPR[alpha]
• More than one core can be observed within a single muscle fiber.
• The number of type 1 fibers with cores varies.
• The diameter of cores can vary.
• Foci of multiple minicores in focal areas can occur.
• Type 1 fiber predominance or uniformity
• Mild to moderate fiber size variation
• Minimal to moderate endomysial fibrosis. Marked fibrosis and increase in adipose tissue have been noted in several cases.
• Occasional increase in internal and central nuclei
• Virtual absence of mitochondria and sarcoplasmic reticulum (SR) in the core region. SR accumulation within the cores has been described on EM.
• Irregular zigzag pattern or complete disruption of the Z-lines but often preservation of the striation pattern
• Reduction in the intermyofibrillar space
• A
• Autosomal recessive inheritance with a known
• Testing both parents for the pathogenic variant (when possible) to confirm or exclude a
• If autosomal recessive inheritance is suspected, deletion/duplication analysis or next generation sequencing to identify the pathogenic variant on the second allele
## Suggestive Findings
Diagnosis of central core disease
In early-onset disease:
Hypotonia and generalized weakness, often accompanied by perinatal complications including poor fetal movement, respiratory insufficiency, and poor suck
Delayed motor milestones (Independent ambulation is commonly achieved between ages three and four years, but varies depending on the severity of the disease.)
Spinal deformities, congenital hip dislocation, high-arched palate, foot deformities, and joint contractures. Rarely, patients may show severe skeletal malformations such as those seen in
In later-onset disease (rare):
Mild symmetric myopathy, predominantly involving the proximal muscles
Mildly affected facial muscles
Occasional involvement of the extraocular muscles (Ophthalmoplegia is relatively common in the autosomal recessive forms.)
• In early-onset disease:
• Hypotonia and generalized weakness, often accompanied by perinatal complications including poor fetal movement, respiratory insufficiency, and poor suck
• Delayed motor milestones (Independent ambulation is commonly achieved between ages three and four years, but varies depending on the severity of the disease.)
• Spinal deformities, congenital hip dislocation, high-arched palate, foot deformities, and joint contractures. Rarely, patients may show severe skeletal malformations such as those seen in
• Hypotonia and generalized weakness, often accompanied by perinatal complications including poor fetal movement, respiratory insufficiency, and poor suck
• Delayed motor milestones (Independent ambulation is commonly achieved between ages three and four years, but varies depending on the severity of the disease.)
• Spinal deformities, congenital hip dislocation, high-arched palate, foot deformities, and joint contractures. Rarely, patients may show severe skeletal malformations such as those seen in
• In later-onset disease (rare):
• Mild symmetric myopathy, predominantly involving the proximal muscles
• Mildly affected facial muscles
• Occasional involvement of the extraocular muscles (Ophthalmoplegia is relatively common in the autosomal recessive forms.)
• Mild symmetric myopathy, predominantly involving the proximal muscles
• Mildly affected facial muscles
• Occasional involvement of the extraocular muscles (Ophthalmoplegia is relatively common in the autosomal recessive forms.)
• Hypotonia and generalized weakness, often accompanied by perinatal complications including poor fetal movement, respiratory insufficiency, and poor suck
• Delayed motor milestones (Independent ambulation is commonly achieved between ages three and four years, but varies depending on the severity of the disease.)
• Spinal deformities, congenital hip dislocation, high-arched palate, foot deformities, and joint contractures. Rarely, patients may show severe skeletal malformations such as those seen in
• Mild symmetric myopathy, predominantly involving the proximal muscles
• Mildly affected facial muscles
• Occasional involvement of the extraocular muscles (Ophthalmoplegia is relatively common in the autosomal recessive forms.)
## Establishing the Diagnosis
The diagnosis of central core disease
In the event that molecular testing is done first:
In a patient with classic clinical presentation of CCD, if the identified
In a patient without visible clinical involvement, muscle biopsy will be of importance if there is a need to interpret
Often well demarcated
May be centrally or peripherally located in the fibers
Run down an appreciable length of the fiber on longitudinal sections
Devoid of mitochondria
Do not stain with oxidative enzyme stains (e.g., NADH-tetrazolium reductase, succinate dehydrogenase, cytochrome
Deficient in phosphorylase activity and glycogen
Sometimes surrounded by a thin rim of high oxidative enzyme activity, giving the appearance of "rimmed cores"
On immunohistochemistry studies, distinct staining patterns that are restricted to the cores: RyR1 protein was focally depleted within the cores, while other proteins including DHPR[alpha]
Less common but nonetheless important pathologic findings in the spectrum of cores include the following [
More than one core can be observed within a single muscle fiber.
The number of type 1 fibers with cores varies.
The diameter of cores can vary.
Foci of multiple minicores in focal areas can occur.
Other pathologic characteristics of muscle:
Type 1 fiber predominance or uniformity
Mild to moderate fiber size variation
Minimal to moderate endomysial fibrosis. Marked fibrosis and increase in adipose tissue have been noted in several cases.
Occasional increase in internal and central nuclei
Note: (1) Nemaline bodies occurring together with cores have been seen in genetically confirmed cases of CCD. When rods are numerous this has sometimes been referred to as core-rod disease. In a large French pedigree demonstrating autosomal dominant inheritance, the association of this disease with
Virtual absence of mitochondria and sarcoplasmic reticulum (SR) in the core region. SR accumulation within the cores has been described on EM.
Irregular zigzag pattern or complete disruption of the Z-lines but often preservation of the striation pattern
Reduction in the intermyofibrillar space
One genetic testing strategy is
An alternative genetic testing strategy is use of a
For an introduction to multigene panels click
Note: Although in the majority of patients CCD results from a single pathogenic variant in
If only one pathogenic variant is identified in a simplex case (i.e., a single occurrence in a family), it is difficult to distinguish between the following:
A
Autosomal recessive inheritance with a known
To resolve this issue, the following can be considered:
Testing both parents for the pathogenic variant (when possible) to confirm or exclude a
If autosomal recessive inheritance is suspected, deletion/duplication analysis or next generation sequencing to identify the pathogenic variant on the second allele
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Central Core Disease
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Exons sequenced vary by laboratory.
In autosomal dominant CCD [
Results from
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
No other locus heterogeneity has been identified. It is possible that other disorders with EC uncoupling could be within the spectrum of CCD, but more studies are warranted. Other candidate genes to be considered include those that code for proteins involved or associated with the triadin, which is the anatomic site of EC uncoupling, and include triadin, junctin, histidine-rich calcium-binding protein, calsequestrin, JP-45, and mitsugamin-29 [
• In a patient with classic clinical presentation of CCD, if the identified
• In a patient without visible clinical involvement, muscle biopsy will be of importance if there is a need to interpret
• Often well demarcated
• May be centrally or peripherally located in the fibers
• Run down an appreciable length of the fiber on longitudinal sections
• Devoid of mitochondria
• Do not stain with oxidative enzyme stains (e.g., NADH-tetrazolium reductase, succinate dehydrogenase, cytochrome
• Deficient in phosphorylase activity and glycogen
• Sometimes surrounded by a thin rim of high oxidative enzyme activity, giving the appearance of "rimmed cores"
• On immunohistochemistry studies, distinct staining patterns that are restricted to the cores: RyR1 protein was focally depleted within the cores, while other proteins including DHPR[alpha]
• More than one core can be observed within a single muscle fiber.
• The number of type 1 fibers with cores varies.
• The diameter of cores can vary.
• Foci of multiple minicores in focal areas can occur.
• Type 1 fiber predominance or uniformity
• Mild to moderate fiber size variation
• Minimal to moderate endomysial fibrosis. Marked fibrosis and increase in adipose tissue have been noted in several cases.
• Occasional increase in internal and central nuclei
• Virtual absence of mitochondria and sarcoplasmic reticulum (SR) in the core region. SR accumulation within the cores has been described on EM.
• Irregular zigzag pattern or complete disruption of the Z-lines but often preservation of the striation pattern
• Reduction in the intermyofibrillar space
• A
• Autosomal recessive inheritance with a known
• Testing both parents for the pathogenic variant (when possible) to confirm or exclude a
• If autosomal recessive inheritance is suspected, deletion/duplication analysis or next generation sequencing to identify the pathogenic variant on the second allele
## Molecular Genetic Testing
One genetic testing strategy is
An alternative genetic testing strategy is use of a
For an introduction to multigene panels click
Note: Although in the majority of patients CCD results from a single pathogenic variant in
If only one pathogenic variant is identified in a simplex case (i.e., a single occurrence in a family), it is difficult to distinguish between the following:
A
Autosomal recessive inheritance with a known
To resolve this issue, the following can be considered:
Testing both parents for the pathogenic variant (when possible) to confirm or exclude a
If autosomal recessive inheritance is suspected, deletion/duplication analysis or next generation sequencing to identify the pathogenic variant on the second allele
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Central Core Disease
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Exons sequenced vary by laboratory.
In autosomal dominant CCD [
Results from
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
No other locus heterogeneity has been identified. It is possible that other disorders with EC uncoupling could be within the spectrum of CCD, but more studies are warranted. Other candidate genes to be considered include those that code for proteins involved or associated with the triadin, which is the anatomic site of EC uncoupling, and include triadin, junctin, histidine-rich calcium-binding protein, calsequestrin, JP-45, and mitsugamin-29 [
• A
• Autosomal recessive inheritance with a known
• Testing both parents for the pathogenic variant (when possible) to confirm or exclude a
• If autosomal recessive inheritance is suspected, deletion/duplication analysis or next generation sequencing to identify the pathogenic variant on the second allele
## Clinical Characteristics
The expressivity of central core disease (CCD) is variable even among family members, ranging clinically from mild (i.e., almost asymptomatic) to severe (i.e., ventilator-dependent) and histologically varying in the extent and localization of cores in the muscle fibers.
Serum creatine kinase concentration may be normal or mildly elevated.
Electromyography may confirm the presence of myopathy and reveal brief, short action potentials and early recruitment.
Although most
Some studies have shown that autosomal recessive CCD, often associated with
In a study of 25 individuals with genetically confirmed CCD,
The 16 individuals with C-terminal
Most individuals with CCD with at least one
Individuals with CCD who have pathogenic variants in the N-terminal domain may have a higher probability of malignant hyperthermia susceptibility than those with pathogenic variants in the C-terminal domain [
In general, the penetrance of CCD-associated
CCD has also been referred to as Shy-Magee syndrome, after the individuals who initially reported it.
Some cases called core-rod disease are not associated with a
An accurate incidence and prevalence of CCD, considered to be the most frequently occurring congenital myopathy, are unknown. By definition, CCD is considered a rare disease by the Office of Rare Disease, implying that it affects fewer than 200,000 in the US population. A recent estimate of 1:100,000 was calculated among patients with genetic muscle disease in Northern England [
• Serum creatine kinase concentration may be normal or mildly elevated.
• Electromyography may confirm the presence of myopathy and reveal brief, short action potentials and early recruitment.
• The 16 individuals with C-terminal
• Most individuals with CCD with at least one
## Clinical Description
The expressivity of central core disease (CCD) is variable even among family members, ranging clinically from mild (i.e., almost asymptomatic) to severe (i.e., ventilator-dependent) and histologically varying in the extent and localization of cores in the muscle fibers.
Serum creatine kinase concentration may be normal or mildly elevated.
Electromyography may confirm the presence of myopathy and reveal brief, short action potentials and early recruitment.
• Serum creatine kinase concentration may be normal or mildly elevated.
• Electromyography may confirm the presence of myopathy and reveal brief, short action potentials and early recruitment.
## Genotype-Phenotype Correlations
Although most
Some studies have shown that autosomal recessive CCD, often associated with
In a study of 25 individuals with genetically confirmed CCD,
The 16 individuals with C-terminal
Most individuals with CCD with at least one
Individuals with CCD who have pathogenic variants in the N-terminal domain may have a higher probability of malignant hyperthermia susceptibility than those with pathogenic variants in the C-terminal domain [
• The 16 individuals with C-terminal
• Most individuals with CCD with at least one
## Penetrance
In general, the penetrance of CCD-associated
## Nomenclature
CCD has also been referred to as Shy-Magee syndrome, after the individuals who initially reported it.
Some cases called core-rod disease are not associated with a
## Prevalence
An accurate incidence and prevalence of CCD, considered to be the most frequently occurring congenital myopathy, are unknown. By definition, CCD is considered a rare disease by the Office of Rare Disease, implying that it affects fewer than 200,000 in the US population. A recent estimate of 1:100,000 was calculated among patients with genetic muscle disease in Northern England [
## Genetically Related (Allelic) Disorders
A clinical grading scale helps determine if a malignant hyperthermia (MH) episode has occurred. Contracture testing, the standard diagnostic test for MH since the mid-1970s, relies on the in vitro measurement of contracture response of biopsied muscle to graded concentrations of caffeine and the anesthetic halothane. Alternatively, calcium-induced calcium release (CICR) test can be performed, but has only been done in Japan. (For further information see
The precise association of MHS and
In several reports cores have been present in muscle biopsy of persons proven to have MH, thus raising controversy as to whether these individuals have CCD with MHS or MHS with cores. For example,
Four clinical categories of MmD have been identified: classic form (75% of individuals), moderate form with hand involvement (<10%), antenatal form with arthrogryposis multiplex congenita (<10%), and ophthalmoplegic form (<10%). Onset of the classic form is usually congenital or occurs in early childhood with neonatal hypotonia, delayed motor development, axial muscle weakness, scoliosis, and significant respiratory involvement (often with secondary cardiac impairment). Spinal rigidity of varying severity is present.
Pathogenic variants in two genes account for about half the cases of MmD. Although further genetic heterogeneity is suggested, no other candidate region or gene has been identified .
CNMDU1 histologic findings are thought to be an earlier manifestation of CCD, as an individual with pathologically confirmed CCD had a muscle biopsy consistent with CNMDU1 earlier in childhood [
## Differential Diagnosis
Structures similar to cores have been observed in the myofibers of individuals with neurogenic atrophy but are more appropriately called "target fibers" in this setting because of the darker band around the pale central area, giving it a target-like appearance. In addition, core-like lesions devoid of this band can also be seen conditions with neurogenic atrophy.
• Structures similar to cores have been observed in the myofibers of individuals with neurogenic atrophy but are more appropriately called "target fibers" in this setting because of the darker band around the pale central area, giving it a target-like appearance. In addition, core-like lesions devoid of this band can also be seen conditions with neurogenic atrophy.
## Management
To establish the extent of disease and needs in an individual diagnosed with central core disease (CCD), the following evaluations are recommended:
Neurologic examination with attention to features of congenital myopathy (hypotonia, failure to thrive, joint contractures, scoliosis), weakness of the limbs, and muscle cramps
Physical and occupational therapy assessments
Evaluation for feeding difficulties, including assessment for sucking and ability to swallow
Pulmonary function testing in most patients, especially those with scoliosis, hypotonia, signs of respiratory distress, and/or history of recurrent chest infections. History should be taken for symptoms of nocturnal hypoxia including early morning headaches, daytime drowsiness, loss of appetite, and deteriorating school performance.
Consultation with a clinical geneticist and/or genetic counselor
Since prognosis is mainly influenced by respiratory status and scoliosis, treatment geared toward these manifestations is essential.
Treatment depends on the severity of symptoms, but mainly consists of supportive measures and rehabilitation that address the following problems:
Hypotonia and weakness. Patients may benefit from physical therapy. Interventions may include stretching programs and mild to moderate low-impact exercise; activities should be balanced in such a way that exhaustion is avoided.
Scoliosis and joint contractures. Some patients may only require physical therapy, while others may need orthopedic surgery (e.g., scoliosis surgery, corrective surgery for congenital hip dislocation and foot deformities).
Respiratory. Patients with more severe symptoms may require respiratory support. Breathing exercises and chest physiotherapy for handling secretions may also be beneficial.
Feeding difficulties. Individuals may require diet supplementation and feeding by means of nasogastric/orogastric routes or gastrostomy.
Secondary complications can include respiratory compromise from scoliosis; hence, orthopedic intervention may reduce the risk of this problem.
Immunization against influenza is encouraged.
Prompt treatment of respiratory infection is important.
Joint contractures may be prevented by encouraging mobility and by active participation in physical therapy.
The following are appropriate:
Routine assessment of the spine for scoliosis and joints for contractures
Routine assessment of respiratory parameters such as respiratory rate, peak expiratory flow rate (PEFR), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1)
Sleep studies especially when patients show signs of nocturnal hypoxia
Regular assessment of motor abilities in order to determine need for physical therapy, occupational therapy, and assistive devices for ambulation, such as a wheelchair
Although it is unknown how CCD is associated with malignant hyperthermia susceptibility or which pathogenic variants in
Individuals suspected of having MH susceptibility are advised to avoid extremes of heat, but this does not mean restriction of athletic activity.
Because CCD is associated with an increased risk for MH susceptibility, it is appropriate to test at-risk relatives of a proband (whether symptomatic or not) for the
See
Because all patients with CCD are considered to be at risk for
Search
• Neurologic examination with attention to features of congenital myopathy (hypotonia, failure to thrive, joint contractures, scoliosis), weakness of the limbs, and muscle cramps
• Physical and occupational therapy assessments
• Evaluation for feeding difficulties, including assessment for sucking and ability to swallow
• Pulmonary function testing in most patients, especially those with scoliosis, hypotonia, signs of respiratory distress, and/or history of recurrent chest infections. History should be taken for symptoms of nocturnal hypoxia including early morning headaches, daytime drowsiness, loss of appetite, and deteriorating school performance.
• Consultation with a clinical geneticist and/or genetic counselor
• Hypotonia and weakness. Patients may benefit from physical therapy. Interventions may include stretching programs and mild to moderate low-impact exercise; activities should be balanced in such a way that exhaustion is avoided.
• Scoliosis and joint contractures. Some patients may only require physical therapy, while others may need orthopedic surgery (e.g., scoliosis surgery, corrective surgery for congenital hip dislocation and foot deformities).
• Respiratory. Patients with more severe symptoms may require respiratory support. Breathing exercises and chest physiotherapy for handling secretions may also be beneficial.
• Feeding difficulties. Individuals may require diet supplementation and feeding by means of nasogastric/orogastric routes or gastrostomy.
• Routine assessment of the spine for scoliosis and joints for contractures
• Routine assessment of respiratory parameters such as respiratory rate, peak expiratory flow rate (PEFR), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1)
• Sleep studies especially when patients show signs of nocturnal hypoxia
• Regular assessment of motor abilities in order to determine need for physical therapy, occupational therapy, and assistive devices for ambulation, such as a wheelchair
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with central core disease (CCD), the following evaluations are recommended:
Neurologic examination with attention to features of congenital myopathy (hypotonia, failure to thrive, joint contractures, scoliosis), weakness of the limbs, and muscle cramps
Physical and occupational therapy assessments
Evaluation for feeding difficulties, including assessment for sucking and ability to swallow
Pulmonary function testing in most patients, especially those with scoliosis, hypotonia, signs of respiratory distress, and/or history of recurrent chest infections. History should be taken for symptoms of nocturnal hypoxia including early morning headaches, daytime drowsiness, loss of appetite, and deteriorating school performance.
Consultation with a clinical geneticist and/or genetic counselor
• Neurologic examination with attention to features of congenital myopathy (hypotonia, failure to thrive, joint contractures, scoliosis), weakness of the limbs, and muscle cramps
• Physical and occupational therapy assessments
• Evaluation for feeding difficulties, including assessment for sucking and ability to swallow
• Pulmonary function testing in most patients, especially those with scoliosis, hypotonia, signs of respiratory distress, and/or history of recurrent chest infections. History should be taken for symptoms of nocturnal hypoxia including early morning headaches, daytime drowsiness, loss of appetite, and deteriorating school performance.
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Since prognosis is mainly influenced by respiratory status and scoliosis, treatment geared toward these manifestations is essential.
Treatment depends on the severity of symptoms, but mainly consists of supportive measures and rehabilitation that address the following problems:
Hypotonia and weakness. Patients may benefit from physical therapy. Interventions may include stretching programs and mild to moderate low-impact exercise; activities should be balanced in such a way that exhaustion is avoided.
Scoliosis and joint contractures. Some patients may only require physical therapy, while others may need orthopedic surgery (e.g., scoliosis surgery, corrective surgery for congenital hip dislocation and foot deformities).
Respiratory. Patients with more severe symptoms may require respiratory support. Breathing exercises and chest physiotherapy for handling secretions may also be beneficial.
Feeding difficulties. Individuals may require diet supplementation and feeding by means of nasogastric/orogastric routes or gastrostomy.
• Hypotonia and weakness. Patients may benefit from physical therapy. Interventions may include stretching programs and mild to moderate low-impact exercise; activities should be balanced in such a way that exhaustion is avoided.
• Scoliosis and joint contractures. Some patients may only require physical therapy, while others may need orthopedic surgery (e.g., scoliosis surgery, corrective surgery for congenital hip dislocation and foot deformities).
• Respiratory. Patients with more severe symptoms may require respiratory support. Breathing exercises and chest physiotherapy for handling secretions may also be beneficial.
• Feeding difficulties. Individuals may require diet supplementation and feeding by means of nasogastric/orogastric routes or gastrostomy.
## Prevention of Secondary Complications
Secondary complications can include respiratory compromise from scoliosis; hence, orthopedic intervention may reduce the risk of this problem.
Immunization against influenza is encouraged.
Prompt treatment of respiratory infection is important.
Joint contractures may be prevented by encouraging mobility and by active participation in physical therapy.
## Surveillance
The following are appropriate:
Routine assessment of the spine for scoliosis and joints for contractures
Routine assessment of respiratory parameters such as respiratory rate, peak expiratory flow rate (PEFR), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1)
Sleep studies especially when patients show signs of nocturnal hypoxia
Regular assessment of motor abilities in order to determine need for physical therapy, occupational therapy, and assistive devices for ambulation, such as a wheelchair
• Routine assessment of the spine for scoliosis and joints for contractures
• Routine assessment of respiratory parameters such as respiratory rate, peak expiratory flow rate (PEFR), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1)
• Sleep studies especially when patients show signs of nocturnal hypoxia
• Regular assessment of motor abilities in order to determine need for physical therapy, occupational therapy, and assistive devices for ambulation, such as a wheelchair
## Agents/Circumstances to Avoid
Although it is unknown how CCD is associated with malignant hyperthermia susceptibility or which pathogenic variants in
Individuals suspected of having MH susceptibility are advised to avoid extremes of heat, but this does not mean restriction of athletic activity.
## Evaluation of Relatives at Risk
Because CCD is associated with an increased risk for MH susceptibility, it is appropriate to test at-risk relatives of a proband (whether symptomatic or not) for the
See
## Pregnancy Management
Because all patients with CCD are considered to be at risk for
## Therapies Under Investigation
Search
## Genetic Counseling
Central core disease (CCD) is usually inherited in an autosomal dominant manner, but may be inherited in an autosomal recessive manner [
Most individuals diagnosed with autosomal dominant CCD have an affected parent or an asymptomatic parent who has an
A proband with autosomal dominant CCD may have the disorder as the result of a
If the pathogenic variant found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a
Recommendations for the evaluation of parents of a proband with an apparent
The family history of some individuals diagnosed with CCD may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations / molecular genetic testing have been performed on the parents of the proband.
Note: If the parent is the individual in whom the pathogenic variant first occurred s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.
If a parent of the proband is affected, the risk to the sibs of inheriting the
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for CCD because of the possibility of reduced penetrance in a parent.
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are often asymptomatic. Although it is unknown which pathogenic variants in
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are generally asymptomatic. Although it is unknown which pathogenic variants in
Carrier testing for family members at risk of being heterozygous for autosomal recessive CCD requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
• Most individuals diagnosed with autosomal dominant CCD have an affected parent or an asymptomatic parent who has an
• A proband with autosomal dominant CCD may have the disorder as the result of a
• If the pathogenic variant found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a
• Recommendations for the evaluation of parents of a proband with an apparent
• The family history of some individuals diagnosed with CCD may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations / molecular genetic testing have been performed on the parents of the proband.
• If a parent of the proband is affected, the risk to the sibs of inheriting the
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for CCD because of the possibility of reduced penetrance in a parent.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are often asymptomatic. Although it is unknown which pathogenic variants in
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are generally asymptomatic. Although it is unknown which pathogenic variants in
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Central core disease (CCD) is usually inherited in an autosomal dominant manner, but may be inherited in an autosomal recessive manner [
## Autosomal Dominant Inheritance – Risk to Family Members
Most individuals diagnosed with autosomal dominant CCD have an affected parent or an asymptomatic parent who has an
A proband with autosomal dominant CCD may have the disorder as the result of a
If the pathogenic variant found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a
Recommendations for the evaluation of parents of a proband with an apparent
The family history of some individuals diagnosed with CCD may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations / molecular genetic testing have been performed on the parents of the proband.
Note: If the parent is the individual in whom the pathogenic variant first occurred s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.
If a parent of the proband is affected, the risk to the sibs of inheriting the
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for CCD because of the possibility of reduced penetrance in a parent.
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.
• Most individuals diagnosed with autosomal dominant CCD have an affected parent or an asymptomatic parent who has an
• A proband with autosomal dominant CCD may have the disorder as the result of a
• If the pathogenic variant found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a
• Recommendations for the evaluation of parents of a proband with an apparent
• The family history of some individuals diagnosed with CCD may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations / molecular genetic testing have been performed on the parents of the proband.
• If a parent of the proband is affected, the risk to the sibs of inheriting the
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for CCD because of the possibility of reduced penetrance in a parent.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.
## Autosomal Recessive Inheritance
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are often asymptomatic. Although it is unknown which pathogenic variants in
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are generally asymptomatic. Although it is unknown which pathogenic variants in
Carrier testing for family members at risk of being heterozygous for autosomal recessive CCD requires prior identification of the
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are often asymptomatic. Although it is unknown which pathogenic variants in
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are generally asymptomatic. Although it is unknown which pathogenic variants in
## Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are often asymptomatic. Although it is unknown which pathogenic variants in
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are generally asymptomatic. Although it is unknown which pathogenic variants in
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are often asymptomatic. Although it is unknown which pathogenic variants in
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are generally asymptomatic. Although it is unknown which pathogenic variants in
## Carrier (Heterozygote) Detection
Carrier testing for family members at risk of being heterozygous for autosomal recessive CCD requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
## Resources
P.O. Box 13312
Pittsburgh PA 15243
11 East State Street
PO Box 1069
Sherburne NY 13460
222 South Riverside Plaza
Suite 1500
Chicago IL 60606
61A Great Suffolk Street
London SE1 0BU
United Kingdom
•
• P.O. Box 13312
• Pittsburgh PA 15243
•
•
• 11 East State Street
• PO Box 1069
• Sherburne NY 13460
•
•
• 222 South Riverside Plaza
• Suite 1500
• Chicago IL 60606
•
•
• 61A Great Suffolk Street
• London SE1 0BU
• United Kingdom
•
## Molecular Genetics
Central Core Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Central Core Disease (
The skeletal muscle isoform of ryanodine receptor 1 (RyR1) mediates Ca
Certain
Selected
Variants listed in the table have been provided by the author.
The
Although most pathogenic variants associated with CCD are clustered in the C-terminal domain 3, which comprises the transmembrane/luminal and pore-forming region of the channel, studies have shown that pathogenic variants in CCD are likewise found in domains 1 and 2, in which pathogenic variants are more commonly associated with malignant hyperthermia (see
The most common pathogenic variants are shown in
Ryanodine receptors belong to the superfamily of intracellular Ca
In vitro studies suggest that a high basal activity of the mutated Ca
The association of C-terminal pathogenic variants with clinically evident muscle weakness may be explained by the leaky-channel model and the excitation-contraction (EC) uncoupling model.
Some non-C-terminal pathogenic variants in ryanodine receptor 1 promote the leak of Ca
C-terminal pathogenic variants, especially those in the pore region of ryanodine receptor 1, may directly affect the channel gating properties, resulting in an abolition of orthograde activation by the voltage-gated L-type Ca
## Molecular Pathogenesis
The skeletal muscle isoform of ryanodine receptor 1 (RyR1) mediates Ca
Certain
Selected
Variants listed in the table have been provided by the author.
The
Although most pathogenic variants associated with CCD are clustered in the C-terminal domain 3, which comprises the transmembrane/luminal and pore-forming region of the channel, studies have shown that pathogenic variants in CCD are likewise found in domains 1 and 2, in which pathogenic variants are more commonly associated with malignant hyperthermia (see
The most common pathogenic variants are shown in
Ryanodine receptors belong to the superfamily of intracellular Ca
In vitro studies suggest that a high basal activity of the mutated Ca
The association of C-terminal pathogenic variants with clinically evident muscle weakness may be explained by the leaky-channel model and the excitation-contraction (EC) uncoupling model.
Some non-C-terminal pathogenic variants in ryanodine receptor 1 promote the leak of Ca
C-terminal pathogenic variants, especially those in the pore region of ryanodine receptor 1, may directly affect the channel gating properties, resulting in an abolition of orthograde activation by the voltage-gated L-type Ca
## References
## Literature Cited
## Chapter Notes
7 November 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
4 December 2014 (me) Comprehensive update posted live
11 May 2010 (me) Comprehensive update posted live
16 May 2007 (me) Review posted live
8 December 2006 (in) Original submission
• 7 November 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
• 4 December 2014 (me) Comprehensive update posted live
• 11 May 2010 (me) Comprehensive update posted live
• 16 May 2007 (me) Review posted live
• 8 December 2006 (in) Original submission
## Revision History
7 November 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
4 December 2014 (me) Comprehensive update posted live
11 May 2010 (me) Comprehensive update posted live
16 May 2007 (me) Review posted live
8 December 2006 (in) Original submission
• 7 November 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
• 4 December 2014 (me) Comprehensive update posted live
• 11 May 2010 (me) Comprehensive update posted live
• 16 May 2007 (me) Review posted live
• 8 December 2006 (in) Original submission
Histologic features of muscle observed in central core disease
A-B. Sections from a child age nine years depicting the classic description of CCD
A. Pronounced type 2 fiber deficiency is seen with myosin ATPase staining with acidic pre-incubation (* shows type 2 fiber).
B. In NADH-TR staining, central cores are seen in almost all fibers, with "rimming" of cores in some fibers (arrow).
C-D. Sections from an individual age 63 years showing the other features of cores seen in CCD. C: Type 2 fiber deficiency is also seen but is not as marked as in A (* shows type 2 fiber). D: Cores are seen, but not in all type 1 fibers. Cores are sometimes found in the subsarcolemmal area or periphery of the fiber, and more than one core can be present in a single fiber (arrow). Cores lacking clearly demarcated borders, (arrowhead) can be seen in higher frequency.
E-F. Sections from a boy age three years with cores and few fibers with rods. E: Nemaline bodies are observed with modified Gomori-trichrome staining (arrows). F: Few cores are seen in NADH-TR staining.
The three shaded mutational hot spot areas:
Exons 1-17 (domain 1)
Exons 39-46 (domain 2)
Exons 90-104 (domain 3)
Closed circles = pathogenic missense variants
Open circles = autosomal recessive pathogenic variants
Triangles = deletions
The most common pathogenic variants are shown in
Adapted from
|
[
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"G Avila, KM O'Connell, RT Dirksen. The pore region of the skeletal muscle ryanodine receptor is a primary locus for excitation-contraction uncoupling in central core disease.. J Gen Physiol 2003;121:277-86",
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"MR Davis, E Haan, H Jungbluth, C Sewry, K North, F Muntoni, T Kuntzer, P Lamont, A Bankier, P Tomlinson, A Sanchez, P Walsh, L Nagarajan, C Oley, A Colley, A Gedeon, R Quinlivan, J Dixon, D James, CR Muller, NG Laing. Principal mutation hot spot for central core disease and related myopathies in the C-terminal transmembrane region of the RYR1 gene.. Neuromuscul Disord 2003;13:151-7",
"RT Dirksen, G Avila. Altered ryanodine receptor function in central core disease: leaky or uncoupled Ca(2+) release channels?. Trends Cardiovasc Med 2002;12:189-97",
"RT Dirksen, G Avila. Distinct effects on Ca2+ handling caused by malignant hyperthermia and central core disease mutations in RyR1.. Biophys J 2004;87:3193-204",
"A Ferreiro, N Monnier, NB Romero, JP Leroy, C Bonnemann, CA Haenggeli, V Straub, WD Voss, Y Nivoche, H Jungbluth, A Lemainque, T Voit, J Lunardi, M Fardeau, P Guicheney. A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene.. Ann Neurol 2002a;51:750-9",
"A Ferreiro, S Quijano-Roy, C Pichereau, B Moghadaszadeh, N Goemans, C Bonnemann, H Jungbluth, V Straub, M Villanova, JP Leroy, NB Romero, JJ Martin, F Muntoni, T Voit, B Estournet, P Richard, M Fardeau, P Guicheney. Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: reassessing the nosology of early-onset myopathies.. Am J Hum Genet 2002b;71:739-49",
"D Fischer, M Herasse, A Ferreiro, HM Barragán-Campos, J Chiras, L Viollet, S Maugenre, JP Leroy, N Monnier, J Lunardi, P Guicheney, M Fardeau, NB Romero. Muscle imaging in dominant core myopathies linked or unlinked to the ryanodine receptor 1 gene.. Neurology 2006;67:2217-20",
"M Herasse, K Parain, I Marty, N Monnier, AM Kaindl, JP Leroy, P Richard, J Lunardi, NB Romero, A Ferreiro. Abnormal distribution of calcium-handling proteins: a novel distinctive marker in core myopathies.. J Neuropathol Exp Neurol 2007;66:57-65",
"M CA Ibarra, S Wu, K Murayama, N Minami, Y Ichihara, H Kikuchi, S Noguchi, YK Hayashi, R Ochiai, I Nishino. Malignant hyperthermia in Japan: mutation screening of the entire ryanodine receptor type 1 gene coding region by direct sequencing.. Anesthesiology 2006;104:1146-54",
"B Ilkovski, ST Cooper, K Nowak, MM Ryan, N Yang, C Schnell, HJ Durling, LG Roddick, I Wilkinson, AJ Kornberg, KJ Collins, G Wallace, P Gunning, EC Hardeman, NG Laing, KN North. Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene.. Am J Hum Genet 2001;68:1333-43",
"H Jungbluth, MR Davis, C Muller, S Counsell, J Allsop, A Chattopadhyay, S Messina, E Mercuri, NG Laing, CA Sewry, G Bydder, F Muntoni. Magnetic resonance imaging of muscle in congenital myopathies associated with RYR1 mutations.. Neuromuscul Disord 2004;14:785-90",
"H Jungbluth, CR Muller, B Halliger-Keller, M Brockington, SC Brown, L Feng, A Chattopadhyay, E Mercuri, AY Manzur, A Ferreiro, NG Laing, MR Davis, HP Roper, V Dubowitz, G Bydder, CA Sewry, F Muntoni. Autosomal recessive inheritance of RYR1 mutations in a congenital myopathy with cores.. Neurology 2002;59:284-7",
"H Jungbluth, H Zhou, CA Sewry, S Robb, S Treves, M Bitoun, P Guicheney, A Buj-Bello, C Bönnenman, F Muntoni. Centronuclear myopathy due to a dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene.. Neuromusc Disord 2007;17:338-45",
"AM Kaindl, F Ruschendorf, S Krause, HH Goebel, K Koehler, C Becker, D Pongratz, J Muller-Hocker, P Nurnberg, G Stoltenburg-Didinger, H Lochmuller, A Huebner. Missense mutations of ACTA1 cause dominant congenital myopathy with cores.. J Med Genet 2004;41:842-8",
"PM Kossugue, JF Paim, MM Navarro, HC Silva, RC Pavanello, J Gurgel-Giannetti, M Zatz, M Vainzof. Central core disease due to recessive mutations in RYR1 gene: Is it more common than described?. Muscle Nerve 2007;35:670-4",
"PJ Lynch, J Tong, M Lehane, A Mallet, L Giblin, JJ Heffron, P Vaughan, G Zafra, DH MacLennan, TV McCarthy. A mutation in the transmembrane/luminal domain of the ryanodine receptor is associated with abnormal Ca2+ release channel function and severe central core disease.. Proc Natl Acad Sci U S A 1999;96:4164-9",
"N Monnier, NB Romero, J Lerale, P Landrieu, Y Nivoche, M Fardeau, J Lunardi. Familial and sporadic forms of central core disease are associated with mutations in the C-terminal domain of the skeletal muscle ryanodine receptor.. Hum Mol Genet 2001;10:2581-92",
"N Monnier, NB Romero, J Lerale, Y Nivoche, D Qi, DH MacLennan, M Fardeau, J Lunardi. An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor.. Hum Mol Genet 2000;9:2599-608",
"TE Nelson. Heat production during anesthetic-induced malignant hyperthermia.. Biosci Rep 2001;21:169-79",
"FL Norwood, C Harling, PF Chinnery, M Eagle, K Bushby, V Straub. Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population.. Brain. 2009;132:3175-86",
"MS Phillips, J Fujii, VK Khanna, S DeLeon, K Yokobata, PJ de Jong, DH MacLennan. The structural organization of the human skeletal muscle ryanodine receptor (RYR1) gene.. Genomics. 1996;34:24-41",
"RM Quinlivan, CR Muller, M Davis, NG Laing, GA Evans, J Dwyer, J Dove, AP Roberts, CA Sewry. Central core disease: clinical, pathological, and genetic features.. Arch Dis Child 2003;88:1051-5",
"NB Romero, N Monnier, L Viollet, A Cortey, M Chevallay, JP Leroy, J Lunardi, M Fardeau. Dominant and recessive central core disease associated with RYR1 mutations and fetal akinesia.. Brain 2003;126:2341-9",
"I Sato, S Wu, MC Ibarra, YK Hayashi, H Fujita, M Tojo, SJ Oh, I Nonaka, S Noguchi, I Nishino. Congenital neuromuscular disease with uniform type 1 fiber and RYR1 mutation.. Neurology 2008;70:114-22",
"TW Sax, RB Rosenbaum. Neuromuscular disorders in pregnancy.. Muscle Nerve. 2006;34:559-71",
"CA Sewry, C Muller, M Davis, JS Dwyer, J Dove, G Evans, R Schroder, D Furst, T Helliwell, N Laing, RC Quinlivan. The spectrum of pathology in central core disease.. Neuromuscul Disord 2002;12:930-8",
"S Shepherd, F Ellis, J Halsall, P Hopkins, R Robinson. RYR1 mutations in UK central core disease patients: more than just the C-terminal transmembrane region of the RYR1 gene.. J Med Genet 2004;41",
"N Tilgen, F Zorzato, B Halliger-Keller, F Muntoni, C Sewry, LM Palmucci, C Schneider, E Hauser, F Lehmann-Horn, CR Muller, S Treves. Identification of four novel mutations in the C-terminal membrane spanning domain of the ryanodine receptor 1: association with central core disease and alteration of calcium homeostasis.. Hum Mol Genet 2001;10:2879-87",
"S Treves, AA Anderson, S Ducreux, A Divet, C Bleunven, C Grasso, S Paesante, F Zorzato. Ryanodine receptor 1 mutations, dysregulation of calcium homeostasis and neuromuscular disorders.. Neuromuscul Disord 2005;15:577-87",
"AV Vega, R Ramos-Mondragón, A Calderón-Rivera, A Zarain-Herzberg, G Avila. Calcitonin gene-related peptide restores disrupted excitation-contraction coupling in myotubes expressing central core disease mutations in RyR1.. J Physiol. 2011;589:4649-69",
"M Wehner, H Rueffert, F Koenig, D Olthoff. Calcium release from sarcoplasmic reticulum is facilitated in human myotubes derived from carriers of the ryanodine receptor type 1 mutations Ile2182Phe and Gly2375Ala.. Genet Test 2003;7:203-11",
"S Wu, MC Ibarra, MC Malicdan, K Murayama, Y Ichihara, H Kikuchi, I Nonaka, S Noguchi, YK Hayashi, I Nishino. Central core disease is due to RYR1 mutations in more than 90% of patients.. Brain 2006;129:1470-80",
"H Zhou, M Brockington, H Jungbluth, D Monk, P Stanier, CA Sewry, GE Moore, F Muntoni. Epigenetic allele silencing unveils recessive RYR1 mutations in core myopathies.. Am J Hum Genet 2006a;79:859-68",
"H Zhou, N Yamaguchi, L Xu, Y Wang, C Sewry, H Jungbluth, F Zorzato, E Bertini, F Muntoni, G Meissner, S Treves. Characterization of recessive RYR1 mutations in core myopathies.. Hum Mol Genet 2006b;15:2791-803",
"F Zorzato, N Yamaguchi, L Xu, G Meissner, CR Muller, P Pouliquin, F Muntoni, C Sewry, T Girard, S Treves. Clinical and functional effects of a deletion in a COOH-terminal lumenal loop of the skeletal muscle ryanodine receptor.. Hum Mol Genet 2003;12:379-88"
] |
16/5/2007
|
4/12/2014
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
cd-chst3
|
cd-chst3
|
[
"CHST3 Deficiency",
"CHST3-Related Skeletal Dysplasia",
"Recessive Larsen Syndrome",
"Recessive Larsen Syndrome",
"CHST3 Deficiency",
"CHST3-Related Skeletal Dysplasia",
"Carbohydrate sulfotransferase 3",
"CHST3",
"Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related"
] |
Chondrodysplasia with Congenital Joint Dislocations,
|
Andrea Superti-Furga, Sheila Unger
|
Summary Chondrodysplasia with congenital joint dislocations, The diagnosis of CDCJD- CDCJD-
|
## Diagnosis
Chondrodysplasia with congenital joint dislocations,
Joint dislocations at birth (knees, hips, radial heads) with short stature (See
Clubfeet
Limitation of range of motion that can involve all large joints
Development of kyphosis and occasionally scoliosis with slight shortening of the trunk in childhood
Progressive spondyloepiphyseal dysplasia with joint anomalies
Generalized mild epiphyseal dysplasia (small epiphyses)
Delayed ossification of the capital femoral epiphyses and femoral necks
Coxa valga (increase in the angle formed between the head and neck of the femur and the shaft of the femur)
Spinal abnormalities
Conspicuous increase in interpediculate distance from T12 to L1 or L2 (See
Notching of the vertebral bodies, similar in appearance to coronal clefts (See
Normal thumbs (not spatulate)
Normal or (more rarely) slightly advanced bone age (especially carpal)
The diagnosis of CDCJD-
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Chondrodysplasia with Congenital Joint Dislocations,
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Cultured fibroblasts can be used to determine proteoglycan sulfation (i.e., sulfotransferase activity). The fibroblasts are incubated with radioactive sulfate [
• Joint dislocations at birth (knees, hips, radial heads) with short stature (See
• Clubfeet
• Limitation of range of motion that can involve all large joints
• Development of kyphosis and occasionally scoliosis with slight shortening of the trunk in childhood
• Progressive spondyloepiphyseal dysplasia with joint anomalies
• Generalized mild epiphyseal dysplasia (small epiphyses)
• Delayed ossification of the capital femoral epiphyses and femoral necks
• Coxa valga (increase in the angle formed between the head and neck of the femur and the shaft of the femur)
• Generalized mild epiphyseal dysplasia (small epiphyses)
• Delayed ossification of the capital femoral epiphyses and femoral necks
• Coxa valga (increase in the angle formed between the head and neck of the femur and the shaft of the femur)
• Spinal abnormalities
• Conspicuous increase in interpediculate distance from T12 to L1 or L2 (See
• Notching of the vertebral bodies, similar in appearance to coronal clefts (See
• Conspicuous increase in interpediculate distance from T12 to L1 or L2 (See
• Notching of the vertebral bodies, similar in appearance to coronal clefts (See
• Normal thumbs (not spatulate)
• Normal or (more rarely) slightly advanced bone age (especially carpal)
• Generalized mild epiphyseal dysplasia (small epiphyses)
• Delayed ossification of the capital femoral epiphyses and femoral necks
• Coxa valga (increase in the angle formed between the head and neck of the femur and the shaft of the femur)
• Conspicuous increase in interpediculate distance from T12 to L1 or L2 (See
• Notching of the vertebral bodies, similar in appearance to coronal clefts (See
## Suggestive Findings
Chondrodysplasia with congenital joint dislocations,
Joint dislocations at birth (knees, hips, radial heads) with short stature (See
Clubfeet
Limitation of range of motion that can involve all large joints
Development of kyphosis and occasionally scoliosis with slight shortening of the trunk in childhood
Progressive spondyloepiphyseal dysplasia with joint anomalies
Generalized mild epiphyseal dysplasia (small epiphyses)
Delayed ossification of the capital femoral epiphyses and femoral necks
Coxa valga (increase in the angle formed between the head and neck of the femur and the shaft of the femur)
Spinal abnormalities
Conspicuous increase in interpediculate distance from T12 to L1 or L2 (See
Notching of the vertebral bodies, similar in appearance to coronal clefts (See
Normal thumbs (not spatulate)
Normal or (more rarely) slightly advanced bone age (especially carpal)
• Joint dislocations at birth (knees, hips, radial heads) with short stature (See
• Clubfeet
• Limitation of range of motion that can involve all large joints
• Development of kyphosis and occasionally scoliosis with slight shortening of the trunk in childhood
• Progressive spondyloepiphyseal dysplasia with joint anomalies
• Generalized mild epiphyseal dysplasia (small epiphyses)
• Delayed ossification of the capital femoral epiphyses and femoral necks
• Coxa valga (increase in the angle formed between the head and neck of the femur and the shaft of the femur)
• Generalized mild epiphyseal dysplasia (small epiphyses)
• Delayed ossification of the capital femoral epiphyses and femoral necks
• Coxa valga (increase in the angle formed between the head and neck of the femur and the shaft of the femur)
• Spinal abnormalities
• Conspicuous increase in interpediculate distance from T12 to L1 or L2 (See
• Notching of the vertebral bodies, similar in appearance to coronal clefts (See
• Conspicuous increase in interpediculate distance from T12 to L1 or L2 (See
• Notching of the vertebral bodies, similar in appearance to coronal clefts (See
• Normal thumbs (not spatulate)
• Normal or (more rarely) slightly advanced bone age (especially carpal)
• Generalized mild epiphyseal dysplasia (small epiphyses)
• Delayed ossification of the capital femoral epiphyses and femoral necks
• Coxa valga (increase in the angle formed between the head and neck of the femur and the shaft of the femur)
• Conspicuous increase in interpediculate distance from T12 to L1 or L2 (See
• Notching of the vertebral bodies, similar in appearance to coronal clefts (See
## Establishing the Diagnosis
The diagnosis of CDCJD-
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Chondrodysplasia with Congenital Joint Dislocations,
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Cultured fibroblasts can be used to determine proteoglycan sulfation (i.e., sulfotransferase activity). The fibroblasts are incubated with radioactive sulfate [
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Chondrodysplasia with Congenital Joint Dislocations,
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
## Biochemical Testing
Cultured fibroblasts can be used to determine proteoglycan sulfation (i.e., sulfotransferase activity). The fibroblasts are incubated with radioactive sulfate [
## Clinical Characteristics
Most children with chondrodysplasia with congenital joint dislocations,
Occasionally, short stature and knee dislocations are seen on prenatal ultrasound examination [
At birth, affected infants are noted to have short stature (birth length: 39-44 cm) and joint dislocations; the large majority have bilateral knee luxation or subluxation. The radial heads and hips are the next most commonly affected joints. Clubfeet are also frequently seen. Despite the congenital joint dislocations, the overall phenotype is one of restricted movement, and many children undergo multiple corrective procedures with only limited success [
In a large family reported from Oman, the adult heights ranged from 110 cm to 130 cm [
Many adults develop arthritic-type changes. They also develop spinal kyphosis, frequently in the cervical spine, and (rarely) scoliosis.
No genotype-phenotype correlations have been observed. The phenotype reported thus far has been strikingly homogeneous regardless of type of
In 1950, Dr LJ Larsen described autosomal dominant Larsen syndrome, now known to be caused by pathogenic variants in
Humerospinal dysostosis was described by
The name "chondrodysplasia with congenital joint dislocations,
No firm data regarding the prevalence of CDCJD-
• Humerospinal dysostosis was described by
## Clinical Description
Most children with chondrodysplasia with congenital joint dislocations,
Occasionally, short stature and knee dislocations are seen on prenatal ultrasound examination [
At birth, affected infants are noted to have short stature (birth length: 39-44 cm) and joint dislocations; the large majority have bilateral knee luxation or subluxation. The radial heads and hips are the next most commonly affected joints. Clubfeet are also frequently seen. Despite the congenital joint dislocations, the overall phenotype is one of restricted movement, and many children undergo multiple corrective procedures with only limited success [
In a large family reported from Oman, the adult heights ranged from 110 cm to 130 cm [
Many adults develop arthritic-type changes. They also develop spinal kyphosis, frequently in the cervical spine, and (rarely) scoliosis.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been observed. The phenotype reported thus far has been strikingly homogeneous regardless of type of
## Nomenclature
In 1950, Dr LJ Larsen described autosomal dominant Larsen syndrome, now known to be caused by pathogenic variants in
Humerospinal dysostosis was described by
The name "chondrodysplasia with congenital joint dislocations,
• Humerospinal dysostosis was described by
## Prevalence
No firm data regarding the prevalence of CDCJD-
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
A summary of key differentiating clinical and radiographic features for chondrodysplasias with multiple dislocations is available in
Genes of Interest in the Differential Diagnosis of Chondrodysplasia with Congenital Joint Dislocations,
Prenatal-onset short stature
Joint dislocations
Advanced bone age
Lacks characteristic CDCJD-
Osteoporosis & fractures in some
Distinctive facial features w/protuberant eyes
Prenatal-onset short stature
Joint dislocations
Multiple coronal clefts on lateral spine radiograph
Distinctive facial features (marked midface hypoplasia, prominent eyes)
Advanced bone age
Prenatal-onset short stature
Joint laxity
Multiple joint dislocations
Scoliosis & kyphosis
Normal birth length
Very delayed proximal carpal ossification
Normal birth length
Distinctive facial features w/↑ incidence of cleft palate
Advanced bone age
Prenatal-onset short stature
Multiple dislocations
Amelogenesis
Advanced carpal ossification
Short limbs
Clubfeet
Joint stiffness / limited mobility
Hitchhiker thumb
Lacks characteristic CDCJD-
Prenatal-onset short stature
Joint dislocations
Multiple coronal clefts on lateral spine radiograph
Distinctive facial features (marked midface hypoplasia, prominent eyes)
Advanced bone age
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; SEMD = spondyloepimetaphyseal dysplasia
Disorder terminology is based on the 2023 revision of the Nosology of Genetic Skeletal Disorders [
The La Réunion variant of recessive Larsen syndrome is caused by a specific
• Prenatal-onset short stature
• Joint dislocations
• Advanced bone age
• Lacks characteristic CDCJD-
• Osteoporosis & fractures in some
• Distinctive facial features w/protuberant eyes
• Prenatal-onset short stature
• Joint dislocations
• Multiple coronal clefts on lateral spine radiograph
• Distinctive facial features (marked midface hypoplasia, prominent eyes)
• Advanced bone age
• Prenatal-onset short stature
• Joint laxity
• Multiple joint dislocations
• Scoliosis & kyphosis
• Normal birth length
• Very delayed proximal carpal ossification
• Normal birth length
• Distinctive facial features w/↑ incidence of cleft palate
• Advanced bone age
• Prenatal-onset short stature
• Multiple dislocations
• Amelogenesis
• Advanced carpal ossification
• Short limbs
• Clubfeet
• Joint stiffness / limited mobility
• Hitchhiker thumb
• Lacks characteristic CDCJD-
• Prenatal-onset short stature
• Joint dislocations
• Multiple coronal clefts on lateral spine radiograph
• Distinctive facial features (marked midface hypoplasia, prominent eyes)
• Advanced bone age
## Management
No clinical practice guidelines for chondrodysplasia with congenital joint dislocations,
To establish the extent of disease in an individual diagnosed with CDCJD-
Chondrodysplasia with Congenital Joint Dislocations,
Orthopedic referral
Referral to specialized skeletal dysplasia clinic if available
Radiographs per orthopedist
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Chondrodysplasia with Congenital Joint Dislocations,
Surgical correction is often only partially successful for joint dislocations & most persons have had multiple procedures by adulthood [
Physical therapy has not been demonstrated to be effective in this disorder.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Chondrodysplasia with Congenital Joint Dislocations,
Clinical joint & spine eval w/orthopedist w/experience in skeletal dysplasia
Radiographs as recommended by orthopedist
Activities with a high impact on joints (e.g., jogging) should be avoided.
Obesity, which places an excessive load on the large weight-bearing joints, should be avoided.
See
Search
• Orthopedic referral
• Referral to specialized skeletal dysplasia clinic if available
• Radiographs per orthopedist
• Surgical correction is often only partially successful for joint dislocations & most persons have had multiple procedures by adulthood [
• Physical therapy has not been demonstrated to be effective in this disorder.
• Clinical joint & spine eval w/orthopedist w/experience in skeletal dysplasia
• Radiographs as recommended by orthopedist
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with CDCJD-
Chondrodysplasia with Congenital Joint Dislocations,
Orthopedic referral
Referral to specialized skeletal dysplasia clinic if available
Radiographs per orthopedist
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Orthopedic referral
• Referral to specialized skeletal dysplasia clinic if available
• Radiographs per orthopedist
## Treatment of Manifestations
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Chondrodysplasia with Congenital Joint Dislocations,
Surgical correction is often only partially successful for joint dislocations & most persons have had multiple procedures by adulthood [
Physical therapy has not been demonstrated to be effective in this disorder.
• Surgical correction is often only partially successful for joint dislocations & most persons have had multiple procedures by adulthood [
• Physical therapy has not been demonstrated to be effective in this disorder.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Chondrodysplasia with Congenital Joint Dislocations,
Clinical joint & spine eval w/orthopedist w/experience in skeletal dysplasia
Radiographs as recommended by orthopedist
• Clinical joint & spine eval w/orthopedist w/experience in skeletal dysplasia
• Radiographs as recommended by orthopedist
## Agents/Circumstances to Avoid
Activities with a high impact on joints (e.g., jogging) should be avoided.
Obesity, which places an excessive load on the large weight-bearing joints, should be avoided.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Chondrodysplasia with congenital joint dislocations,
The parents of an affected child are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic. There is no evidence that they are at increased risk for degenerative joint disease.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing CDCJD-
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with CDCJD-
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic. There is no evidence that they are at increased risk for degenerative joint disease.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing CDCJD-
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with CDCJD-
## Mode of Inheritance
Chondrodysplasia with congenital joint dislocations,
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic. There is no evidence that they are at increased risk for degenerative joint disease.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing CDCJD-
• The parents of an affected child are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic. There is no evidence that they are at increased risk for degenerative joint disease.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing CDCJD-
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with CDCJD-
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with CDCJD-
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related (
Sulfation studies as well as the nature of the known pathogenic variants and the mode of inheritance suggest that the pathogenesis of the disorder results from decreased/absent catalytic activity of the enzyme. No hot spots have been identified, but the majority of known pathogenic variants are clustered in the sulfotransferase domain.
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Sulfation studies as well as the nature of the known pathogenic variants and the mode of inheritance suggest that the pathogenesis of the disorder results from decreased/absent catalytic activity of the enzyme. No hot spots have been identified, but the majority of known pathogenic variants are clustered in the sulfotransferase domain.
Variants listed in the table have been provided by the authors.
## Chapter Notes
1 August 2024 (sw) Comprehensive update posted live
31 January 2019 (sw) Comprehensive update posted live
1 September 2011 (me) Review posted live
28 March 2011 (asf) Original submission
• 1 August 2024 (sw) Comprehensive update posted live
• 31 January 2019 (sw) Comprehensive update posted live
• 1 September 2011 (me) Review posted live
• 28 March 2011 (asf) Original submission
## Revision History
1 August 2024 (sw) Comprehensive update posted live
31 January 2019 (sw) Comprehensive update posted live
1 September 2011 (me) Review posted live
28 March 2011 (asf) Original submission
• 1 August 2024 (sw) Comprehensive update posted live
• 31 January 2019 (sw) Comprehensive update posted live
• 1 September 2011 (me) Review posted live
• 28 March 2011 (asf) Original submission
## References
## Literature Cited
A newborn with chondrodysplasia with congenital joint dislocations,
An individual with chondrodysplasia with congenital joint dislocations,
An individual with chondrodysplasia with congenital joint dislocations,
|
[] |
1/9/2011
|
1/8/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
cda1
|
cda1
|
[
"CDAN1-interacting nuclease 1",
"Codanin-1",
"CDAN1",
"CDIN1",
"Congenital Dyserythropoietic Anemia Type I"
] |
Congenital Dyserythropoietic Anemia Type I
|
Hannah Tamary, Orly Dgany
|
Summary Congenital dyserythropoietic anemia type I (CDA I) is characterized by moderate-to-severe macrocytic anemia presenting occasionally in utero as severe anemia associated with hydrops fetalis but more commonly in neonates as hepatomegaly, early jaundice, and intrauterine growth restriction. Some individuals present in childhood or adulthood. After the neonatal period, most affected individuals have lifelong moderate anemia, usually accompanied by jaundice and splenomegaly. Secondary hemochromatosis develops with age as a result of increased iron absorption even in those who are not transfused. Distal limb anomalies occur in 4%-14% of affected individuals. The diagnosis of CDA I is suspected based on hematologic findings and established with identification of biallelic pathogenic variants in CDA I is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CDA I-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.
|
## Diagnosis
Congenital dyserythropoietic anemia type I (CDA I)
Moderate-to-severe macrocytic anemia with mean corpuscular volume (MCV) >90 fL in the presence of normal folic acid and serum vitamin B
Inappropriately low number of reticulocytes for the degree of anemia compared to other hemolytic anemias (secondary to ineffective erythropoiesis)
On peripheral blood smear: macrocytosis, elliptocytes, basophilic stippling, and occasional mature nucleated erythrocytes
In bone marrow aspirate:
On light microscopy, erythroid hyperplasia, few double-nucleated erythroblasts, and interchromatin bridges between erythroblasts (in 0.6%-2.8% of erythroblasts)
On electron microscopy, erythroid precursors with spongy appearance of heterochromatin (in ≤60% of erythroblasts) and invaginations of the nuclear membrane
Jaundice
Splenomegaly resulting from marrow expansion secondary to ineffective erythropoiesis
Distal limb anomalies including hypoplastic nails and syndactyly
The diagnosis of CDA I
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Congenital Dyserythropoietic Anemia Type I (CDA I)
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
In 60% of affected individuals two pathogenic variants were identified by sequence analysis, in 28% only one pathogenic variant was identified, and in 11% no pathogenic variant was identified (Note: Testing to detect splice site variants and large deletions was not performed) [Authors and other labs, combined data, unpublished].
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Author, personal observation
The existence of at least one additional locus is suggested by the absence of pathogenic variants in
• Moderate-to-severe macrocytic anemia with mean corpuscular volume (MCV) >90 fL in the presence of normal folic acid and serum vitamin B
• Inappropriately low number of reticulocytes for the degree of anemia compared to other hemolytic anemias (secondary to ineffective erythropoiesis)
• On peripheral blood smear: macrocytosis, elliptocytes, basophilic stippling, and occasional mature nucleated erythrocytes
• In bone marrow aspirate:
• On light microscopy, erythroid hyperplasia, few double-nucleated erythroblasts, and interchromatin bridges between erythroblasts (in 0.6%-2.8% of erythroblasts)
• On electron microscopy, erythroid precursors with spongy appearance of heterochromatin (in ≤60% of erythroblasts) and invaginations of the nuclear membrane
• On light microscopy, erythroid hyperplasia, few double-nucleated erythroblasts, and interchromatin bridges between erythroblasts (in 0.6%-2.8% of erythroblasts)
• On electron microscopy, erythroid precursors with spongy appearance of heterochromatin (in ≤60% of erythroblasts) and invaginations of the nuclear membrane
• On light microscopy, erythroid hyperplasia, few double-nucleated erythroblasts, and interchromatin bridges between erythroblasts (in 0.6%-2.8% of erythroblasts)
• On electron microscopy, erythroid precursors with spongy appearance of heterochromatin (in ≤60% of erythroblasts) and invaginations of the nuclear membrane
• Jaundice
• Splenomegaly resulting from marrow expansion secondary to ineffective erythropoiesis
• Distal limb anomalies including hypoplastic nails and syndactyly
## Suggestive Findings
Congenital dyserythropoietic anemia type I (CDA I)
Moderate-to-severe macrocytic anemia with mean corpuscular volume (MCV) >90 fL in the presence of normal folic acid and serum vitamin B
Inappropriately low number of reticulocytes for the degree of anemia compared to other hemolytic anemias (secondary to ineffective erythropoiesis)
On peripheral blood smear: macrocytosis, elliptocytes, basophilic stippling, and occasional mature nucleated erythrocytes
In bone marrow aspirate:
On light microscopy, erythroid hyperplasia, few double-nucleated erythroblasts, and interchromatin bridges between erythroblasts (in 0.6%-2.8% of erythroblasts)
On electron microscopy, erythroid precursors with spongy appearance of heterochromatin (in ≤60% of erythroblasts) and invaginations of the nuclear membrane
Jaundice
Splenomegaly resulting from marrow expansion secondary to ineffective erythropoiesis
Distal limb anomalies including hypoplastic nails and syndactyly
• Moderate-to-severe macrocytic anemia with mean corpuscular volume (MCV) >90 fL in the presence of normal folic acid and serum vitamin B
• Inappropriately low number of reticulocytes for the degree of anemia compared to other hemolytic anemias (secondary to ineffective erythropoiesis)
• On peripheral blood smear: macrocytosis, elliptocytes, basophilic stippling, and occasional mature nucleated erythrocytes
• In bone marrow aspirate:
• On light microscopy, erythroid hyperplasia, few double-nucleated erythroblasts, and interchromatin bridges between erythroblasts (in 0.6%-2.8% of erythroblasts)
• On electron microscopy, erythroid precursors with spongy appearance of heterochromatin (in ≤60% of erythroblasts) and invaginations of the nuclear membrane
• On light microscopy, erythroid hyperplasia, few double-nucleated erythroblasts, and interchromatin bridges between erythroblasts (in 0.6%-2.8% of erythroblasts)
• On electron microscopy, erythroid precursors with spongy appearance of heterochromatin (in ≤60% of erythroblasts) and invaginations of the nuclear membrane
• On light microscopy, erythroid hyperplasia, few double-nucleated erythroblasts, and interchromatin bridges between erythroblasts (in 0.6%-2.8% of erythroblasts)
• On electron microscopy, erythroid precursors with spongy appearance of heterochromatin (in ≤60% of erythroblasts) and invaginations of the nuclear membrane
• Jaundice
• Splenomegaly resulting from marrow expansion secondary to ineffective erythropoiesis
• Distal limb anomalies including hypoplastic nails and syndactyly
## Establishing the Diagnosis
The diagnosis of CDA I
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Congenital Dyserythropoietic Anemia Type I (CDA I)
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
In 60% of affected individuals two pathogenic variants were identified by sequence analysis, in 28% only one pathogenic variant was identified, and in 11% no pathogenic variant was identified (Note: Testing to detect splice site variants and large deletions was not performed) [Authors and other labs, combined data, unpublished].
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Author, personal observation
The existence of at least one additional locus is suggested by the absence of pathogenic variants in
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Congenital Dyserythropoietic Anemia Type I (CDA I)
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
In 60% of affected individuals two pathogenic variants were identified by sequence analysis, in 28% only one pathogenic variant was identified, and in 11% no pathogenic variant was identified (Note: Testing to detect splice site variants and large deletions was not performed) [Authors and other labs, combined data, unpublished].
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Author, personal observation
The existence of at least one additional locus is suggested by the absence of pathogenic variants in
## Clinical Characteristics
Osteoporosis was found in the majority of individuals [
The phenotype does not differ based on associated gene.
No phenotype-genotype correlations are known. Marked clinical variability is observed even among individuals with the same pathogenic variants.
About 100 simplex cases (i.e., single occurrences in a family) – mainly from Europe – and about 70 consanguineous Israeli Bedouin families have been described in the literature. Six
• Osteoporosis was found in the majority of individuals [
## Clinical Description
Osteoporosis was found in the majority of individuals [
• Osteoporosis was found in the majority of individuals [
## Phenotype Correlations by Gene
The phenotype does not differ based on associated gene.
## Genotype-Phenotype Correlations
No phenotype-genotype correlations are known. Marked clinical variability is observed even among individuals with the same pathogenic variants.
## Nomenclature
## Prevalence
About 100 simplex cases (i.e., single occurrences in a family) – mainly from Europe – and about 70 consanguineous Israeli Bedouin families have been described in the literature. Six
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Congenital anemias in the differential diagnosis of congenital dyserythropoietic anemia type I (CDA I) are summarized in
Congenital Anemias of Interest in the Differential Diagnosis of Congenital Dyserythropoietic Anemia Type I
AD = autosomal dominant; AR = autosomal recessive; BM = bone marrow; CDA = congenital dyserythropoietic anemia; DiffDx = differential diagnosis; EM = electron microscopy; HbF = fetal hemoglobin; MCV = mean corpuscular volume; MOI = mode of inheritance; RBC = red blood cell
CDA II is also known as HEMPAS (
## Management
No clinical practice guidelines for congenital dyserythropoietic anemia type I (CDA I), have been published.
To establish the extent of disease and needs in an individual diagnosed with CDA I, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Congenital Dyserythropoietic Anemia Type I
Hemoglobin concentration
Serum bilirubin concentration
CDA = congenital dyserythropoietic anemia; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with Congenital Dyserythropoietic Anemia Type I
Intramuscular or subcutaneous injections of IFN-
Treatment should be given by a physician experienced in IFN administration.
Splenectomy is of unproven value & has not been studied systematically; it failed to ↑ hemoglobin levels & also may → thromboembolic complications.
Expert opinion by European Haematology Assoc suggested reserving splenectomy for painful splenomegaly, symptomatic thrombocytopenia, or leukopenia [
IFN = interferon
Recommended Surveillance for Individuals with Congenital Dyserythropoietic Anemia Type I
Avoid any preparation containing iron.
Evaluation of the younger sibs of a proband for early manifestations of CDA I is recommended so that monitoring of hemoglobin and ferritin levels and treatment can begin as soon as necessary in those who are affected.
Evaluation of at-risk family members should include CBC to identify macrocytic anemia as well as typical findings on blood smear including macrocytosis, elliptocytes, and basophilic stippling.
The diagnosis can be confirmed by molecular genetic testing if the pathogenic variants in the family have been identified.
See
Anemia places pregnancies of affected women at high risk for delivery-related and outcome complications [
Search
• Hemoglobin concentration
• Serum bilirubin concentration
• Intramuscular or subcutaneous injections of IFN-
• Treatment should be given by a physician experienced in IFN administration.
• Splenectomy is of unproven value & has not been studied systematically; it failed to ↑ hemoglobin levels & also may → thromboembolic complications.
• Expert opinion by European Haematology Assoc suggested reserving splenectomy for painful splenomegaly, symptomatic thrombocytopenia, or leukopenia [
• Evaluation of at-risk family members should include CBC to identify macrocytic anemia as well as typical findings on blood smear including macrocytosis, elliptocytes, and basophilic stippling.
• The diagnosis can be confirmed by molecular genetic testing if the pathogenic variants in the family have been identified.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CDA I, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Congenital Dyserythropoietic Anemia Type I
Hemoglobin concentration
Serum bilirubin concentration
CDA = congenital dyserythropoietic anemia; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Hemoglobin concentration
• Serum bilirubin concentration
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Congenital Dyserythropoietic Anemia Type I
Intramuscular or subcutaneous injections of IFN-
Treatment should be given by a physician experienced in IFN administration.
Splenectomy is of unproven value & has not been studied systematically; it failed to ↑ hemoglobin levels & also may → thromboembolic complications.
Expert opinion by European Haematology Assoc suggested reserving splenectomy for painful splenomegaly, symptomatic thrombocytopenia, or leukopenia [
IFN = interferon
• Intramuscular or subcutaneous injections of IFN-
• Treatment should be given by a physician experienced in IFN administration.
• Splenectomy is of unproven value & has not been studied systematically; it failed to ↑ hemoglobin levels & also may → thromboembolic complications.
• Expert opinion by European Haematology Assoc suggested reserving splenectomy for painful splenomegaly, symptomatic thrombocytopenia, or leukopenia [
## Surveillance
Recommended Surveillance for Individuals with Congenital Dyserythropoietic Anemia Type I
## Agents/Circumstances to Avoid
Avoid any preparation containing iron.
## Evaluation of Relatives at Risk
Evaluation of the younger sibs of a proband for early manifestations of CDA I is recommended so that monitoring of hemoglobin and ferritin levels and treatment can begin as soon as necessary in those who are affected.
Evaluation of at-risk family members should include CBC to identify macrocytic anemia as well as typical findings on blood smear including macrocytosis, elliptocytes, and basophilic stippling.
The diagnosis can be confirmed by molecular genetic testing if the pathogenic variants in the family have been identified.
See
• Evaluation of at-risk family members should include CBC to identify macrocytic anemia as well as typical findings on blood smear including macrocytosis, elliptocytes, and basophilic stippling.
• The diagnosis can be confirmed by molecular genetic testing if the pathogenic variants in the family have been identified.
## Pregnancy Management
Anemia places pregnancies of affected women at high risk for delivery-related and outcome complications [
## Therapies Under Investigation
Search
## Genetic Counseling
Congenital dyserythropoietic anemia type I (CDA I) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one CDA I-causing pathogenic variant based on family history).
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a CDA I-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Unless an individual with CDA I has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a CDA I-causing pathogenic variant.
In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that the reproductive partner of the proband is affected or is a carrier. Thus, the risk to offspring is most accurately determined after molecular genetic testing of the proband's reproductive partner (see
Carrier testing for at-risk relatives requires prior identification of the CDA I-causing pathogenic variants in the family.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
If the CDA I-causing pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one CDA I-causing pathogenic variant based on family history).
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a CDA I-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Unless an individual with CDA I has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a CDA I-causing pathogenic variant.
• In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that the reproductive partner of the proband is affected or is a carrier. Thus, the risk to offspring is most accurately determined after molecular genetic testing of the proband's reproductive partner (see
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Congenital dyserythropoietic anemia type I (CDA I) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one CDA I-causing pathogenic variant based on family history).
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a CDA I-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Unless an individual with CDA I has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a CDA I-causing pathogenic variant.
In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that the reproductive partner of the proband is affected or is a carrier. Thus, the risk to offspring is most accurately determined after molecular genetic testing of the proband's reproductive partner (see
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one CDA I-causing pathogenic variant based on family history).
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a CDA I-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Unless an individual with CDA I has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a CDA I-causing pathogenic variant.
• In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that the reproductive partner of the proband is affected or is a carrier. Thus, the risk to offspring is most accurately determined after molecular genetic testing of the proband's reproductive partner (see
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the CDA I-causing pathogenic variants in the family.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
If the CDA I-causing pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
Congenital Dyserythropoietic Anemia Type I: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Congenital Dyserythropoietic Anemia Type I (
The mechanism by which pathogenic variants in
Congenital Dyserythropoietic Anemia Type I: Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
The mechanism by which pathogenic variants in
Congenital Dyserythropoietic Anemia Type I: Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
29 July 2021 (sw) Comprehensive update posted live
25 August 2016 (ha) Comprehensive update posted live
20 February 2014 (me) Comprehensive update posted live
1 September 2011 (me) Comprehensive update posted live
21 April 2009 (et) Review posted live
12 November 2008 (ht) Original submission
• 29 July 2021 (sw) Comprehensive update posted live
• 25 August 2016 (ha) Comprehensive update posted live
• 20 February 2014 (me) Comprehensive update posted live
• 1 September 2011 (me) Comprehensive update posted live
• 21 April 2009 (et) Review posted live
• 12 November 2008 (ht) Original submission
## Revision History
29 July 2021 (sw) Comprehensive update posted live
25 August 2016 (ha) Comprehensive update posted live
20 February 2014 (me) Comprehensive update posted live
1 September 2011 (me) Comprehensive update posted live
21 April 2009 (et) Review posted live
12 November 2008 (ht) Original submission
• 29 July 2021 (sw) Comprehensive update posted live
• 25 August 2016 (ha) Comprehensive update posted live
• 20 February 2014 (me) Comprehensive update posted live
• 1 September 2011 (me) Comprehensive update posted live
• 21 April 2009 (et) Review posted live
• 12 November 2008 (ht) Original submission
## References
## Literature Cited
|
[
"A Abu-Quider, M Asleh, H Shalev, Y Fruchtman, M Ben-Harosh, G Beck, J Kapelushnik. Treatment of transfusion-dependent congenital dyserythropoietic anemia Type I patients with pegylated interferon alpha-2a.. Eur J Haematol. 2020;105:216-22",
"K Ask, Z Jasencakova, P Menard, Y Feng, G Almouzni, A. Groth. Codanin-1, mutated in the anaemic disease CDAI, regulates Asf1 function in S-phase histone supply.. EMBO J. 2012;31:2013-23",
"M Ayas, A al-Jefri, A Baothman. Transfusion-dependent congenital dyserythropoietic anemia type I successfully treated with allogeneic stem cell transplantation.. Bone Marrow Transplant 2002;29:681-2",
"C Babbs, NA Roberts, L Sanchez-Pulido, SJ McGowan, MR Ahmed, JM Brown, MA Sabry. Bentley DR, McVean GA, Donnelly P, Gileadi O, Ponting CP, Higgs DR, Buckle VJ. Homozygous mutations in a predicted endonuclease are a novel cause of congenital dyserythropoietic anemia type I.. Haematologica. 2013;98:1383-7",
"O Dgany, N Avidan, J Delaunay, T Krasnov, L Shalmon, H Shalev, T Eidelitz-Markus, J Kapelushnik, D Cattan, A Pariente, M Tulliez, A Crétien, PO Schischmanoff, A Iolascon, E Fibach, A Koren, J Rössler, M Le Merrer, I Yaniv, R Zaizov, E Ben-Asher, T Olender, D Lancet, JS Beckmann, H Tamary. Congenital dyserythropoietic anemia type I is caused by mutations in codanin-1.. Am J Hum Genet. 2002;71:1467-74",
"S Frimmel, C Kniestedt. Angioid streaks in types I and II congenital dyserythropoietic anaemia (CDA).. Klin Monbl Augenheilkd. 2016;233:482-7",
"H Heimpel, V Anselstetter, L Chrobak, J Denecke, B Einsiedler, K Gallmeier, A Griesshammer, T Marquardt, G Janka-Schaub, M Kron, E Kohne. Congenital dyserythropoietic anemia type II: epidemiology, clinical appearance, and prognosis based on long-term observation.. Blood 2003;102:4576-81",
"H Heimpel, K Schwarz, M Ebnöther, JS Goede, D Heydrich, T Kamp, L Plaumann, B Rath, J Roessler, O Schildknecht, M Schmid, W Wuillemin, B Einsiedler, R Leichtle, H Tamary, E Kohne. Congenital dyserythropoietic anemia type I (CDA I): molecular genetics, clinical appearance, and prognosis based on long-term observation.. Blood 2006;107:334-40",
"A Iolascon, I Andolfo, W Barcellini, F Corcione, L Garçon, L De Franceschi, C Pignata, G Graziadei, D Pospisilova, DC Rees, M de Montalembert, S Rivella, A Gambale, R Russo, L Ribeiro, J Vives-Corrons, PA Martinez, A Kattamis, B Gulbis, MD Cappellini, I Roberts, H Tamary. Recommendations regarding splenectomy in hereditary hemolytic anemias.. Haematologica. 2017;102:1304-13",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"T Lavabre-Bertrand, J Ramos, C Delfour, L Henry, I Guiraud, S Carillo, A Wagner, JP Bureau, P Blanc. Long-term alpha interferon treatment is effective on anaemia and significantly reduces iron overload in congenital dyserythropoiesis type I.. Eur J Haematol 2004;73:380-3",
"M Liljeholm, AF Irvine, AL Vikberg, A Norberg, S Month, H Sandström, A Wahlin, M Mishima, I Golovleva. Congenital dyserythropoietic anemia type III (CDA III) is caused by a mutation in kinesin family member, KIF23.. Blood. 2013;121:4791-9",
"M Méndez, MI Moreno-Carralero, VL Peri, R Camacho-Galán, JM Bosch-Benítez, J Huerta-Aragonés, J Sánchez-Calero-Guilarte, MB Moreno-Risco, JM Alonso-Domínguez, MJ Morán-Jiménez. Congenital dyserythropoietic anemia types Ib, II, and III: novel variants in the CDIN1 gene and functional study of a novel variant in the KIF23 gene.. Ann Hematol. 2021;100:353-64",
"M Miano, DJ Eikema, M Aljurf, PJ Van't Veer, G Öztürk, M Wölfl, F Smiers, A Schulz, G Socié, K Vettenranta, CD de Heredia, M Zecca, J Maertens, M Rovira, J Sierra, D Uckan-Cetinkaya, E Skorobogatova, AB Antmen, JH Dalle, M Markiewicz, RM Hamladji, V Kitra-Roussou, G La Nasa, G Kriván, A Al-Seiraihy, S Giardino, AM Risitano, RP de Latour, C Dufour. Stem cell transplantation for congenital dyserythropoietic anemia: an analysis from the European Society for Blood and Marrow Transplantation.. Haematologica. 2019;104:e335-e339",
"S Noy-Lotan, O Dgany, N Marcoux, A Atkins, GM Kupfer, L Bosques, C Gottschalk, O Steinberg-Shemer, B Motro, H Tamary. Cdan1 is essential for primitive erythropoiesis.. Front Physiol. 2021;12",
"J Palmblad, B Sander, B Bain, M Klimkowska, E Björck. Congenital dyserythropoietic anemia type 1: a case with novel compound heterozygous mutations in the C15orf41 gene.. Am J Hematol. 2018;93:E213-E215",
"M Rathe, MB Møller, PW Greisen, N Fisker. Successful management of transfusion-dependent congenital dyserythropoietic anemia type 1b with interferon alfa-2a.. Pediatr Blood Cancer. 2018;65",
"E Roberts, KC Madhusudhana, R Newsom, JO Cullis. Blindness due to angioid streaks in congenital dyserythropoietic anaemia type I.. Br J Haematol. 2006;133:456",
"R Russo, I Andolfo, F Manna, A Gambale, R Marra, BE Rosato, P Caforio, V Pinto, P Pignataro, K Radhakrishnan, S Unal, G Tomaiuolo, GL Forni, A Iolascon. Multi-gene panel testing improves diagnosis and management of patients with hereditary anemias.. Am J Hematol. 2018;93:672-82",
"R Russo, R Marra, I Andolfo, G De Rosa, BE Rosato, F Manna, A Gambale, M Raia, S Unal, S Barella, A Iolascon. Characterization of two cases of congenital dyserythropoietic anemia type I shed light on the uncharacterized C15orf41 protein.. Front Physiol. 2019;10:621",
"H Shalev, K Al-Athamen, I Levi, A Levitas, H Tamary. Morbidity and mortality of adult patients with congenital dyserythropoietic anemia type I.. Eur J Haematol. 2017;98:13-8",
"H Shalev, GP Avraham, R Hershkovitz, A Levy, E Sheiner, I Levi, H Tamary. Pregnancy outcome in congenital dyserythropoietic anemia type I.. Eur J Haematol 2008;81:317-21",
"H Shalev, J Kapelushnik, A Moser, O Dgany, T Krasnov, H Tamary. A comprehensive study of the neonatal manifestations of congenital dyserythropoietic anemia type I.. J Pediatr Hematol Oncol 2004;26:746-8",
"G Swickley, Y Bloch, L Malka, A Meiri, S Noy-Lotan, A Yanai, H Tamary, B Motro. Characterization of the interactions between Codanin-1 and C15Orf41, two proteins implicated in congenital dyserythropoietic anemia type I disease.. BMC Mol Cell Biol. 2020;21:18",
"H Tamary, H Offret, O Dgany, B Foliguet, SN Wickramasinghe, T Krasnov, F Rumilly, C Goujard, M Fénéant-Thibault, T Cynober, J Delaunay. Congenital dyserythropoietic anaemia, type I, in a Caucasian patient with retinal angioid streaks (homozygous Arg1042Trp mutation in codanin-1).. Eur J Haematol 2008;80:271-4",
"Y Wang, Y Ru, G Liu, S Dong, Y Li, X Zhu, F Zhang, YZ Chang, G Nie. Identification of CDAN1, C15ORF41 and SEC23B mutations in Chinese patients affected by congenital dyserythropoietic anemia.. Gene. 2018;640:73-8",
"SN Wickramasinghe, WG Wood. Advances in the understanding of the congenital dyserythropoietic anaemias.. Br J Haematol 2005;131:431-46"
] |
21/4/2009
|
29/7/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
cdg-1a
|
cdg-1a
|
[
"CDG-Ia",
"Congenital Disorder of Glycosylation Type 1a (CDG1a)",
"Phosphomannomutase 2 Deficiency",
"Phosphomannomutase 2 Deficiency",
"CDG-Ia",
"Congenital Disorder of Glycosylation Type 1a (CDG1a)",
"Phosphomannomutase 2",
"PMM2",
"PMM2-CDG"
] |
PMM2-CDG
|
Christina Lam, Donna M Krasnewich
|
Summary PMM2-CDG, the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides, is divided into three clinical stages: infantile multisystem, late-infantile and childhood ataxia–intellectual disability, and adult stable disability. The clinical manifestations and course are highly variable, ranging from infants who die in the first year of life to mildly affected adults. Clinical findings tend to be similar in sibs. In the infantile multisystem presentation, infants show axial hypotonia, hyporeflexia, esotropia, and developmental delay. Feeding issues, vomiting, faltering growth, and developmental delay are frequently seen. Subcutaneous fat may be excessive over the buttocks and suprapubic region. Two distinct clinical courses are observed: (1) a nonfatal neurologic course with faltering growth, strabismus, developmental delay, cerebellar hypoplasia, and hepatopathy in infancy followed by neuropathy and retinitis pigmentosa in the first or second decade; and (2) a more severe neurologic-multivisceral course with approximately 20% mortality in the first year of life. The late-infantile and childhood ataxia–intellectual disability stage, which begins between ages three and ten years, is characterized by hypotonia, ataxia, severely delayed language and motor development, inability to walk, and IQ of 40 to 70; other findings include seizures, stroke-like episodes or transient unilateral loss of function, coagulopathy, retinitis pigmentosa, joint contractures, and skeletal deformities. In the adult stable disability stage, intellectual ability is stable; peripheral neuropathy is variable, progressive retinitis pigmentosa and myopia are seen, thoracic and spinal deformities with osteoporosis worsen, and premature aging is observed; females may lack secondary sexual development and males may exhibit decreased testicular volume. Hypogonadotropic hypogonadism and coagulopathy may occur. The risk for deep venous thrombosis is increased. The diagnosis of PMM2-CDG is established in a proband with type I transferrin isoform analysis and identification of either biallelic pathogenic variants in PMM2-CDG is inherited in an autosomal recessive manner. At conception, the theoretic risks to sibs of an affected individual are a 25% risk of being affected, a 50% risk of being an asymptomatic carrier, and a 25% risk of being unaffected and not a carrier; however, based on outcomes of at-risk pregnancies, the risk of having an affected child is closer to 1/3 than to the expected 1/4. Carrier testing for at-risk family members and prenatal testing for a pregnancy at increased risk are possible if both
|
## Diagnosis
PMM2-CDG is the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides.
PMM2-CDG
Faltering growth
Hypothyroidism, hypogonadism
Esotropia
Pericardial effusion
Abnormal subcutaneous fat pattern including increased suprapubic fat pad, skin dimpling, and inverted nipples or subcutaneous fat pads having a toughened, puffy, or uneven consistency
Seizures
Stroke-like episodes
Recurrent infections with concerns about immunologic dysfunction and vaccine non-responsiveness
Osteopenia, scoliosis
Cerebellar hypoplasia/atrophy and small brain stem and additional characteristic findings on brain MRI (See
Hepatic dysfunction (elevated transaminases)
Coagulopathy with abnormal prothrombin time, low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
Occasional hypoglycemia seen in infants, with some due to hyperinsulinemia
Possible hypothyroidism reflected by elevated TSH; however, thyroxine levels, performed by equilibrium dialysis, are the most reliable marker for thyroid function.
Osteopenia frequently with normal calcium, magnesium, and phosphate levels
Proteinuria and aminoaciduria with elevated creatinine reported in some individuals
Cerebellar dysfunction (ataxia, dysarthria, dysmetria) and characteristic findings on brain MRI (See
Non-progressive cognitive impairment
Seizures
Stroke-like episodes
Peripheral neuropathy with or without muscle wasting
Absent or atypical secondary sexual development in females, small testes in males
Retinitis pigmentosa and myopia
Progressive scoliosis with truncal shortening
Joint contractures
Elevated liver function tests (transaminases)
Low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
Gonadal dysfunction in most but not all adult females with varying levels of FSH, LH, and estradiol. Most males have normal pubescence but may have low testosterone and sex hormone-binding globulin.
The diagnosis of PMM2-CDG
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Possible results of such testing include:
Note: (1) There are significant concerns about the diagnostic validity of analysis of serum transferrin glycoforms before age three weeks [
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Note: Three pathogenic variants are common in individuals of European ancestry and may be included on carrier screening panels:
The pathogenic variant
The pathogenic variant
The pathogenic variants
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by neurologic and/or multiorgan dysfunction
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in PMM2-CDG
See
See
In individuals with either an abnormal transferrin isoform pattern on analysis of serum transferrin glycoforms or enzymatically confirmed phosphomannomutase 2 deficiency [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Reported deletions include a 28-kb deletion that includes exon 8 [
•
• Faltering growth
• Hypothyroidism, hypogonadism
• Esotropia
• Pericardial effusion
• Abnormal subcutaneous fat pattern including increased suprapubic fat pad, skin dimpling, and inverted nipples or subcutaneous fat pads having a toughened, puffy, or uneven consistency
• Seizures
• Stroke-like episodes
• Recurrent infections with concerns about immunologic dysfunction and vaccine non-responsiveness
• Osteopenia, scoliosis
• Cerebellar hypoplasia/atrophy and small brain stem and additional characteristic findings on brain MRI (See
• Faltering growth
• Hypothyroidism, hypogonadism
• Esotropia
• Pericardial effusion
• Abnormal subcutaneous fat pattern including increased suprapubic fat pad, skin dimpling, and inverted nipples or subcutaneous fat pads having a toughened, puffy, or uneven consistency
• Seizures
• Stroke-like episodes
• Recurrent infections with concerns about immunologic dysfunction and vaccine non-responsiveness
• Osteopenia, scoliosis
• Cerebellar hypoplasia/atrophy and small brain stem and additional characteristic findings on brain MRI (See
•
• Hepatic dysfunction (elevated transaminases)
• Coagulopathy with abnormal prothrombin time, low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
• Occasional hypoglycemia seen in infants, with some due to hyperinsulinemia
• Possible hypothyroidism reflected by elevated TSH; however, thyroxine levels, performed by equilibrium dialysis, are the most reliable marker for thyroid function.
• Osteopenia frequently with normal calcium, magnesium, and phosphate levels
• Proteinuria and aminoaciduria with elevated creatinine reported in some individuals
• Hepatic dysfunction (elevated transaminases)
• Coagulopathy with abnormal prothrombin time, low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
• Occasional hypoglycemia seen in infants, with some due to hyperinsulinemia
• Possible hypothyroidism reflected by elevated TSH; however, thyroxine levels, performed by equilibrium dialysis, are the most reliable marker for thyroid function.
• Osteopenia frequently with normal calcium, magnesium, and phosphate levels
• Proteinuria and aminoaciduria with elevated creatinine reported in some individuals
• Faltering growth
• Hypothyroidism, hypogonadism
• Esotropia
• Pericardial effusion
• Abnormal subcutaneous fat pattern including increased suprapubic fat pad, skin dimpling, and inverted nipples or subcutaneous fat pads having a toughened, puffy, or uneven consistency
• Seizures
• Stroke-like episodes
• Recurrent infections with concerns about immunologic dysfunction and vaccine non-responsiveness
• Osteopenia, scoliosis
• Cerebellar hypoplasia/atrophy and small brain stem and additional characteristic findings on brain MRI (See
• Hepatic dysfunction (elevated transaminases)
• Coagulopathy with abnormal prothrombin time, low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
• Occasional hypoglycemia seen in infants, with some due to hyperinsulinemia
• Possible hypothyroidism reflected by elevated TSH; however, thyroxine levels, performed by equilibrium dialysis, are the most reliable marker for thyroid function.
• Osteopenia frequently with normal calcium, magnesium, and phosphate levels
• Proteinuria and aminoaciduria with elevated creatinine reported in some individuals
•
• Cerebellar dysfunction (ataxia, dysarthria, dysmetria) and characteristic findings on brain MRI (See
• Non-progressive cognitive impairment
• Seizures
• Stroke-like episodes
• Peripheral neuropathy with or without muscle wasting
• Absent or atypical secondary sexual development in females, small testes in males
• Retinitis pigmentosa and myopia
• Progressive scoliosis with truncal shortening
• Joint contractures
• Cerebellar dysfunction (ataxia, dysarthria, dysmetria) and characteristic findings on brain MRI (See
• Non-progressive cognitive impairment
• Seizures
• Stroke-like episodes
• Peripheral neuropathy with or without muscle wasting
• Absent or atypical secondary sexual development in females, small testes in males
• Retinitis pigmentosa and myopia
• Progressive scoliosis with truncal shortening
• Joint contractures
•
• Elevated liver function tests (transaminases)
• Low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
• Gonadal dysfunction in most but not all adult females with varying levels of FSH, LH, and estradiol. Most males have normal pubescence but may have low testosterone and sex hormone-binding globulin.
• Elevated liver function tests (transaminases)
• Low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
• Gonadal dysfunction in most but not all adult females with varying levels of FSH, LH, and estradiol. Most males have normal pubescence but may have low testosterone and sex hormone-binding globulin.
• Cerebellar dysfunction (ataxia, dysarthria, dysmetria) and characteristic findings on brain MRI (See
• Non-progressive cognitive impairment
• Seizures
• Stroke-like episodes
• Peripheral neuropathy with or without muscle wasting
• Absent or atypical secondary sexual development in females, small testes in males
• Retinitis pigmentosa and myopia
• Progressive scoliosis with truncal shortening
• Joint contractures
• Elevated liver function tests (transaminases)
• Low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
• Gonadal dysfunction in most but not all adult females with varying levels of FSH, LH, and estradiol. Most males have normal pubescence but may have low testosterone and sex hormone-binding globulin.
• The pathogenic variant
• The pathogenic variant
• The pathogenic variants
## Suggestive Findings
PMM2-CDG
Faltering growth
Hypothyroidism, hypogonadism
Esotropia
Pericardial effusion
Abnormal subcutaneous fat pattern including increased suprapubic fat pad, skin dimpling, and inverted nipples or subcutaneous fat pads having a toughened, puffy, or uneven consistency
Seizures
Stroke-like episodes
Recurrent infections with concerns about immunologic dysfunction and vaccine non-responsiveness
Osteopenia, scoliosis
Cerebellar hypoplasia/atrophy and small brain stem and additional characteristic findings on brain MRI (See
Hepatic dysfunction (elevated transaminases)
Coagulopathy with abnormal prothrombin time, low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
Occasional hypoglycemia seen in infants, with some due to hyperinsulinemia
Possible hypothyroidism reflected by elevated TSH; however, thyroxine levels, performed by equilibrium dialysis, are the most reliable marker for thyroid function.
Osteopenia frequently with normal calcium, magnesium, and phosphate levels
Proteinuria and aminoaciduria with elevated creatinine reported in some individuals
Cerebellar dysfunction (ataxia, dysarthria, dysmetria) and characteristic findings on brain MRI (See
Non-progressive cognitive impairment
Seizures
Stroke-like episodes
Peripheral neuropathy with or without muscle wasting
Absent or atypical secondary sexual development in females, small testes in males
Retinitis pigmentosa and myopia
Progressive scoliosis with truncal shortening
Joint contractures
Elevated liver function tests (transaminases)
Low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
Gonadal dysfunction in most but not all adult females with varying levels of FSH, LH, and estradiol. Most males have normal pubescence but may have low testosterone and sex hormone-binding globulin.
•
• Faltering growth
• Hypothyroidism, hypogonadism
• Esotropia
• Pericardial effusion
• Abnormal subcutaneous fat pattern including increased suprapubic fat pad, skin dimpling, and inverted nipples or subcutaneous fat pads having a toughened, puffy, or uneven consistency
• Seizures
• Stroke-like episodes
• Recurrent infections with concerns about immunologic dysfunction and vaccine non-responsiveness
• Osteopenia, scoliosis
• Cerebellar hypoplasia/atrophy and small brain stem and additional characteristic findings on brain MRI (See
• Faltering growth
• Hypothyroidism, hypogonadism
• Esotropia
• Pericardial effusion
• Abnormal subcutaneous fat pattern including increased suprapubic fat pad, skin dimpling, and inverted nipples or subcutaneous fat pads having a toughened, puffy, or uneven consistency
• Seizures
• Stroke-like episodes
• Recurrent infections with concerns about immunologic dysfunction and vaccine non-responsiveness
• Osteopenia, scoliosis
• Cerebellar hypoplasia/atrophy and small brain stem and additional characteristic findings on brain MRI (See
•
• Hepatic dysfunction (elevated transaminases)
• Coagulopathy with abnormal prothrombin time, low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
• Occasional hypoglycemia seen in infants, with some due to hyperinsulinemia
• Possible hypothyroidism reflected by elevated TSH; however, thyroxine levels, performed by equilibrium dialysis, are the most reliable marker for thyroid function.
• Osteopenia frequently with normal calcium, magnesium, and phosphate levels
• Proteinuria and aminoaciduria with elevated creatinine reported in some individuals
• Hepatic dysfunction (elevated transaminases)
• Coagulopathy with abnormal prothrombin time, low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
• Occasional hypoglycemia seen in infants, with some due to hyperinsulinemia
• Possible hypothyroidism reflected by elevated TSH; however, thyroxine levels, performed by equilibrium dialysis, are the most reliable marker for thyroid function.
• Osteopenia frequently with normal calcium, magnesium, and phosphate levels
• Proteinuria and aminoaciduria with elevated creatinine reported in some individuals
• Faltering growth
• Hypothyroidism, hypogonadism
• Esotropia
• Pericardial effusion
• Abnormal subcutaneous fat pattern including increased suprapubic fat pad, skin dimpling, and inverted nipples or subcutaneous fat pads having a toughened, puffy, or uneven consistency
• Seizures
• Stroke-like episodes
• Recurrent infections with concerns about immunologic dysfunction and vaccine non-responsiveness
• Osteopenia, scoliosis
• Cerebellar hypoplasia/atrophy and small brain stem and additional characteristic findings on brain MRI (See
• Hepatic dysfunction (elevated transaminases)
• Coagulopathy with abnormal prothrombin time, low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
• Occasional hypoglycemia seen in infants, with some due to hyperinsulinemia
• Possible hypothyroidism reflected by elevated TSH; however, thyroxine levels, performed by equilibrium dialysis, are the most reliable marker for thyroid function.
• Osteopenia frequently with normal calcium, magnesium, and phosphate levels
• Proteinuria and aminoaciduria with elevated creatinine reported in some individuals
•
• Cerebellar dysfunction (ataxia, dysarthria, dysmetria) and characteristic findings on brain MRI (See
• Non-progressive cognitive impairment
• Seizures
• Stroke-like episodes
• Peripheral neuropathy with or without muscle wasting
• Absent or atypical secondary sexual development in females, small testes in males
• Retinitis pigmentosa and myopia
• Progressive scoliosis with truncal shortening
• Joint contractures
• Cerebellar dysfunction (ataxia, dysarthria, dysmetria) and characteristic findings on brain MRI (See
• Non-progressive cognitive impairment
• Seizures
• Stroke-like episodes
• Peripheral neuropathy with or without muscle wasting
• Absent or atypical secondary sexual development in females, small testes in males
• Retinitis pigmentosa and myopia
• Progressive scoliosis with truncal shortening
• Joint contractures
•
• Elevated liver function tests (transaminases)
• Low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
• Gonadal dysfunction in most but not all adult females with varying levels of FSH, LH, and estradiol. Most males have normal pubescence but may have low testosterone and sex hormone-binding globulin.
• Elevated liver function tests (transaminases)
• Low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
• Gonadal dysfunction in most but not all adult females with varying levels of FSH, LH, and estradiol. Most males have normal pubescence but may have low testosterone and sex hormone-binding globulin.
• Cerebellar dysfunction (ataxia, dysarthria, dysmetria) and characteristic findings on brain MRI (See
• Non-progressive cognitive impairment
• Seizures
• Stroke-like episodes
• Peripheral neuropathy with or without muscle wasting
• Absent or atypical secondary sexual development in females, small testes in males
• Retinitis pigmentosa and myopia
• Progressive scoliosis with truncal shortening
• Joint contractures
• Elevated liver function tests (transaminases)
• Low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
• Gonadal dysfunction in most but not all adult females with varying levels of FSH, LH, and estradiol. Most males have normal pubescence but may have low testosterone and sex hormone-binding globulin.
## Establishing the Diagnosis
The diagnosis of PMM2-CDG
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Possible results of such testing include:
Note: (1) There are significant concerns about the diagnostic validity of analysis of serum transferrin glycoforms before age three weeks [
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Note: Three pathogenic variants are common in individuals of European ancestry and may be included on carrier screening panels:
The pathogenic variant
The pathogenic variant
The pathogenic variants
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by neurologic and/or multiorgan dysfunction
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in PMM2-CDG
See
See
In individuals with either an abnormal transferrin isoform pattern on analysis of serum transferrin glycoforms or enzymatically confirmed phosphomannomutase 2 deficiency [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Reported deletions include a 28-kb deletion that includes exon 8 [
• The pathogenic variant
• The pathogenic variant
• The pathogenic variants
## Option 1
Note: Three pathogenic variants are common in individuals of European ancestry and may be included on carrier screening panels:
The pathogenic variant
The pathogenic variant
The pathogenic variants
For an introduction to multigene panels click
• The pathogenic variant
• The pathogenic variant
• The pathogenic variants
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by neurologic and/or multiorgan dysfunction
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in PMM2-CDG
See
See
In individuals with either an abnormal transferrin isoform pattern on analysis of serum transferrin glycoforms or enzymatically confirmed phosphomannomutase 2 deficiency [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Reported deletions include a 28-kb deletion that includes exon 8 [
## Clinical Characteristics
Some features of PMM2-CDG are usually present in infancy, but may be too subtle to recognize and thus not come to medical attention. The clinical course varies by severity and includes the following typical presentations and stages: hydrops fetalis at the severe end, infantile multisystem presentation, late-infantile and childhood ataxia–intellectual disability stage, and an adult stable disability stage [
PMM2-CDG: Frequency of Select Features
ID = intellectual disability; NA = not applicable
NIHF has been reported in 12 individuals along with antenatal complications of hydropic placenta and polyhydramnios. All individuals who have presented with antenatal/neonatal hydrops fetalis died by age three months.
An early-onset infantile multisystem presentation is characterized by feeding issues and faltering growth, developmental delay, seizures, ocular manifestations, dysmorphic features, and multivisceral involvement. There is variability in presentation, with some children showing only faltering growth and developmental delay and never requiring hospitalization. Strabismus and cerebellar hypoplasia are absent in some individuals.
Rarely, infants have a complicated early-infantile course presenting with fever, infection or seizure, and clinical deterioration that leads to hypoalbuminemia and third spacing with progression to anasarca. Approximately 20% of affected infants die within the first year of life with a severe neurologic-multivisceral course. Infants with this more severe course may have faltering growth, vomiting, intractable hypoalbuminemia, anasarca, pericardial effusion, renal hyperechogenicity, renal cysts, nephrotic syndrome, hepatic fibrosis, and multiorgan failure [
Hypoglycemia is reported in infancy with 40% due to hyperinsulinemia [
The onset of late-infantile and childhood ataxia–intellectual disability stage occurs between ages three and ten years. Children continue to gain developmental skills with a course characterized by hypotonia and ataxia. Language and motor development are delayed and walking without support is rarely achieved [
Affected individuals may have stroke-like episodes or transient unilateral loss of function sometimes associated with fever, seizure, dehydration, or trauma in childhood or adulthood. Recovery may occur over a few hours to several months. Persistent neurologic deficits after a stroke-like episode occasionally occur but are rare. The etiology of these stroke-like episodes has not been fully elucidated [
Kyphoscoliosis, thoracic deformities, and thoracic shortening may also occur in older children but are more typically seen in adolescents and affected adults. One child with PMM2-CDG had skeletal dysplasia, characterized by platyspondyly affecting all the vertebrae and severe spinal cord compression at the level of the craniocervical junction [
Intracranial hemorrhage, while not common, has been described [
A progressive peripheral neuropathy may begin in this age range.
Retinitis pigmentosa due to a progressive photoreceptor degeneration [
Adults with PMM2-CDG typically demonstrate stable rather than progressive intellectual disability. Some adults have normal cognitive abilities while most have IQs in the 40-70 range.
Additional neurologic features include variable progressive peripheral neuropathy and cerebellar ataxia [
Progression of thoracic and spinal deformities can result in severe kyphoscoliosis and shortening and widening of the ribcage. Osteopenia and osteoporosis are common in adults [
Women can lack secondary sexual development as a result of hypogonadotropic hypogonadism [
Other endocrine dysfunction includes hyperprolactinemia, insulin resistance, and rarely hyperinsulinemic hypoglycemia [
While low levels of coagulation factors (both pro- and anticoagulant) rarely cause clinical issues in daily activities, these factors must be assessed if an individual with PMM2-CDG undergoes surgery or an invasive procedure. These studies should include prothrombin time, fibrinogen, factor IX, factor XI, antithrombin, and protein C and protein S. Imbalances of pro- and anticoagulant factors may lead to either bleeding or thrombosis. Deep venous thrombosis (DVT) has been reported in adults and children with PMM2-CDG [
Renal microcysts may be identified on renal ultrasound examination but renal function is typically preserved throughout adulthood [
Myelination varies from normal to delayed or insufficient [
Serial brain CT examinations performed on three children with PMM2-CDG revealed that enlargement of the spaces between the folia of the cerebellar hemispheres, especially from the anterior to the posterior aspect, as well as atrophy of the anterior vermis, appeared to progress until around age five years [
PMM2-CDG is caused by deficiency of phosphomannomutase 2 (PMM2) enzyme activity resulting in the defective synthesis of N-linked oligosaccharides, sugars linked together in a specific pattern and attached to proteins and lipids (N-linked glycans link to the amide group of asparagine via an N-acetylglucosamine residue) [
Some genotype-phenotype correlations have been proposed, although recognition that there is significant phenotypic variability even with the same genotype is prudent.
C-terminal pathogenic variants, including
The phenotypic spectrum of the [
A severe phenotype presenting with a high mortality rate was observed with the [
The pathogenic variant
In 2009 the nomenclature for all types of CDG was changed to include the official gene symbol (not italicized) followed by "-CDG." If the type has a known letter name, it follows in parenthesis; thus the new nomenclature for this disorder is PMM2-CDG [
PMM2-CDG was previously referred to as CDG-1a; carbohydrate-deficient glycoprotein syndrome, type 1a (CDGS1a); and Jaeken syndrome.
PMM2-CDG is the most common form of
The expected carrier frequency for a
• C-terminal pathogenic variants, including
• The phenotypic spectrum of the [
• A severe phenotype presenting with a high mortality rate was observed with the [
• The pathogenic variant
## Clinical Description
Some features of PMM2-CDG are usually present in infancy, but may be too subtle to recognize and thus not come to medical attention. The clinical course varies by severity and includes the following typical presentations and stages: hydrops fetalis at the severe end, infantile multisystem presentation, late-infantile and childhood ataxia–intellectual disability stage, and an adult stable disability stage [
PMM2-CDG: Frequency of Select Features
ID = intellectual disability; NA = not applicable
NIHF has been reported in 12 individuals along with antenatal complications of hydropic placenta and polyhydramnios. All individuals who have presented with antenatal/neonatal hydrops fetalis died by age three months.
An early-onset infantile multisystem presentation is characterized by feeding issues and faltering growth, developmental delay, seizures, ocular manifestations, dysmorphic features, and multivisceral involvement. There is variability in presentation, with some children showing only faltering growth and developmental delay and never requiring hospitalization. Strabismus and cerebellar hypoplasia are absent in some individuals.
Rarely, infants have a complicated early-infantile course presenting with fever, infection or seizure, and clinical deterioration that leads to hypoalbuminemia and third spacing with progression to anasarca. Approximately 20% of affected infants die within the first year of life with a severe neurologic-multivisceral course. Infants with this more severe course may have faltering growth, vomiting, intractable hypoalbuminemia, anasarca, pericardial effusion, renal hyperechogenicity, renal cysts, nephrotic syndrome, hepatic fibrosis, and multiorgan failure [
Hypoglycemia is reported in infancy with 40% due to hyperinsulinemia [
The onset of late-infantile and childhood ataxia–intellectual disability stage occurs between ages three and ten years. Children continue to gain developmental skills with a course characterized by hypotonia and ataxia. Language and motor development are delayed and walking without support is rarely achieved [
Affected individuals may have stroke-like episodes or transient unilateral loss of function sometimes associated with fever, seizure, dehydration, or trauma in childhood or adulthood. Recovery may occur over a few hours to several months. Persistent neurologic deficits after a stroke-like episode occasionally occur but are rare. The etiology of these stroke-like episodes has not been fully elucidated [
Kyphoscoliosis, thoracic deformities, and thoracic shortening may also occur in older children but are more typically seen in adolescents and affected adults. One child with PMM2-CDG had skeletal dysplasia, characterized by platyspondyly affecting all the vertebrae and severe spinal cord compression at the level of the craniocervical junction [
Intracranial hemorrhage, while not common, has been described [
A progressive peripheral neuropathy may begin in this age range.
Retinitis pigmentosa due to a progressive photoreceptor degeneration [
Adults with PMM2-CDG typically demonstrate stable rather than progressive intellectual disability. Some adults have normal cognitive abilities while most have IQs in the 40-70 range.
Additional neurologic features include variable progressive peripheral neuropathy and cerebellar ataxia [
Progression of thoracic and spinal deformities can result in severe kyphoscoliosis and shortening and widening of the ribcage. Osteopenia and osteoporosis are common in adults [
Women can lack secondary sexual development as a result of hypogonadotropic hypogonadism [
Other endocrine dysfunction includes hyperprolactinemia, insulin resistance, and rarely hyperinsulinemic hypoglycemia [
While low levels of coagulation factors (both pro- and anticoagulant) rarely cause clinical issues in daily activities, these factors must be assessed if an individual with PMM2-CDG undergoes surgery or an invasive procedure. These studies should include prothrombin time, fibrinogen, factor IX, factor XI, antithrombin, and protein C and protein S. Imbalances of pro- and anticoagulant factors may lead to either bleeding or thrombosis. Deep venous thrombosis (DVT) has been reported in adults and children with PMM2-CDG [
Renal microcysts may be identified on renal ultrasound examination but renal function is typically preserved throughout adulthood [
Myelination varies from normal to delayed or insufficient [
Serial brain CT examinations performed on three children with PMM2-CDG revealed that enlargement of the spaces between the folia of the cerebellar hemispheres, especially from the anterior to the posterior aspect, as well as atrophy of the anterior vermis, appeared to progress until around age five years [
## Nonimmune Hydrops Fetalis (NIHF)
NIHF has been reported in 12 individuals along with antenatal complications of hydropic placenta and polyhydramnios. All individuals who have presented with antenatal/neonatal hydrops fetalis died by age three months.
## Infantile Multisystem Presentation
An early-onset infantile multisystem presentation is characterized by feeding issues and faltering growth, developmental delay, seizures, ocular manifestations, dysmorphic features, and multivisceral involvement. There is variability in presentation, with some children showing only faltering growth and developmental delay and never requiring hospitalization. Strabismus and cerebellar hypoplasia are absent in some individuals.
Rarely, infants have a complicated early-infantile course presenting with fever, infection or seizure, and clinical deterioration that leads to hypoalbuminemia and third spacing with progression to anasarca. Approximately 20% of affected infants die within the first year of life with a severe neurologic-multivisceral course. Infants with this more severe course may have faltering growth, vomiting, intractable hypoalbuminemia, anasarca, pericardial effusion, renal hyperechogenicity, renal cysts, nephrotic syndrome, hepatic fibrosis, and multiorgan failure [
Hypoglycemia is reported in infancy with 40% due to hyperinsulinemia [
## Late-Infantile and Childhood Ataxia–Intellectual Disability Stage
The onset of late-infantile and childhood ataxia–intellectual disability stage occurs between ages three and ten years. Children continue to gain developmental skills with a course characterized by hypotonia and ataxia. Language and motor development are delayed and walking without support is rarely achieved [
Affected individuals may have stroke-like episodes or transient unilateral loss of function sometimes associated with fever, seizure, dehydration, or trauma in childhood or adulthood. Recovery may occur over a few hours to several months. Persistent neurologic deficits after a stroke-like episode occasionally occur but are rare. The etiology of these stroke-like episodes has not been fully elucidated [
Kyphoscoliosis, thoracic deformities, and thoracic shortening may also occur in older children but are more typically seen in adolescents and affected adults. One child with PMM2-CDG had skeletal dysplasia, characterized by platyspondyly affecting all the vertebrae and severe spinal cord compression at the level of the craniocervical junction [
Intracranial hemorrhage, while not common, has been described [
A progressive peripheral neuropathy may begin in this age range.
Retinitis pigmentosa due to a progressive photoreceptor degeneration [
## Adult Stable Disability Stage
Adults with PMM2-CDG typically demonstrate stable rather than progressive intellectual disability. Some adults have normal cognitive abilities while most have IQs in the 40-70 range.
Additional neurologic features include variable progressive peripheral neuropathy and cerebellar ataxia [
Progression of thoracic and spinal deformities can result in severe kyphoscoliosis and shortening and widening of the ribcage. Osteopenia and osteoporosis are common in adults [
Women can lack secondary sexual development as a result of hypogonadotropic hypogonadism [
Other endocrine dysfunction includes hyperprolactinemia, insulin resistance, and rarely hyperinsulinemic hypoglycemia [
While low levels of coagulation factors (both pro- and anticoagulant) rarely cause clinical issues in daily activities, these factors must be assessed if an individual with PMM2-CDG undergoes surgery or an invasive procedure. These studies should include prothrombin time, fibrinogen, factor IX, factor XI, antithrombin, and protein C and protein S. Imbalances of pro- and anticoagulant factors may lead to either bleeding or thrombosis. Deep venous thrombosis (DVT) has been reported in adults and children with PMM2-CDG [
Renal microcysts may be identified on renal ultrasound examination but renal function is typically preserved throughout adulthood [
Myelination varies from normal to delayed or insufficient [
Serial brain CT examinations performed on three children with PMM2-CDG revealed that enlargement of the spaces between the folia of the cerebellar hemispheres, especially from the anterior to the posterior aspect, as well as atrophy of the anterior vermis, appeared to progress until around age five years [
## Pathophysiology
PMM2-CDG is caused by deficiency of phosphomannomutase 2 (PMM2) enzyme activity resulting in the defective synthesis of N-linked oligosaccharides, sugars linked together in a specific pattern and attached to proteins and lipids (N-linked glycans link to the amide group of asparagine via an N-acetylglucosamine residue) [
## Genotype-Phenotype Correlations
Some genotype-phenotype correlations have been proposed, although recognition that there is significant phenotypic variability even with the same genotype is prudent.
C-terminal pathogenic variants, including
The phenotypic spectrum of the [
A severe phenotype presenting with a high mortality rate was observed with the [
The pathogenic variant
• C-terminal pathogenic variants, including
• The phenotypic spectrum of the [
• A severe phenotype presenting with a high mortality rate was observed with the [
• The pathogenic variant
## Nomenclature
In 2009 the nomenclature for all types of CDG was changed to include the official gene symbol (not italicized) followed by "-CDG." If the type has a known letter name, it follows in parenthesis; thus the new nomenclature for this disorder is PMM2-CDG [
PMM2-CDG was previously referred to as CDG-1a; carbohydrate-deficient glycoprotein syndrome, type 1a (CDGS1a); and Jaeken syndrome.
## Prevalence
PMM2-CDG is the most common form of
The expected carrier frequency for a
## Genetically Related (Allelic) Disorders
A child with biallelic
## Differential Diagnosis
Metabolic Disorders to Consider in the Differential Diagnosis of PMM2-CDG in Infants Who Have Not Yet Had an MRI
IUGR
DD/ID
Neurologic dysfunction
Liver disease
Can have abnormal transferrin glycoform analysis
Can be indistinguishable
PMM2 enzyme activity is abnormal only in PMM2-CDG.
Multisystem involvement
Pigmentary retinopathy
Movement disorder
Do not typically have episodes of metabolic decompensation or clinical presentations assoc w/classic mt disorder phenotypes;
Do not typically have significantly ↑ acidemia if not assoc w/hypoperfusion;
Have abnormal transferrin glycoform analysis & deficient PMM2 activity.
Multisystem involvement
DD/ID
Neurologic dysfunction
Liver disease
Hypotonia
Growth deficiency
Feeding intolerance
DD/ID
Spasticity
Do not typically have episodes of metabolic decompensation;
Do not have hyperammonemia;
Have abnormal transferrin glycoform analysis & deficient PMM2 activity.
CDDG = congenital disorder of deglycosylation; CDG = congenital disorder of glycosylation; CDG-N-linked = congenital disorders of N-linked glycosylation; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; IUGR = intrauterine growth restriction; mt = mitochondrial; NGLY1-CDDG =
See OMIM Phenotypic Series:
Metabolic Disorders with Overlapping MRI Findings in the Differential Diagnosis of PMM2-CDG
DD = developmental delay; ID = intellectual disability; NBIA = neurodegeneration with brain iron accumulation; PHARC =
With the exception of delta-1-pyrroline-5-carboxylate synthetase deficiency (which can be inherited in either an autosomal dominant and autosomal recessive manner) and Leigh syndrome (which can be inherited in an autosomal recessive, autosomal dominant, X-linked, or maternal manner), the disorders in
Many genes (nuclear and mitochondrial) are known to be associated with Leigh syndrome.
• IUGR
• DD/ID
• Neurologic dysfunction
• Liver disease
• Can have abnormal transferrin glycoform analysis
• Can be indistinguishable
• PMM2 enzyme activity is abnormal only in PMM2-CDG.
• Multisystem involvement
• Pigmentary retinopathy
• Movement disorder
• Do not typically have episodes of metabolic decompensation or clinical presentations assoc w/classic mt disorder phenotypes;
• Do not typically have significantly ↑ acidemia if not assoc w/hypoperfusion;
• Have abnormal transferrin glycoform analysis & deficient PMM2 activity.
• Multisystem involvement
• DD/ID
• Neurologic dysfunction
• Liver disease
• Hypotonia
• Growth deficiency
• Feeding intolerance
• DD/ID
• Spasticity
• Do not typically have episodes of metabolic decompensation;
• Do not have hyperammonemia;
• Have abnormal transferrin glycoform analysis & deficient PMM2 activity.
## Management
To establish the extent of disease and needs in an individual diagnosed with PMM2-CDG, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with PMM2-CDG
Gastroenterology / nutrition / feeding team eval
To incl eval of growth, aspiration risk, & nutritional status
Consider eval for gastrostomy tube placement in infants w/dysphagia &/or aspiration risk.
Neurologic eval
Assess for ataxia, dysmetria, dysarthria.
Administer clinical ataxia scale (e.g., ICARS).
Consider baseline neuroimaging.
Baseline EEG if seizures are a concern
Nerve conduction studies in older affected persons
Motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
In infants: gross motor & fine motor skills
In older children / adults assess mobility, ADL, & need for adaptive devices.
In infants, eval to assess suck & swallow
In older children / adults assess communication both oral & w/adaptive devices to optimize care & independence.
Vision
Ocular mobility
Structural anomalies of the lens & retina
Intraocular pressure
Measurement of ALT, AST, serum albumin concentration
Liver ultrasound
Complete blood count
Assessment of bleeding & clotting parameters by hematologist incl prothrombin time, protein C, protein S, antithrombin III, factor IX, & factor XI
Height assessment
TSH, thyroid binding globulin & free T4
Calcium, magnesium, & phosphorus
Glucose
Blood pressure
Serum creatinine
Urinalysis to evaluate for proteinuria & aminoaciduria
Renal ultrasound exam to evaluate for microcysts
Orthopedics / physical medicine & rehab / PT & OT assessment for contractures & skeletal deformities
C-spine radiographs in neutral, extension, & flexion to assess for atlantoaxial instability
Assessment for kyphoscoliosis starting at adolescence
DXA scan starting in adolescence
Leukocyte count & immunoglobulin levels
Antibody titer testing after vaccinations
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; ALT = alanine transaminase AST = aspartate transaminase; DXA = dual-energy x-ray absorptiometry; ICARS = International Cooperative Ataxia Rating Scale; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; T4 = thyroxine; TSH = thyroid-stimulating hormone
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with PMM2-CDG
Symptomatic treatment in a pediatric tertiary care center is recommended.
Some children are responsive to aggressive albumin replacement w/furosemide; others may have a more refractory course.
Because infants w/PMM2-CDG have less physiologic reserve than peers, parents should have a low threshold for eval by physician for prolonged fever, vomiting, or diarrhea.
Aggressive intervention w/antipyretics & antibiotics if warranted & hydration may improve morbidity assoc w/severe infantile phase.
Parents should also be advised that some infants w/PMM2-CDG never experience a hospital visit, while others may require frequent hospitalizations.
Consultation w/gastroenterologist & nutritionist
In infants, any type of formula or breast milk fortification for maximal caloric intake
Nasogastric tube or gastrostomy tube for nutritional support if needed until oral motor skills improve
Thickening of infant feeds
Maintenance of upright position after eating; antacids
Speech therapy / oral motor therapy to aid transition to oral feeds
Carbohydrates, fats, & protein are tolerated.
Early in life, children may do better on elemental formulas.
Children w/gastrostomy tube should be encouraged to eat by mouth if risk of aspiration is low.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Hydration by IV if necessary
PT, OT, & speech therapies during recovery period
Referral to an early intervention program for PT, OT, & speech therapy
Referral to a developmental pediatrician to monitor progress & facilitate ongoing developmental services.
Treatment per ophthalmologist
Many pericardial effusions resolve w/o intervention.
Consultation w/hematologist (to document coagulation status & factor levels)
Discussion w/surgeon & hematologist prior to surgery
When necessary, infusion of fresh frozen plasma corrects the factor deficiency & clinical bleeding.
Counseling regarding avoidance of fractures
Management per orthopedic & physical medicine, well-supported wheelchairs, appropriate transfer devices for the home, & PT.
Occasionally, surgical treatment of kyphoscoliosis is warranted.
Treatment per immunologist
Consider post vaccination titers to establish vaccine responsiveness.
Aggressive education throughout school years in functional life skills &/or vocational training helps the transition when schooling is completed.
Independence in self-care & ADL should be encouraged.
Address issues of independent living w/young adults & parents.
Support & resources for parents of a disabled adult
Support caregiver understanding of need for long-term care plans & successor caregivers for affected older adults.
ADL = activities of daily living; ASM = anti-seizure medication; DVT = deep venous thrombosis; GER = gastroesophageal reflux; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
Recommended Surveillance for Individuals with PMM2-CDG
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations incl seizures, changes in tone, movement disorders.
Ophthalmology exam
Cardiology assessment
AST, ALT, & albumin
Annually until normalization
Those w/chronic ↑ of transaminases, at risk for fibrosis, may need noninvasive elastography.
Height assessment
TSH & free T4
Glucose
Calcium, magnesium, phosphate
Blood pressure
Urine dipstick for proteinuria
Serum creatinine
Annually &/or as needed
Consultation at time of surgery
If prothrombin time is prolonged, factors II, V, VII, VIII & X should be measured.
ALT = alanine transaminase AST = aspartate transaminase; DXA = dual-energy x-ray absorptiometry; T4 = thyroxine; TSH = thyroid-stimulating hormone
Acetaminophen and other agents metabolized by the liver should be used with caution.
Newborns at risk should have molecular testing for the familial
See
Search
• To incl eval of growth, aspiration risk, & nutritional status
• Consider eval for gastrostomy tube placement in infants w/dysphagia &/or aspiration risk.
• Neurologic eval
• Assess for ataxia, dysmetria, dysarthria.
• Administer clinical ataxia scale (e.g., ICARS).
• Consider baseline neuroimaging.
• Baseline EEG if seizures are a concern
• Nerve conduction studies in older affected persons
• Motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• In infants: gross motor & fine motor skills
• In older children / adults assess mobility, ADL, & need for adaptive devices.
• In infants, eval to assess suck & swallow
• In older children / adults assess communication both oral & w/adaptive devices to optimize care & independence.
• Vision
• Ocular mobility
• Structural anomalies of the lens & retina
• Intraocular pressure
• Measurement of ALT, AST, serum albumin concentration
• Liver ultrasound
• Complete blood count
• Assessment of bleeding & clotting parameters by hematologist incl prothrombin time, protein C, protein S, antithrombin III, factor IX, & factor XI
• Height assessment
• TSH, thyroid binding globulin & free T4
• Calcium, magnesium, & phosphorus
• Glucose
• Blood pressure
• Serum creatinine
• Urinalysis to evaluate for proteinuria & aminoaciduria
• Renal ultrasound exam to evaluate for microcysts
• Orthopedics / physical medicine & rehab / PT & OT assessment for contractures & skeletal deformities
• C-spine radiographs in neutral, extension, & flexion to assess for atlantoaxial instability
• Assessment for kyphoscoliosis starting at adolescence
• DXA scan starting in adolescence
• Leukocyte count & immunoglobulin levels
• Antibody titer testing after vaccinations
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Symptomatic treatment in a pediatric tertiary care center is recommended.
• Some children are responsive to aggressive albumin replacement w/furosemide; others may have a more refractory course.
• Because infants w/PMM2-CDG have less physiologic reserve than peers, parents should have a low threshold for eval by physician for prolonged fever, vomiting, or diarrhea.
• Aggressive intervention w/antipyretics & antibiotics if warranted & hydration may improve morbidity assoc w/severe infantile phase.
• Parents should also be advised that some infants w/PMM2-CDG never experience a hospital visit, while others may require frequent hospitalizations.
• Consultation w/gastroenterologist & nutritionist
• In infants, any type of formula or breast milk fortification for maximal caloric intake
• Nasogastric tube or gastrostomy tube for nutritional support if needed until oral motor skills improve
• Thickening of infant feeds
• Maintenance of upright position after eating; antacids
• Speech therapy / oral motor therapy to aid transition to oral feeds
• Carbohydrates, fats, & protein are tolerated.
• Early in life, children may do better on elemental formulas.
• Children w/gastrostomy tube should be encouraged to eat by mouth if risk of aspiration is low.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Hydration by IV if necessary
• PT, OT, & speech therapies during recovery period
• Referral to an early intervention program for PT, OT, & speech therapy
• Referral to a developmental pediatrician to monitor progress & facilitate ongoing developmental services.
• Consultation w/hematologist (to document coagulation status & factor levels)
• Discussion w/surgeon & hematologist prior to surgery
• When necessary, infusion of fresh frozen plasma corrects the factor deficiency & clinical bleeding.
• Counseling regarding avoidance of fractures
• Management per orthopedic & physical medicine, well-supported wheelchairs, appropriate transfer devices for the home, & PT.
• Occasionally, surgical treatment of kyphoscoliosis is warranted.
• Treatment per immunologist
• Consider post vaccination titers to establish vaccine responsiveness.
• Aggressive education throughout school years in functional life skills &/or vocational training helps the transition when schooling is completed.
• Independence in self-care & ADL should be encouraged.
• Address issues of independent living w/young adults & parents.
• Support & resources for parents of a disabled adult
• Support caregiver understanding of need for long-term care plans & successor caregivers for affected older adults.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations incl seizures, changes in tone, movement disorders.
• Annually until normalization
• Those w/chronic ↑ of transaminases, at risk for fibrosis, may need noninvasive elastography.
• Height assessment
• TSH & free T4
• Glucose
• Calcium, magnesium, phosphate
• Blood pressure
• Urine dipstick for proteinuria
• Serum creatinine
• Annually &/or as needed
• Consultation at time of surgery
• If prothrombin time is prolonged, factors II, V, VII, VIII & X should be measured.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with PMM2-CDG, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with PMM2-CDG
Gastroenterology / nutrition / feeding team eval
To incl eval of growth, aspiration risk, & nutritional status
Consider eval for gastrostomy tube placement in infants w/dysphagia &/or aspiration risk.
Neurologic eval
Assess for ataxia, dysmetria, dysarthria.
Administer clinical ataxia scale (e.g., ICARS).
Consider baseline neuroimaging.
Baseline EEG if seizures are a concern
Nerve conduction studies in older affected persons
Motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
In infants: gross motor & fine motor skills
In older children / adults assess mobility, ADL, & need for adaptive devices.
In infants, eval to assess suck & swallow
In older children / adults assess communication both oral & w/adaptive devices to optimize care & independence.
Vision
Ocular mobility
Structural anomalies of the lens & retina
Intraocular pressure
Measurement of ALT, AST, serum albumin concentration
Liver ultrasound
Complete blood count
Assessment of bleeding & clotting parameters by hematologist incl prothrombin time, protein C, protein S, antithrombin III, factor IX, & factor XI
Height assessment
TSH, thyroid binding globulin & free T4
Calcium, magnesium, & phosphorus
Glucose
Blood pressure
Serum creatinine
Urinalysis to evaluate for proteinuria & aminoaciduria
Renal ultrasound exam to evaluate for microcysts
Orthopedics / physical medicine & rehab / PT & OT assessment for contractures & skeletal deformities
C-spine radiographs in neutral, extension, & flexion to assess for atlantoaxial instability
Assessment for kyphoscoliosis starting at adolescence
DXA scan starting in adolescence
Leukocyte count & immunoglobulin levels
Antibody titer testing after vaccinations
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; ALT = alanine transaminase AST = aspartate transaminase; DXA = dual-energy x-ray absorptiometry; ICARS = International Cooperative Ataxia Rating Scale; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; T4 = thyroxine; TSH = thyroid-stimulating hormone
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl eval of growth, aspiration risk, & nutritional status
• Consider eval for gastrostomy tube placement in infants w/dysphagia &/or aspiration risk.
• Neurologic eval
• Assess for ataxia, dysmetria, dysarthria.
• Administer clinical ataxia scale (e.g., ICARS).
• Consider baseline neuroimaging.
• Baseline EEG if seizures are a concern
• Nerve conduction studies in older affected persons
• Motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• In infants: gross motor & fine motor skills
• In older children / adults assess mobility, ADL, & need for adaptive devices.
• In infants, eval to assess suck & swallow
• In older children / adults assess communication both oral & w/adaptive devices to optimize care & independence.
• Vision
• Ocular mobility
• Structural anomalies of the lens & retina
• Intraocular pressure
• Measurement of ALT, AST, serum albumin concentration
• Liver ultrasound
• Complete blood count
• Assessment of bleeding & clotting parameters by hematologist incl prothrombin time, protein C, protein S, antithrombin III, factor IX, & factor XI
• Height assessment
• TSH, thyroid binding globulin & free T4
• Calcium, magnesium, & phosphorus
• Glucose
• Blood pressure
• Serum creatinine
• Urinalysis to evaluate for proteinuria & aminoaciduria
• Renal ultrasound exam to evaluate for microcysts
• Orthopedics / physical medicine & rehab / PT & OT assessment for contractures & skeletal deformities
• C-spine radiographs in neutral, extension, & flexion to assess for atlantoaxial instability
• Assessment for kyphoscoliosis starting at adolescence
• DXA scan starting in adolescence
• Leukocyte count & immunoglobulin levels
• Antibody titer testing after vaccinations
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with PMM2-CDG
Symptomatic treatment in a pediatric tertiary care center is recommended.
Some children are responsive to aggressive albumin replacement w/furosemide; others may have a more refractory course.
Because infants w/PMM2-CDG have less physiologic reserve than peers, parents should have a low threshold for eval by physician for prolonged fever, vomiting, or diarrhea.
Aggressive intervention w/antipyretics & antibiotics if warranted & hydration may improve morbidity assoc w/severe infantile phase.
Parents should also be advised that some infants w/PMM2-CDG never experience a hospital visit, while others may require frequent hospitalizations.
Consultation w/gastroenterologist & nutritionist
In infants, any type of formula or breast milk fortification for maximal caloric intake
Nasogastric tube or gastrostomy tube for nutritional support if needed until oral motor skills improve
Thickening of infant feeds
Maintenance of upright position after eating; antacids
Speech therapy / oral motor therapy to aid transition to oral feeds
Carbohydrates, fats, & protein are tolerated.
Early in life, children may do better on elemental formulas.
Children w/gastrostomy tube should be encouraged to eat by mouth if risk of aspiration is low.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Hydration by IV if necessary
PT, OT, & speech therapies during recovery period
Referral to an early intervention program for PT, OT, & speech therapy
Referral to a developmental pediatrician to monitor progress & facilitate ongoing developmental services.
Treatment per ophthalmologist
Many pericardial effusions resolve w/o intervention.
Consultation w/hematologist (to document coagulation status & factor levels)
Discussion w/surgeon & hematologist prior to surgery
When necessary, infusion of fresh frozen plasma corrects the factor deficiency & clinical bleeding.
Counseling regarding avoidance of fractures
Management per orthopedic & physical medicine, well-supported wheelchairs, appropriate transfer devices for the home, & PT.
Occasionally, surgical treatment of kyphoscoliosis is warranted.
Treatment per immunologist
Consider post vaccination titers to establish vaccine responsiveness.
Aggressive education throughout school years in functional life skills &/or vocational training helps the transition when schooling is completed.
Independence in self-care & ADL should be encouraged.
Address issues of independent living w/young adults & parents.
Support & resources for parents of a disabled adult
Support caregiver understanding of need for long-term care plans & successor caregivers for affected older adults.
ADL = activities of daily living; ASM = anti-seizure medication; DVT = deep venous thrombosis; GER = gastroesophageal reflux; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
• Symptomatic treatment in a pediatric tertiary care center is recommended.
• Some children are responsive to aggressive albumin replacement w/furosemide; others may have a more refractory course.
• Because infants w/PMM2-CDG have less physiologic reserve than peers, parents should have a low threshold for eval by physician for prolonged fever, vomiting, or diarrhea.
• Aggressive intervention w/antipyretics & antibiotics if warranted & hydration may improve morbidity assoc w/severe infantile phase.
• Parents should also be advised that some infants w/PMM2-CDG never experience a hospital visit, while others may require frequent hospitalizations.
• Consultation w/gastroenterologist & nutritionist
• In infants, any type of formula or breast milk fortification for maximal caloric intake
• Nasogastric tube or gastrostomy tube for nutritional support if needed until oral motor skills improve
• Thickening of infant feeds
• Maintenance of upright position after eating; antacids
• Speech therapy / oral motor therapy to aid transition to oral feeds
• Carbohydrates, fats, & protein are tolerated.
• Early in life, children may do better on elemental formulas.
• Children w/gastrostomy tube should be encouraged to eat by mouth if risk of aspiration is low.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Hydration by IV if necessary
• PT, OT, & speech therapies during recovery period
• Referral to an early intervention program for PT, OT, & speech therapy
• Referral to a developmental pediatrician to monitor progress & facilitate ongoing developmental services.
• Consultation w/hematologist (to document coagulation status & factor levels)
• Discussion w/surgeon & hematologist prior to surgery
• When necessary, infusion of fresh frozen plasma corrects the factor deficiency & clinical bleeding.
• Counseling regarding avoidance of fractures
• Management per orthopedic & physical medicine, well-supported wheelchairs, appropriate transfer devices for the home, & PT.
• Occasionally, surgical treatment of kyphoscoliosis is warranted.
• Treatment per immunologist
• Consider post vaccination titers to establish vaccine responsiveness.
• Aggressive education throughout school years in functional life skills &/or vocational training helps the transition when schooling is completed.
• Independence in self-care & ADL should be encouraged.
• Address issues of independent living w/young adults & parents.
• Support & resources for parents of a disabled adult
• Support caregiver understanding of need for long-term care plans & successor caregivers for affected older adults.
## Surveillance
Recommended Surveillance for Individuals with PMM2-CDG
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations incl seizures, changes in tone, movement disorders.
Ophthalmology exam
Cardiology assessment
AST, ALT, & albumin
Annually until normalization
Those w/chronic ↑ of transaminases, at risk for fibrosis, may need noninvasive elastography.
Height assessment
TSH & free T4
Glucose
Calcium, magnesium, phosphate
Blood pressure
Urine dipstick for proteinuria
Serum creatinine
Annually &/or as needed
Consultation at time of surgery
If prothrombin time is prolonged, factors II, V, VII, VIII & X should be measured.
ALT = alanine transaminase AST = aspartate transaminase; DXA = dual-energy x-ray absorptiometry; T4 = thyroxine; TSH = thyroid-stimulating hormone
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations incl seizures, changes in tone, movement disorders.
• Annually until normalization
• Those w/chronic ↑ of transaminases, at risk for fibrosis, may need noninvasive elastography.
• Height assessment
• TSH & free T4
• Glucose
• Calcium, magnesium, phosphate
• Blood pressure
• Urine dipstick for proteinuria
• Serum creatinine
• Annually &/or as needed
• Consultation at time of surgery
• If prothrombin time is prolonged, factors II, V, VII, VIII & X should be measured.
## Agents/Circumstances to Avoid
Acetaminophen and other agents metabolized by the liver should be used with caution.
## Evaluation of Relatives at Risk
Newborns at risk should have molecular testing for the familial
See
## Therapies Under Investigation
Search
## Genetic Counseling
PMM2-CDG is inherited in an autosomal recessive manner.
The parents of an affected child are typically heterozygotes (i.e., carriers of one
Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for a
And the child appears to have homozygous
And the child has compound heterozygous
Heterozygotes are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
If the proband has PMM2-CDG as the result of uniparental isodisomy for chromosome 16 and only one parent is heterozygous for a
Heterozygotes are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of being heterozygotes (i.e., carriers of one
Note: Transferrin isoform analysis on fetal serum is an unreliable diagnostic test. PMM2 enzyme activity may also be falsely low in poorly growing amniocytes or chorionic villi.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are typically heterozygotes (i.e., carriers of one
• Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for a
• And the child appears to have homozygous
• And the child has compound heterozygous
• And the child appears to have homozygous
• And the child has compound heterozygous
• Heterozygotes are asymptomatic and are not at risk of developing the disorder.
• And the child appears to have homozygous
• And the child has compound heterozygous
• If both parents are known to be heterozygous for a
• If the proband has PMM2-CDG as the result of uniparental isodisomy for chromosome 16 and only one parent is heterozygous for a
• Heterozygotes are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of being heterozygotes (i.e., carriers of one
## Mode of Inheritance
PMM2-CDG is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are typically heterozygotes (i.e., carriers of one
Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for a
And the child appears to have homozygous
And the child has compound heterozygous
Heterozygotes are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
If the proband has PMM2-CDG as the result of uniparental isodisomy for chromosome 16 and only one parent is heterozygous for a
Heterozygotes are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are typically heterozygotes (i.e., carriers of one
• Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for a
• And the child appears to have homozygous
• And the child has compound heterozygous
• And the child appears to have homozygous
• And the child has compound heterozygous
• Heterozygotes are asymptomatic and are not at risk of developing the disorder.
• And the child appears to have homozygous
• And the child has compound heterozygous
• If both parents are known to be heterozygous for a
• If the proband has PMM2-CDG as the result of uniparental isodisomy for chromosome 16 and only one parent is heterozygous for a
• Heterozygotes are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of being heterozygotes (i.e., carriers of one
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of being heterozygotes (i.e., carriers of one
## Prenatal Testing and Preimplantation Genetic Testing
Note: Transferrin isoform analysis on fetal serum is an unreliable diagnostic test. PMM2 enzyme activity may also be falsely low in poorly growing amniocytes or chorionic villi.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
•
•
•
• Canada
•
•
•
## Molecular Genetics
PMM2-CDG: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for PMM2-CDG (
Deficient PMM2 causes hypoglycosylation by lowering the intracellular mannose-1-phosphate pool, leading to deficiency of GDP-mannose, and thus deficient lipid-linked oligosaccharide synthesis. With deficiency of lipid-linked oligosaccharides, glycosylation of proteins at the asparagine residue becomes deficient, leading to dysfunction of these underglycosylated proteins.
Notable
May be assoc w/a milder phenotype [
Assoc w/high early mortality & severe multiorgan insufficiency [
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Deficient PMM2 causes hypoglycosylation by lowering the intracellular mannose-1-phosphate pool, leading to deficiency of GDP-mannose, and thus deficient lipid-linked oligosaccharide synthesis. With deficiency of lipid-linked oligosaccharides, glycosylation of proteins at the asparagine residue becomes deficient, leading to dysfunction of these underglycosylated proteins.
Notable
May be assoc w/a milder phenotype [
Assoc w/high early mortality & severe multiorgan insufficiency [
Variants listed in the table have been provided by the authors.
## Chapter Notes
Christina Lam is a board-certified clinical geneticist and medical biochemical geneticist. After completion of her pediatrics and genetics residency at UCLA and her medical biochemical genetics and clinical research fellowship at the National Institutes of Health, she joined the faculty at the University of Washington in Seattle, Washington, practicing medical biochemical genetics mostly at Seattle Children's Hospital. She received her MD from the David Geffen School of Medicine at UCLA in 2007. She is currently an Assistant Professor of Pediatrics at the University of Washington.
Donna Krasnewich is a board-certified clinical biochemical geneticist and pediatrician. She trained at Wayne State University School of Medicine in Detroit, Michigan, and received her MD and PhD in pharmacology in 1986. After completing her fellowship in genetics at the National Institutes of Health (NIH), she joined the faculty of the National Human Genome Research Institutes (NHGRI) at NIH where she saw children with developmental delay and congenital disorders of glycosylation. In 2009 she moved to the National Institute of General Medical Sciences where she is a Program Director in the Division of Genetics.
Our thanks to all the individuals with CDG and their families, who have shared their important stories with us. In addition, we are grateful to medical teams who have cared for individuals with CDG and added critical information to our knowledge base. Lastly, we appreciate the CDG advocacy group
Christina Lam, MD (2021-present)Susan E Sparks, MD, PhD; Sanofi Genzyme (2005-2021)Donna M Krasnewich, MD, PhD (2005-present)
20 May 2021 (sw) Comprehensive update posted live
29 October 2015 (me) Comprehensive update posted live
21 April 2011 (me) Comprehensive update posted live
8 July 2008 (me) Comprehensive update posted live
15 August 2005 (me) Review posted live
27 February 2004 (dk) Original submission
• 20 May 2021 (sw) Comprehensive update posted live
• 29 October 2015 (me) Comprehensive update posted live
• 21 April 2011 (me) Comprehensive update posted live
• 8 July 2008 (me) Comprehensive update posted live
• 15 August 2005 (me) Review posted live
• 27 February 2004 (dk) Original submission
## Author Notes
Christina Lam is a board-certified clinical geneticist and medical biochemical geneticist. After completion of her pediatrics and genetics residency at UCLA and her medical biochemical genetics and clinical research fellowship at the National Institutes of Health, she joined the faculty at the University of Washington in Seattle, Washington, practicing medical biochemical genetics mostly at Seattle Children's Hospital. She received her MD from the David Geffen School of Medicine at UCLA in 2007. She is currently an Assistant Professor of Pediatrics at the University of Washington.
Donna Krasnewich is a board-certified clinical biochemical geneticist and pediatrician. She trained at Wayne State University School of Medicine in Detroit, Michigan, and received her MD and PhD in pharmacology in 1986. After completing her fellowship in genetics at the National Institutes of Health (NIH), she joined the faculty of the National Human Genome Research Institutes (NHGRI) at NIH where she saw children with developmental delay and congenital disorders of glycosylation. In 2009 she moved to the National Institute of General Medical Sciences where she is a Program Director in the Division of Genetics.
## Acknowledgments
Our thanks to all the individuals with CDG and their families, who have shared their important stories with us. In addition, we are grateful to medical teams who have cared for individuals with CDG and added critical information to our knowledge base. Lastly, we appreciate the CDG advocacy group
## Author History
Christina Lam, MD (2021-present)Susan E Sparks, MD, PhD; Sanofi Genzyme (2005-2021)Donna M Krasnewich, MD, PhD (2005-present)
## Revision History
20 May 2021 (sw) Comprehensive update posted live
29 October 2015 (me) Comprehensive update posted live
21 April 2011 (me) Comprehensive update posted live
8 July 2008 (me) Comprehensive update posted live
15 August 2005 (me) Review posted live
27 February 2004 (dk) Original submission
• 20 May 2021 (sw) Comprehensive update posted live
• 29 October 2015 (me) Comprehensive update posted live
• 21 April 2011 (me) Comprehensive update posted live
• 8 July 2008 (me) Comprehensive update posted live
• 15 August 2005 (me) Review posted live
• 27 February 2004 (dk) Original submission
## References
## Literature Cited
N-linked glycans are synthesized by adding individual charged sugars in a specific order to the growing multi-sugar structure, or oligosaccharide. Phosphomannomutase 2 (PMM2) is required for synthesis of one of these charged sugars, mannose-1-phosphate (man-1-P) from mannose-6-phosphate (man-6-P). Without adequate pools of man-1-P (as a result of decreased activity of PMM2), synthesis of complete N-linked glycans will be affected. The early steps of this complex multistep pathway occur in the endoplasmic reticulum, followed by completion of the synthesis after the growing structure is transferred to the Golgi.
|
[
"S Akaboshi, K Ohno, K Takeshita. Neuroradiological findings in the carbohydrate-deficient glycoprotein syndrome.. Neuroradiology 1995;37:491-5",
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"J Jaeken, T Hennet, G Matthijs, HH Freeze. CDG nomenclature: time for a change!. Biochim Biophys Acta. 2009;1792:825-6",
"J Jaeken, D Lefeber, G Matthijs. Clinical utility gene card for: Phosphomannomutase 2 deficiency.. Eur J Hum Genet. 2014;22",
"J Jaeken, G Matthijs. Congenital disorders of glycosylation.. Annu Rev Genomics Hum Genet 2001;2:129-51",
"H Jensen, S Kjaergaard, F Klie, HU Moller. Ophthalmic manifestations of congenital disorder of glycosylation type 1a.. Ophthalmic Genet 2003;24:81-8",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
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"D Krasnewich, K O'Brien, S Sparks. Clinical features in adults with congenital disorders of glycosylation type Ia (CDG-Ia).. Am J Med Genet 2007;145C:302-6",
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"C Marco-Marín, JM Escamilla-Honrubia, JL Llácer, M Seri, E Panza, V. Δ Rubio. 1-Pyrroline-5-carboxylate synthetase deficiency: an emergent multifaceted urea cycle-related disorder.. J Inherit Metab Dis. 2020;43:657-70",
"E Marklová, Z Albahri. Screening and diagnosis of congenital disorders of glycosylation.. Clin Chim Acta. 2007;385:6-20",
"T Marquardt, J Denecke. Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies.. Eur J Pediatr 2003;162:359-79",
"T Marquardt, G Hulskamp, J Gehrmann, V Debus, E Harms, HG Kehl. Severe transient myocardial ischaemia caused by hypertrophic cardiomyopathy in a patient with congenital disorder of glycosylation type Ia.. Eur J Pediatr 2002;161:524-7",
"G Matthijs, E Schollen, C Bjursell, A Erlandson, H Freeze, F Imtiaz, S Kjaergaard, T Martinsson, M Schwartz, N Seta, S Vuillaumier-Barrot, V Westphal, B Winchester. Mutations in PMM2 that cause congenital disorders of glycosylation, type Ia (CDG-Ia).. Hum Mutat 2000;16:386-94",
"G Matthijs, E Schollen, L Heykants, S Grunewald. Phosphomannomutase deficiency: the molecular basis of the classical Jaeken syndrome (CDGS type Ia).. Mol Genet Metab 1999;68:220-6",
"G Matthijs, E Schollen, E Van Schaftingen, JJ Cassiman, J Jaeken. Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient glycoprotein syndrome type 1A.. Am J Hum Genet 1998;62:542-50",
"BS Miller, HH Freeze. New disorders in carbohydrate metabolism: congenital disorders of glycosylation and their impact on the endocrine system.. Rev Endocr Metab Disord 2003;4:103-13",
"BS Miller, MJ Khosravi, MC Patterson, CA Conover. IGF system in children with congenital disorders of glycosylation.. Clin Endocrinol (Oxf) 2009;70:892-7",
"M Mohamed, M Theodore, H Claahsen-van der Grinten, AE van Herwaarden, K Huijben, L van Dongen, D Kouwenberg, DJ Lefeber, RA Wevers, E Morava. Thyroid function in PMM2-CDG: diagnostic approach and proposed management.. Mol Genet Metab. 2012;105:681-3",
"ML Monin, C Mignot, P De Lonlay, B Héron, A Masurel, M Mathieu-Dramard, C Lenaerts, C Thauvin, M Gérard, E Roze, A Jacquette, P Charles, C de Baracé, V Drouin-Garraud, P Khau Van Kien, V Cormier-Daire, M Mayer, H Ogier, A Brice, N Seta, D Héron. 29 French adult patients with PMM2-congenital disorder of glycosylation: outcome of the classical pediatric phenotype and depiction of a late-onset phenotype.. Orphanet J Rare Dis. 2014;9:207",
"E Morava, HN Wosik, J Sykut-Cegielska, M Adamowicz, M Guillard, RA Wevers, DJ Lefeber, JR Cruysberg. Ophthalmological abnormalities in children with congenital disorders of glycosylation type I.. Br J Ophthalmol 2009;93:350-4",
"C Pancho, A Garcia-Cazorla, V Varea, R Artuch, I Ferrer, MA Vilaseca, P Briones, J Campistol. Congenital disorder of glycosylation type Ia revealed by hypertransaminasemia and failure to thrive in a young boy with normal development.. J Pediatr Gastroenterol Nutr. 2005;40:230-2",
"JH Park, A Zühlsdorf, Y Wada, C Roll, S Rust, I Du Chesne, M Grüneberg, J Reunert, T Marquardt. The novel transferrin E592A variant impairs the diagnostics of congenital disorders of glycosylation.. Clin Chim Acta 2014;436:135-9",
"B Pérez, P Briones, D Quelhas, R Artuch, AI Vega, E Quintana, L Gort, MJ Ecay, G Matthijs, M Ugarte, C Pérez-Cerdá. The molecular landscape of phosphomannose mutase deficiency in Iberian peninsula: identification of 15 population-specific mutations.. JIMD Rep 2011;1:117-23",
"B Pérez-Dueñas, A García-Cazorla, M Pineda, P Poo, J Campistol, V Cusí, E Schollen, G Matthijs, S Grunewald, P Briones, C Pérez-Cerdá, R Artuch, MA Vilaseca. Long-term evolution of eight Spanish patients with CDG type Ia: typical and atypical manifestations.. Eur J Paediatr Neurol. 2009;13:444-51",
"V Peters, JM Penzien, G Reiter, C Korner, R Hackler, B Assmann, J Fang, JR Schaefer, GF Hoffmann, PH Heidemann. Congenital disorder of glycosylation IId (CDG-IId) -- a new entity: clinical presentation with Dandy-Walker malformation and myopathy.. Neuropediatrics 2002;33:27-32",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"S Romano, F Bajolle, V Valayannopoulos, S Lyonnet, V Colomb, C de Baracé, P Vouhe, P Pouard, S Vuillaumier-Barrot, T Dupré, Y de Keyzer, D Sidi, N Seta, D Bonnet, P de Lonlay. Conotruncal heart defects in three patients with congenital disorder of glycosylation type Ia (CDG Ia).. J Med Genet. 2009;46:287-8",
"V Sanz-Nebot, E Balaguer, F Benavente, C Neusub, J Barbosa. Characterization of transferrin glycoforms in human serum by CE-UV and CE-ESI-MS.. Electrophoresis 2007;28:1949-57",
"SM Schade van Westrum, PJ Nederkoorn, PR Schuurman, T Vulsma, M Duran, BT Poll-The. Skeletal dysplasia and myelopathy in congenital disorder of glycosylation type IA.. J Pediatr 2006;148:115-7",
"M Schiff, C Roda, ML Monin, A Arion, M Barth, N Bednarek, M Bidet, C Bloch, N Boddaert, D Borgel, A Brassier, A Brice, A Bruneel, R Buissonniere, B Chabrol, MC Chevalier, V Cormier-Daire, C De Barace, E De Maistre, A De Saint-Martin, N Dorison, V Drouin-Garraud, T Dupre, B Echenne, P Edery, F Feillet, I Fontan, C Francannet, F Labarthe, C Gitiaux, D Heron, M Hully, S Lamoureux, D Coignard, C Mignot, G Morin, T Pascreau, O Pincemaille, M Polak, A Roubertie, CA Thauvin-Robinet, G Viot, S Vuillaumier-Barrot, N Seta, P De Lonlay. Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature.. J Med Genet. 2017;54:843-51",
"KL Schoffer, JD O'Sullivan, J McGill. Congenital disorder of glycosylation type Ia presenting as early-onset cerebellar ataxia in an adult.. Mov Disord. 2006;21:869-72",
"E Schollen, L Keldermans, F Foulquier, P Briones, A Chabas, F Sanchez-Valverde, M Adamowicz, E Pronicka, R Wevers, G Matthijs. Characterization of two unusual truncating PMM2 mutations in two CDG-Ia patients.. Mol Genet Metab 2007;90:408-13",
"E Schollen, S Kjaergaard, E Legius, M Schwartz, G. Matthijs. Lack of Hardy-Weinberg equilibrium for the most prevalent PMM2 mutation in CDG-Ia (congenital disorders of glycosylation type Ia).. Eur J Hum Genet. 2000;8:367-71",
"E Schollen, S Kjaergaard, T Martinsson, S Vuillaumier-Barrot, M Dunoe, L Keldermans, N Seta, G Matthijs. Increased recurrence risk in congenital disorders of glycosylation type Ia (CDG-Ia) due to a transmission ratio distortion.. J Med Genet 2004;41:877-80",
"E Schollen, E Pardon, L Heykants, J Renard, NA Doggett, DF Callen, JJ Cassiman, G Matthijs. Comparative analysis of the phosphomannomutase genes PMM1, PMM2 and PMM2psi: the sequence variation in the processed pseudogene is a reflection of the mutations found in the functional gene.. Hum Mol Genet 1998;7:157-64",
"B Shanti, M Silink, K Bhattacharya, NJ Howard, K Carpenter, M Fietz, P Clayton, J Christodoulou. Congenital disorder of glycosylation type Ia: Heterogeneity I the clinical presentation from multivisceral failure to hyperinsulinaemic hypoglycaemia as leading symptoms in three infants with phosphomannomutase deficiency.. J Inherit Metab Dis. 2009;32:S241-51",
"MD Sinha, C Horsfield, D Komaromy, CJ Booth, MP Champion. Congenital disorders of glycosylation: a rare cause of nephrotic syndrome.. Nephrol Dial Transplant 2009;24:2591-4",
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"RT Starosta, S Boyer, S Tahata, K Raymond, HE Lee, L Wolfe, C Lam, AC Edmondson, IVD Schwartz, E Morava. Liver manifestations in a cohort of 39 patients with congenital disorders of glycosylation: pin-pointing the characteristics of liver injury and proposing recommendations for follow-up.. Orphanet J Rare Dis. 2021;16:20",
"H Stefanits, V Konstantopoulou, M Kuess, I Milenkovic, C Matula. Initial diagnosis of the congenital disorder of glycosylation PMM2-CDG (CDG1a) in a 4-year-old girl after neurosurgical intervention for cerebral hemorrhage.. J Neurosurg Pediatr. 2014;14:546-9",
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"JM van de Kamp, DJ Lefeber, GJ Ruijter, SJ Steggerda, NS den Hollander, SM Willems, G Matthijs, BJ Poorthuis, RA Wevers. Congenital disorders of glycosylation type Ia presenting with hydrops fetalis.. J Med Genet 2007;44:277-80",
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"V Westphal, S Kjaergaard, E Schollen, K Martens, S Grunewald, M Schwartz, G Matthijs, HH Freeze. A frequent mild mutation in ALG6 may exacerbate the clinical severity of patients with congenital disorder of glycosylation Ia (CDG-Ia) caused by phosphomannomutase deficiency.. Hum Mol Genet. 2002;11:599-604",
"DF Wolthuis, MC Janssen, D Cassiman, DJ Lefeber, E Morava. Defining the phenotype and diagnostic considerations in adults with congenital disorders of N-linked glycosylation.. Expert Rev Mol Diagn. 2014;14:217-24",
"A Zühlsdorf, JH Park, Y Wada, S Rust, J Reunert, I DuChesne, M Grüneberg, T Marquardt. Transferrin variants: pitfalls in the diagnostics of congenital disorders of glycosylation.. Clin Biochem. 2015;48:11-13"
] |
15/8/2005
|
20/5/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
cdg
|
cdg
|
[
"Carbohydrate-Deficient Glycoprotein Syndromes",
"CDG Syndromes",
"CDG Syndromes",
"Carbohydrate-Deficient Glycoprotein Syndromes",
"PMM2-CDG",
"Alpha-1,2-mannosyltransferase ALG9",
"Alpha-1,3/1,6-mannosyltransferase ALG2",
"Alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase",
"Beta-1,4-galactosyltransferase 1",
"Chitobiosyldiphosphodolichol beta-mannosyltransferase",
"CMP-sialic acid transporter",
"Conserved oligomeric Golgi complex subunit 1",
"Conserved oligomeric Golgi complex subunit 2",
"Conserved oligomeric Golgi complex subunit 4",
"Conserved oligomeric Golgi complex subunit 5",
"Conserved oligomeric Golgi complex subunit 6",
"Conserved oligomeric Golgi complex subunit 7",
"Conserved oligomeric Golgi complex subunit 8",
"Dehydrodolichyl diphosphate synthase complex subunit DHDDS",
"Dolichol kinase",
"Dolichol phosphate-mannose biosynthesis regulatory protein",
"Dolichol-phosphate mannosyltransferase subunit 1",
"Dolichol-phosphate mannosyltransferase subunit 3",
"Dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase",
"Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase",
"Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 48 kDa subunit",
"Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit MAGT1",
"Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit STT3A",
"Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit STT3B",
"Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit TUSC3",
"Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase",
"Dol-P-Man:Man(7)GlcNAc(2)-PP-Dol alpha-1,6-mannosyltransferase",
"Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase",
"GDP-fucose transporter 1",
"GDP-Man:Man(3)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase",
"Man(5)GlcNAc(2)-PP-dolichol translocation protein RFT1",
"Mannose-1-phosphate guanylyltransferase regulatory subunit alpha",
"Mannose-6-phosphate isomerase",
"Mannose-P-dolichol utilization defect 1 protein",
"Mannosyl-oligosaccharide glucosidase",
"Phosphoacetylglucosamine mutase",
"Phosphoglucomutase-1",
"Phosphomannomutase 2",
"Polyprenal reductase",
"Putative divalent cation/proton antiporter TMEM165",
"Translocon-associated protein subunit delta",
"UDP-galactose translocator",
"UDP-N-acetylglucosamine transferase subunit ALG13",
"UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferase",
"ALG1",
"ALG11",
"ALG12",
"ALG13",
"ALG2",
"ALG3",
"ALG6",
"ALG8",
"ALG9",
"B4GALT1",
"COG1",
"COG2",
"COG4",
"COG5",
"COG6",
"COG7",
"COG8",
"DDOST",
"DHDDS",
"DOLK",
"DPAGT1",
"DPM1",
"DPM2",
"DPM3",
"GMPPA",
"MAGT1",
"MAN1B1",
"MGAT2",
"MOGS",
"MPDU1",
"MPI",
"PGM1",
"PGM3",
"PMM2",
"RFT1",
"SLC35A1",
"SLC35A2",
"SLC35C1",
"SRD5A3",
"SSR4",
"STT3A",
"STT3B",
"TMEM165",
"TUSC3",
"Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview",
"Overview"
] |
Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview
|
Susan E Sparks, Donna M Krasnewich
|
Summary Many human disorders of glycosylation pathways have now been identified; they include defects in synthetic pathways for N-linked oligosaccharides, O-linked oligosaccharides, shared substrates, glycophosphatidylinositol (GPI) anchors, and dolichols. This overview will focus on disorders of the N-linked glycan synthetic pathway and some disorders that overlap this metabolic network (multiple-pathway disorders). The purpose of this overview is to: Describe the Review the Provide an Inform (when possible) Inform
|
## Clinical Characteristics of Congenital Disorders of Glycosylation
CDG-N-linked are a group of disorders caused by the defective synthesis of N-linked oligosaccharides, sugars linked together in a specific pattern and attached to proteins and lipids (N-linked glycans link to the amide group of asparagine via an N-acetylglucosamine residue) [
Almost all types of congenital disorders of glycosylation (CDG) present in infancy. Because of the important biologic functions of the oligosaccharides in both glycoproteins and glycolipids, incorrect synthesis of these compounds results in broad multisystem clinical manifestations [
For many types of CDG, the phenotype is not completely known because only a few affected individuals have been reported.
Note: In 2009 the nomenclature for all types of CDG was changed to include the official gene symbol (not italicized) followed by "-CDG." If the type has a known letter name, it is added in parentheses as shown for CDG type 1a; new nomenclature: PMM2-CDG (
The infantile multisystem stage, the most commonly seen stage, is characterized by failure to thrive, inverted nipples, abnormal subcutaneous fat distribution, and cerebellar hypoplasia, in combination with facial dysmorphism and developmental delay.
Neuroimaging may demonstrate the following:
An enlarged cisterna magna and superior cerebellar cistern in late infancy to early childhood
In 13 affected individuals, the extent of cerebellar involvement on brain imaging correlated with functional and cognitive assessments [
Occasionally both infratentorial and supratentorial changes compatible with atrophy
Dandy-Walker malformations and small white matter cysts
Myelination that varies from normal to insufficient or delayed maturation
Areas of ischemia or edema followed by focal necrosis in those who have had a recent stroke-like episode [
The clinical presentation may be milder than in PMM2-CDG (
Rare features have included brachydactyly, deep vein thrombosis, pseudotumor cerebri with normal brain MRI, pubertal abnormalities including hyperandrogenism with virilization, and retinal degeneration [
A pair of sibs who had a milder presentation with pseudo-gynecomastia, hypotonia, intellectual disability, and ataxia were described [
Note: Biallelic pathogenic variants in
Note: Biallelic pathogenic variants in
• An enlarged cisterna magna and superior cerebellar cistern in late infancy to early childhood
• In 13 affected individuals, the extent of cerebellar involvement on brain imaging correlated with functional and cognitive assessments [
• Occasionally both infratentorial and supratentorial changes compatible with atrophy
• Dandy-Walker malformations and small white matter cysts
• Myelination that varies from normal to insufficient or delayed maturation
• Areas of ischemia or edema followed by focal necrosis in those who have had a recent stroke-like episode [
• The clinical presentation may be milder than in PMM2-CDG (
• Rare features have included brachydactyly, deep vein thrombosis, pseudotumor cerebri with normal brain MRI, pubertal abnormalities including hyperandrogenism with virilization, and retinal degeneration [
## Clinical Manifestations
Almost all types of congenital disorders of glycosylation (CDG) present in infancy. Because of the important biologic functions of the oligosaccharides in both glycoproteins and glycolipids, incorrect synthesis of these compounds results in broad multisystem clinical manifestations [
For many types of CDG, the phenotype is not completely known because only a few affected individuals have been reported.
Note: In 2009 the nomenclature for all types of CDG was changed to include the official gene symbol (not italicized) followed by "-CDG." If the type has a known letter name, it is added in parentheses as shown for CDG type 1a; new nomenclature: PMM2-CDG (
The infantile multisystem stage, the most commonly seen stage, is characterized by failure to thrive, inverted nipples, abnormal subcutaneous fat distribution, and cerebellar hypoplasia, in combination with facial dysmorphism and developmental delay.
Neuroimaging may demonstrate the following:
An enlarged cisterna magna and superior cerebellar cistern in late infancy to early childhood
In 13 affected individuals, the extent of cerebellar involvement on brain imaging correlated with functional and cognitive assessments [
Occasionally both infratentorial and supratentorial changes compatible with atrophy
Dandy-Walker malformations and small white matter cysts
Myelination that varies from normal to insufficient or delayed maturation
Areas of ischemia or edema followed by focal necrosis in those who have had a recent stroke-like episode [
The clinical presentation may be milder than in PMM2-CDG (
Rare features have included brachydactyly, deep vein thrombosis, pseudotumor cerebri with normal brain MRI, pubertal abnormalities including hyperandrogenism with virilization, and retinal degeneration [
A pair of sibs who had a milder presentation with pseudo-gynecomastia, hypotonia, intellectual disability, and ataxia were described [
Note: Biallelic pathogenic variants in
Note: Biallelic pathogenic variants in
• An enlarged cisterna magna and superior cerebellar cistern in late infancy to early childhood
• In 13 affected individuals, the extent of cerebellar involvement on brain imaging correlated with functional and cognitive assessments [
• Occasionally both infratentorial and supratentorial changes compatible with atrophy
• Dandy-Walker malformations and small white matter cysts
• Myelination that varies from normal to insufficient or delayed maturation
• Areas of ischemia or edema followed by focal necrosis in those who have had a recent stroke-like episode [
• The clinical presentation may be milder than in PMM2-CDG (
• Rare features have included brachydactyly, deep vein thrombosis, pseudotumor cerebri with normal brain MRI, pubertal abnormalities including hyperandrogenism with virilization, and retinal degeneration [
## CDG N-Linked
The infantile multisystem stage, the most commonly seen stage, is characterized by failure to thrive, inverted nipples, abnormal subcutaneous fat distribution, and cerebellar hypoplasia, in combination with facial dysmorphism and developmental delay.
Neuroimaging may demonstrate the following:
An enlarged cisterna magna and superior cerebellar cistern in late infancy to early childhood
In 13 affected individuals, the extent of cerebellar involvement on brain imaging correlated with functional and cognitive assessments [
Occasionally both infratentorial and supratentorial changes compatible with atrophy
Dandy-Walker malformations and small white matter cysts
Myelination that varies from normal to insufficient or delayed maturation
Areas of ischemia or edema followed by focal necrosis in those who have had a recent stroke-like episode [
The clinical presentation may be milder than in PMM2-CDG (
Rare features have included brachydactyly, deep vein thrombosis, pseudotumor cerebri with normal brain MRI, pubertal abnormalities including hyperandrogenism with virilization, and retinal degeneration [
A pair of sibs who had a milder presentation with pseudo-gynecomastia, hypotonia, intellectual disability, and ataxia were described [
Note: Biallelic pathogenic variants in
Note: Biallelic pathogenic variants in
• An enlarged cisterna magna and superior cerebellar cistern in late infancy to early childhood
• In 13 affected individuals, the extent of cerebellar involvement on brain imaging correlated with functional and cognitive assessments [
• Occasionally both infratentorial and supratentorial changes compatible with atrophy
• Dandy-Walker malformations and small white matter cysts
• Myelination that varies from normal to insufficient or delayed maturation
• Areas of ischemia or edema followed by focal necrosis in those who have had a recent stroke-like episode [
• The clinical presentation may be milder than in PMM2-CDG (
• Rare features have included brachydactyly, deep vein thrombosis, pseudotumor cerebri with normal brain MRI, pubertal abnormalities including hyperandrogenism with virilization, and retinal degeneration [
## Multiple-Pathway Disorders
## Causes of Congenital Disorders of Glycosylation
Forty-two different enzymes in the N-linked oligosaccharide synthetic pathway or interactive pathways are currently recognized to be deficient in each of the types of CDG-N-linked or among the multiple-pathway disorders (see
Molecular Genetics of Congenital Disorders of Glycosylation
AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked inheritance
The nomenclature used for CDG types includes a Roman numeral, I or II, and a letter (a-z) [
Proportion of CDG types as reported in
Data are compiled from the following standard references: gene from
The prevalence of PMM2-CDG (
## Evaluation Strategy
Results of such testing may reveal the following:
Note: (1) The diagnostic validity of analysis of serum transferrin glycoforms before age three weeks is controversial [
The type of CDG is established in a proband by the identification of biallelic pathogenic (or likely pathogenic) variants (or a hemizygous pathogenic variant in a male with an X-linked CGD) in one of the 44 known CDG-associated genes (see
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
If previous biochemical testing is not diagnostic for or suggestive of a particular CDG, molecular testing approaches most often involve use of a
Note: Single-gene testing, such as sequencing of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
## Molecular Genetic Testing
The type of CDG is established in a proband by the identification of biallelic pathogenic (or likely pathogenic) variants (or a hemizygous pathogenic variant in a male with an X-linked CGD) in one of the 44 known CDG-associated genes (see
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
If previous biochemical testing is not diagnostic for or suggestive of a particular CDG, molecular testing approaches most often involve use of a
Note: Single-gene testing, such as sequencing of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
## Management
Baseline renal ultrasound should be performed on all affected children at the time of diagnosis [
While proteinuria in affected children is extremely rare, routine urinalysis to evaluate for proteinuria is recommended after diagnosis. Follow-up urinalysis should be considered in the first three years of life or if clinical signs indicate.
MPI-CDG (
In the first reported case, mannose normalized hypoproteinemia and coagulation defects and rapidly improved the protein-losing enteropathy and hypoglycemia [
In two children with MPI-CDG (
Recurrent episodes of thromboembolism and consumptive coagulopathy did not recur in an individual with MPI-CDG (
For some individuals with MPI-CDG (
A woman age 28 years with MPI-CDG (
Because infants with CDG have more limited reserves than their peers, parents should have a low threshold for evaluation by a physician for prolonged fever, vomiting, or diarrhea. Aggressive intervention with antipyretics, antibiotics (if warranted), and hydration may prevent stroke-like episodes, seizures in children with potentially lower seizure threshold as well as the morbidity associated with the "infantile catastrophic phase."
Assessment by a physician with attention to overall health and possible need for referral for speech, occupational, and physical therapy
Eye examination
Liver function tests; thyroid panel; serum concentrations of the clotting factors protein C, protein S, factor IX, and antithrombin III
Periodic assessment of bleeding and clotting parameters by a hematologist
Follow up with an orthopedist when scoliosis becomes evident
Acetominophen and other agents metabolized by the liver should be used with caution.
It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment (in the treatable forms of N-linked CDG) and those who require developmental monitoring and medical management.
Evaluations can include:
Molecular genetic testing if the pathogenic variant(s) in the family are known;
Serum transferrin analysis if the pathogenic variant(s) in the family are not known and transferrin was abnormal in the proband.
See
In one individual with SLC35C1-CDG (
Search
• Baseline renal ultrasound should be performed on all affected children at the time of diagnosis [
• While proteinuria in affected children is extremely rare, routine urinalysis to evaluate for proteinuria is recommended after diagnosis. Follow-up urinalysis should be considered in the first three years of life or if clinical signs indicate.
• Baseline renal ultrasound should be performed on all affected children at the time of diagnosis [
• While proteinuria in affected children is extremely rare, routine urinalysis to evaluate for proteinuria is recommended after diagnosis. Follow-up urinalysis should be considered in the first three years of life or if clinical signs indicate.
• Baseline renal ultrasound should be performed on all affected children at the time of diagnosis [
• While proteinuria in affected children is extremely rare, routine urinalysis to evaluate for proteinuria is recommended after diagnosis. Follow-up urinalysis should be considered in the first three years of life or if clinical signs indicate.
• In the first reported case, mannose normalized hypoproteinemia and coagulation defects and rapidly improved the protein-losing enteropathy and hypoglycemia [
• In two children with MPI-CDG (
• Recurrent episodes of thromboembolism and consumptive coagulopathy did not recur in an individual with MPI-CDG (
• For some individuals with MPI-CDG (
• A woman age 28 years with MPI-CDG (
• Assessment by a physician with attention to overall health and possible need for referral for speech, occupational, and physical therapy
• Eye examination
• Liver function tests; thyroid panel; serum concentrations of the clotting factors protein C, protein S, factor IX, and antithrombin III
• Periodic assessment of bleeding and clotting parameters by a hematologist
• Follow up with an orthopedist when scoliosis becomes evident
• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Serum transferrin analysis if the pathogenic variant(s) in the family are not known and transferrin was abnormal in the proband.
## Treatment of Manifestations
Baseline renal ultrasound should be performed on all affected children at the time of diagnosis [
While proteinuria in affected children is extremely rare, routine urinalysis to evaluate for proteinuria is recommended after diagnosis. Follow-up urinalysis should be considered in the first three years of life or if clinical signs indicate.
• Baseline renal ultrasound should be performed on all affected children at the time of diagnosis [
• While proteinuria in affected children is extremely rare, routine urinalysis to evaluate for proteinuria is recommended after diagnosis. Follow-up urinalysis should be considered in the first three years of life or if clinical signs indicate.
• Baseline renal ultrasound should be performed on all affected children at the time of diagnosis [
• While proteinuria in affected children is extremely rare, routine urinalysis to evaluate for proteinuria is recommended after diagnosis. Follow-up urinalysis should be considered in the first three years of life or if clinical signs indicate.
• Baseline renal ultrasound should be performed on all affected children at the time of diagnosis [
• While proteinuria in affected children is extremely rare, routine urinalysis to evaluate for proteinuria is recommended after diagnosis. Follow-up urinalysis should be considered in the first three years of life or if clinical signs indicate.
## Prevention of Primary Manifestations
MPI-CDG (
In the first reported case, mannose normalized hypoproteinemia and coagulation defects and rapidly improved the protein-losing enteropathy and hypoglycemia [
In two children with MPI-CDG (
Recurrent episodes of thromboembolism and consumptive coagulopathy did not recur in an individual with MPI-CDG (
For some individuals with MPI-CDG (
A woman age 28 years with MPI-CDG (
• In the first reported case, mannose normalized hypoproteinemia and coagulation defects and rapidly improved the protein-losing enteropathy and hypoglycemia [
• In two children with MPI-CDG (
• Recurrent episodes of thromboembolism and consumptive coagulopathy did not recur in an individual with MPI-CDG (
• For some individuals with MPI-CDG (
• A woman age 28 years with MPI-CDG (
## Prevention of Secondary Complications
Because infants with CDG have more limited reserves than their peers, parents should have a low threshold for evaluation by a physician for prolonged fever, vomiting, or diarrhea. Aggressive intervention with antipyretics, antibiotics (if warranted), and hydration may prevent stroke-like episodes, seizures in children with potentially lower seizure threshold as well as the morbidity associated with the "infantile catastrophic phase."
## Surveillance
Assessment by a physician with attention to overall health and possible need for referral for speech, occupational, and physical therapy
Eye examination
Liver function tests; thyroid panel; serum concentrations of the clotting factors protein C, protein S, factor IX, and antithrombin III
Periodic assessment of bleeding and clotting parameters by a hematologist
Follow up with an orthopedist when scoliosis becomes evident
• Assessment by a physician with attention to overall health and possible need for referral for speech, occupational, and physical therapy
• Eye examination
• Liver function tests; thyroid panel; serum concentrations of the clotting factors protein C, protein S, factor IX, and antithrombin III
• Periodic assessment of bleeding and clotting parameters by a hematologist
• Follow up with an orthopedist when scoliosis becomes evident
## Agents/Circumstances to Avoid
Acetominophen and other agents metabolized by the liver should be used with caution.
## Evaluation of Relatives at Risk
It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment (in the treatable forms of N-linked CDG) and those who require developmental monitoring and medical management.
Evaluations can include:
Molecular genetic testing if the pathogenic variant(s) in the family are known;
Serum transferrin analysis if the pathogenic variant(s) in the family are not known and transferrin was abnormal in the proband.
See
• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Serum transferrin analysis if the pathogenic variant(s) in the family are not known and transferrin was abnormal in the proband.
## Therapies Under Investigation
In one individual with SLC35C1-CDG (
Search
## Genetic Counseling
Most congenital disorders of N-linked glycosylation and multiple pathway (CDG-N-linked) are inherited in an autosomal recessive manner. MGAT1-CDG, ALG13-CDG, SLC35A2-CDG, and SSR4-CDG are inherited in an X-linked manner.
The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant).
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. See, however,
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Adults with CDG – except for those with MPI-CDG (
The offspring of an individual with MPI-CDG (
The father of a male with MAGT1-CDG, ALG13-CDG, SLC35A2-CDG, or SSR4-CDG will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism.
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a
If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers. There have not been any reported cases of a heterozygous female (carrier) being affected.
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism.
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the pathogenic variant(s) have been identified in the family, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for a congenital disorder of N-linked glycosylation or multiple pathway are possible.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. See, however,
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Adults with CDG – except for those with MPI-CDG (
• The offspring of an individual with MPI-CDG (
• The father of a male with MAGT1-CDG, ALG13-CDG, SLC35A2-CDG, or SSR4-CDG will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a
• If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers. There have not been any reported cases of a heterozygous female (carrier) being affected.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Most congenital disorders of N-linked glycosylation and multiple pathway (CDG-N-linked) are inherited in an autosomal recessive manner. MGAT1-CDG, ALG13-CDG, SLC35A2-CDG, and SSR4-CDG are inherited in an X-linked manner.
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant).
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. See, however,
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Adults with CDG – except for those with MPI-CDG (
The offspring of an individual with MPI-CDG (
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. See, however,
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Adults with CDG – except for those with MPI-CDG (
• The offspring of an individual with MPI-CDG (
## X-linked Inheritance – Risk to Family Members
The father of a male with MAGT1-CDG, ALG13-CDG, SLC35A2-CDG, or SSR4-CDG will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism.
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a
If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers. There have not been any reported cases of a heterozygous female (carrier) being affected.
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism.
• The father of a male with MAGT1-CDG, ALG13-CDG, SLC35A2-CDG, or SSR4-CDG will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a
• If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers. There have not been any reported cases of a heterozygous female (carrier) being affected.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the pathogenic variant(s) have been identified in the family, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for a congenital disorder of N-linked glycosylation or multiple pathway are possible.
## Resources
Canada
•
•
•
• Canada
•
## Chapter Notes
Susan Sparks is a board-certified pediatrician, clinical geneticist, and clinical biochemical geneticist. She is currently a medical director at Sanofi Genzyme. After completion of her genetics and biochemical genetics fellowship at the National Institutes of Health, she held faculty positions at Children's National Medical Center in Washington, DC, and Levine Children's Hospital at Carolinas Medical Center in Charlotte, NC. She received her MD and PhD in molecular biology and pharmacology from the Chicago Medical School in 1997 and 1999, respectively.
Donna Krasnewich is a board-certified clinical biochemical geneticist and pediatrician. She trained at Wayne State University School of Medicine in Detroit, Michigan, and received her MD and PhD in pharmacology in 1986. After completing her fellowship in genetics at the National Institutes of Health (NIH), she joined the faculty of the National Human Genome Research Institutes (NHGRI) at NIH and was the Deputy Clinical Director of NHGRI. She is currently a Program Director at NIH in the National Institute of General Medical Sciences and continues her interest in children with developmental delay and congenital disorders of glycosylation.
12 January 2017 (ma) Comprehensive update posted live
21 April 2011 (me) Comprehensive update posted live
23 June 2008 (me) Comprehensive update posted live
15 August 2005 (me) Overview posted live
27 February 2004 (dk) Original submission
• 12 January 2017 (ma) Comprehensive update posted live
• 21 April 2011 (me) Comprehensive update posted live
• 23 June 2008 (me) Comprehensive update posted live
• 15 August 2005 (me) Overview posted live
• 27 February 2004 (dk) Original submission
## Author Notes
Susan Sparks is a board-certified pediatrician, clinical geneticist, and clinical biochemical geneticist. She is currently a medical director at Sanofi Genzyme. After completion of her genetics and biochemical genetics fellowship at the National Institutes of Health, she held faculty positions at Children's National Medical Center in Washington, DC, and Levine Children's Hospital at Carolinas Medical Center in Charlotte, NC. She received her MD and PhD in molecular biology and pharmacology from the Chicago Medical School in 1997 and 1999, respectively.
Donna Krasnewich is a board-certified clinical biochemical geneticist and pediatrician. She trained at Wayne State University School of Medicine in Detroit, Michigan, and received her MD and PhD in pharmacology in 1986. After completing her fellowship in genetics at the National Institutes of Health (NIH), she joined the faculty of the National Human Genome Research Institutes (NHGRI) at NIH and was the Deputy Clinical Director of NHGRI. She is currently a Program Director at NIH in the National Institute of General Medical Sciences and continues her interest in children with developmental delay and congenital disorders of glycosylation.
## Revision History
12 January 2017 (ma) Comprehensive update posted live
21 April 2011 (me) Comprehensive update posted live
23 June 2008 (me) Comprehensive update posted live
15 August 2005 (me) Overview posted live
27 February 2004 (dk) Original submission
• 12 January 2017 (ma) Comprehensive update posted live
• 21 April 2011 (me) Comprehensive update posted live
• 23 June 2008 (me) Comprehensive update posted live
• 15 August 2005 (me) Overview posted live
• 27 February 2004 (dk) Original submission
## References
## Literature Cited
|
[] |
15/8/2005
|
12/1/2017
|
30/1/2014
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cdh-ov
|
cdh-ov
|
[
"AT-rich interactive domain-containing protein 1A",
"AT-rich interactive domain-containing protein 1B",
"Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe",
"Chromodomain-helicase-DNA-binding protein 7",
"Collagen alpha-1(III) chain",
"COUP transcription factor 2",
"Cyclin-dependent kinase inhibitor 1C",
"Cytochrome c oxidase subunit 7B, mitochondrial",
"Delta-like protein 3",
"Double-strand-break repair protein rad21 homolog",
"E3 ubiquitin-protein ligase RLIM",
"Ephrin-B1",
"Extracellular matrix organizing protein FRAS1",
"Fibrillin-1",
"Fibroblast growth factor receptor 2",
"FRAS1-related extracellular matrix protein 2",
"Glypican-3",
"GPI ethanolamine phosphate transferase 1",
"Histone deacetylase 8",
"Histone-lysine N-methyltransferase 2D",
"Holocytochrome c-type synthase",
"Latent-transforming growth factor beta-binding protein 4",
"Low-density lipoprotein receptor-related protein 2",
"Lysine-specific demethylase 6A",
"Mesoderm posterior protein 2",
"Myelin regulatory factor",
"NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial",
"Nipped-B-like protein",
"Pogo transposable element with ZNF domain",
"Protein ripply2",
"Protein-serine O-palmitoleoyltransferase porcupine",
"Receptor for retinol uptake STRA6",
"Retinoic acid receptor beta",
"Solute carrier family 2, facilitated glucose transporter member 10",
"Structural maintenance of chromosomes protein 1A",
"Structural maintenance of chromosomes protein 3",
"SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4",
"SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1",
"SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1",
"T-box transcription factor TBX6",
"Transcription factor GATA-4",
"Transcription factor GATA-6",
"Transcription factor HES-7",
"Transcription factor SOX-11",
"Wilms tumor protein",
"Zinc finger protein ZFPM2",
"ARID1A",
"ARID1B",
"CDKN1C",
"CHD7",
"COL3A1",
"COX7B",
"DLL3",
"EFNB1",
"FBN1",
"FGFR2",
"FRAS1",
"FREM2",
"GATA4",
"GATA6",
"GPC3",
"HCCS",
"HDAC8",
"HES7",
"KDM6A",
"KMT2D",
"LFNG",
"LRP2",
"LTBP4",
"MESP2",
"MYRF",
"NDUFB11",
"NIPBL",
"NR2F2",
"PIGN",
"POGZ",
"PORCN",
"RAD21",
"RARB",
"RIPPLY2",
"RLIM",
"SLC2A10",
"SMARCA4",
"SMARCB1",
"SMARCE1",
"SMC1A",
"SMC3",
"SOX11",
"STRA6",
"TBX6",
"WT1",
"ZFPM2",
"Congenital Diaphragmatic Hernia",
"Overview"
] |
Congenital Diaphragmatic Hernia Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Mauro Longoni, Barbara R Pober, Frances A High
|
Summary The purpose of this overview is to: Describe the Review the Provide an Review Inform
|
## Clinical Characteristics of Congenital Diaphragmatic Hernia
Congenital diaphragmatic hernia (CDH) refers to a developmental defect of the formation of the diaphragm that, in most individuals, is evident at birth. CDH is characterized by: (1) incomplete formation/muscularization of the diaphragm resulting in absence or deficiency of the diaphragm, or (2) eventration resulting in elevation of a portion of the diaphragm that is thinned as a result of incomplete muscularization. The prevalence of CDH is estimated at 3-3.6/10,000 live births [
Infants with CDH often present in the neonatal period with severe respiratory distress.
Presentation after infancy, occurring in 5%-10% of affected individuals, includes respiratory distress, such as from pleural effusion due to entrapment of the bowel in the chest, or gastrointestinal distress, such as abdominal pain from chronic or intermittent intestinal obstruction. About 1% of individuals are completely asymptomatic and the defect is discovered incidentally on imaging studies [
At least 10% of individuals reherniate following initial surgical repair; the risk is considerably greater among those whose hernia repair required a prosthetic patch.
Although CDH is classified into several types, distinction among hernias can be problematic. An anatomic depiction of the normal diaphragm is presented in
Posterolateral hernias comprise approximately 80%-90% of all CDH and appear to fall into two types:
A diaphragmatic defect accompanied by an absent or extremely deficient rim of posterior and lateral musculature (see
A diaphragmatic defect with an intact rim of posterior and lateral musculature
About 85% of Bochdalek hernias occur on the left side, about 10% on the right, and approximately 5% are bilateral.
CDH can occur as either an isolated or complex anomaly:
Congenital diaphragmatic hernias are increasingly diagnosed prenatally; however, they are occasionally diagnosed in symptomatic neonates and even asymptomatic or mildly symptomatic children, teens, and adults.
Prenatal investigations by second-trimester two-dimensional (2D) ultrasound and/or MRI detect more than 60% of affected fetuses with right-sided defects and more than 80% of those with left-sided CDH [
Demonstrate abnormal positioning of the umbilical and portal veins, which are indicative of liver herniation;
Identify right-sided hernias, which can be difficult to detect on ultrasound examination because of the similar echogenicity of lung and liver.
MRI has limited benefit early in gestation.
Lung measurements in individuals with CDH are not standardized.
Survival rates and treatment protocols from different centers are not comparable.
CDH can be detected in a neonate by:
Presence of a scaphoid abdomen, diminished breath sounds ipsilateral to the side of the hernia, and displacement of the heart sounds contralateral to the hernia.
Chest radiograph shows visible bowel gas above the diaphragm accompanied by a mediastinal shift.
Rarely, older children or adults with inconspicuous congenital diaphragmatic defects can be suspected because of respiratory or gastrointestinal symptoms including chronic cough, recurrent pulmonary infections, pleural effusions, pneumonia, or dysphagia. Intestinal obstruction and volvulus may be presenting symptoms, as abnormalities in the usual intestinal rotation during fetal development are common. Finally, some individuals may be diagnosed incidentally by plain chest radiographs or other imaging procedures. In these individuals, the degree of respiratory symptoms is correlated with the degree of pulmonary hypoplasia and can be limited.
Infants with CDH often present in the neonatal period with severe respiratory distress, occasionally after a stable period of 24-48 hours followed by acute respiratory distress. Breath sounds are diminished ipsilateral to the hernia. Almost all individuals with CDH have some degree of pulmonary hypoplasia. The pathogenesis of the pulmonary hypoplasia associated with CDH appears to have both a primary component (i.e., the hypoplasia occurs independent of the diaphragm defect) and a secondary component (i.e., arising from competition for thoracic space particularly in the lung ipsilateral to the hernia). Evidence for the presence of a primary defect in lung development arises mostly from studies in animal models, some of which show that the lung hypoplasia precedes the herniation of abdominal viscera.
Infants with CDH typically require mechanical ventilation and sometimes extracorporeal membrane oxygenation (ECMO) in the newborn period. Major respiratory complications include tracheobronchomalacia, pneumothorax, and secondary lung infection (especially viral pneumonia) that could precipitate terminal respiratory failure even months after surgery. Many infants require ongoing oxygen supplementation and diuretics following surgical correction of CDH. Given the remarkable growth and recuperative capacity of the lung, these treatments can usually be discontinued within the first two years of life.
By early childhood, few children have respiratory symptoms at rest; however, formal testing in older children shows small airway obstruction and diminished blood flow on ventilation-perfusion (V-Q) scan, especially to the lung ipsilateral to the hernia. Reduced exercise tolerance can be a lifelong problem. Intermittent wheezing requiring bronchodilator use is common in people with CDH, and they are at risk for respiratory decompensation with intercurrent illness.
Abnormal pulmonary vascular development and function is a significant problem in infants with CDH. Guidelines for the diagnosis of pediatric pulmonary hypertension were set forth by the American Heart Association and American Thoracic Society [
"Failure to thrive" with growth parameters lower than than the third centile of normal is common among infants with more significant pulmonary hypoplasia and/or a more prolonged hospitalization following surgical repair of CDH. Growth failure is caused, in large part, by oral aversion and feeding difficulties (often requiring gastrostomy tube insertion for the first few years of life) and gastroesophageal reflux (frequently requiring pharmacotherapy and/or surgical fundoplication). Some infants and children require long-term high-calorie nutritional supplements.
Reporting of neurodevelopmental outcomes is complicated by lack of standardization in terms of outcomes assessed, age of assessment, and metrics used (reviewed in
Chest asymmetry is found in as many as half of individuals with CDH. Pectus deformity, most often of the excavatum type, and scoliosis (≥10° Cobb's angle) are found in approximately 25% of individuals. These musculoskeletal abnormalities occur more often following repair of large diaphragmatic defects, possibly as a result of the extra tension exerted on the chest wall during surgical repair.
Sensorineural hearing loss (SNHL) has been found in 25% of individuals with CDH and as many as 100% of individuals treated with ECMO in some series [
• A diaphragmatic defect accompanied by an absent or extremely deficient rim of posterior and lateral musculature (see
• A diaphragmatic defect with an intact rim of posterior and lateral musculature
• Demonstrate abnormal positioning of the umbilical and portal veins, which are indicative of liver herniation;
• Identify right-sided hernias, which can be difficult to detect on ultrasound examination because of the similar echogenicity of lung and liver.
• MRI has limited benefit early in gestation.
• Lung measurements in individuals with CDH are not standardized.
• Survival rates and treatment protocols from different centers are not comparable.
• Presence of a scaphoid abdomen, diminished breath sounds ipsilateral to the side of the hernia, and displacement of the heart sounds contralateral to the hernia.
• Chest radiograph shows visible bowel gas above the diaphragm accompanied by a mediastinal shift.
## Clinical Description
Congenital diaphragmatic hernia (CDH) refers to a developmental defect of the formation of the diaphragm that, in most individuals, is evident at birth. CDH is characterized by: (1) incomplete formation/muscularization of the diaphragm resulting in absence or deficiency of the diaphragm, or (2) eventration resulting in elevation of a portion of the diaphragm that is thinned as a result of incomplete muscularization. The prevalence of CDH is estimated at 3-3.6/10,000 live births [
Infants with CDH often present in the neonatal period with severe respiratory distress.
Presentation after infancy, occurring in 5%-10% of affected individuals, includes respiratory distress, such as from pleural effusion due to entrapment of the bowel in the chest, or gastrointestinal distress, such as abdominal pain from chronic or intermittent intestinal obstruction. About 1% of individuals are completely asymptomatic and the defect is discovered incidentally on imaging studies [
At least 10% of individuals reherniate following initial surgical repair; the risk is considerably greater among those whose hernia repair required a prosthetic patch.
Although CDH is classified into several types, distinction among hernias can be problematic. An anatomic depiction of the normal diaphragm is presented in
Posterolateral hernias comprise approximately 80%-90% of all CDH and appear to fall into two types:
A diaphragmatic defect accompanied by an absent or extremely deficient rim of posterior and lateral musculature (see
A diaphragmatic defect with an intact rim of posterior and lateral musculature
About 85% of Bochdalek hernias occur on the left side, about 10% on the right, and approximately 5% are bilateral.
CDH can occur as either an isolated or complex anomaly:
• A diaphragmatic defect accompanied by an absent or extremely deficient rim of posterior and lateral musculature (see
• A diaphragmatic defect with an intact rim of posterior and lateral musculature
## Establishing the Diagnosis of CDH
Congenital diaphragmatic hernias are increasingly diagnosed prenatally; however, they are occasionally diagnosed in symptomatic neonates and even asymptomatic or mildly symptomatic children, teens, and adults.
Prenatal investigations by second-trimester two-dimensional (2D) ultrasound and/or MRI detect more than 60% of affected fetuses with right-sided defects and more than 80% of those with left-sided CDH [
Demonstrate abnormal positioning of the umbilical and portal veins, which are indicative of liver herniation;
Identify right-sided hernias, which can be difficult to detect on ultrasound examination because of the similar echogenicity of lung and liver.
MRI has limited benefit early in gestation.
Lung measurements in individuals with CDH are not standardized.
Survival rates and treatment protocols from different centers are not comparable.
CDH can be detected in a neonate by:
Presence of a scaphoid abdomen, diminished breath sounds ipsilateral to the side of the hernia, and displacement of the heart sounds contralateral to the hernia.
Chest radiograph shows visible bowel gas above the diaphragm accompanied by a mediastinal shift.
Rarely, older children or adults with inconspicuous congenital diaphragmatic defects can be suspected because of respiratory or gastrointestinal symptoms including chronic cough, recurrent pulmonary infections, pleural effusions, pneumonia, or dysphagia. Intestinal obstruction and volvulus may be presenting symptoms, as abnormalities in the usual intestinal rotation during fetal development are common. Finally, some individuals may be diagnosed incidentally by plain chest radiographs or other imaging procedures. In these individuals, the degree of respiratory symptoms is correlated with the degree of pulmonary hypoplasia and can be limited.
• Demonstrate abnormal positioning of the umbilical and portal veins, which are indicative of liver herniation;
• Identify right-sided hernias, which can be difficult to detect on ultrasound examination because of the similar echogenicity of lung and liver.
• MRI has limited benefit early in gestation.
• Lung measurements in individuals with CDH are not standardized.
• Survival rates and treatment protocols from different centers are not comparable.
• Presence of a scaphoid abdomen, diminished breath sounds ipsilateral to the side of the hernia, and displacement of the heart sounds contralateral to the hernia.
• Chest radiograph shows visible bowel gas above the diaphragm accompanied by a mediastinal shift.
## Prenatal Diagnosis
Prenatal investigations by second-trimester two-dimensional (2D) ultrasound and/or MRI detect more than 60% of affected fetuses with right-sided defects and more than 80% of those with left-sided CDH [
Demonstrate abnormal positioning of the umbilical and portal veins, which are indicative of liver herniation;
Identify right-sided hernias, which can be difficult to detect on ultrasound examination because of the similar echogenicity of lung and liver.
MRI has limited benefit early in gestation.
Lung measurements in individuals with CDH are not standardized.
Survival rates and treatment protocols from different centers are not comparable.
• Demonstrate abnormal positioning of the umbilical and portal veins, which are indicative of liver herniation;
• Identify right-sided hernias, which can be difficult to detect on ultrasound examination because of the similar echogenicity of lung and liver.
• MRI has limited benefit early in gestation.
• Lung measurements in individuals with CDH are not standardized.
• Survival rates and treatment protocols from different centers are not comparable.
## Postnatal Diagnosis
CDH can be detected in a neonate by:
Presence of a scaphoid abdomen, diminished breath sounds ipsilateral to the side of the hernia, and displacement of the heart sounds contralateral to the hernia.
Chest radiograph shows visible bowel gas above the diaphragm accompanied by a mediastinal shift.
Rarely, older children or adults with inconspicuous congenital diaphragmatic defects can be suspected because of respiratory or gastrointestinal symptoms including chronic cough, recurrent pulmonary infections, pleural effusions, pneumonia, or dysphagia. Intestinal obstruction and volvulus may be presenting symptoms, as abnormalities in the usual intestinal rotation during fetal development are common. Finally, some individuals may be diagnosed incidentally by plain chest radiographs or other imaging procedures. In these individuals, the degree of respiratory symptoms is correlated with the degree of pulmonary hypoplasia and can be limited.
• Presence of a scaphoid abdomen, diminished breath sounds ipsilateral to the side of the hernia, and displacement of the heart sounds contralateral to the hernia.
• Chest radiograph shows visible bowel gas above the diaphragm accompanied by a mediastinal shift.
## Clinical Manifestations
Infants with CDH often present in the neonatal period with severe respiratory distress, occasionally after a stable period of 24-48 hours followed by acute respiratory distress. Breath sounds are diminished ipsilateral to the hernia. Almost all individuals with CDH have some degree of pulmonary hypoplasia. The pathogenesis of the pulmonary hypoplasia associated with CDH appears to have both a primary component (i.e., the hypoplasia occurs independent of the diaphragm defect) and a secondary component (i.e., arising from competition for thoracic space particularly in the lung ipsilateral to the hernia). Evidence for the presence of a primary defect in lung development arises mostly from studies in animal models, some of which show that the lung hypoplasia precedes the herniation of abdominal viscera.
Infants with CDH typically require mechanical ventilation and sometimes extracorporeal membrane oxygenation (ECMO) in the newborn period. Major respiratory complications include tracheobronchomalacia, pneumothorax, and secondary lung infection (especially viral pneumonia) that could precipitate terminal respiratory failure even months after surgery. Many infants require ongoing oxygen supplementation and diuretics following surgical correction of CDH. Given the remarkable growth and recuperative capacity of the lung, these treatments can usually be discontinued within the first two years of life.
By early childhood, few children have respiratory symptoms at rest; however, formal testing in older children shows small airway obstruction and diminished blood flow on ventilation-perfusion (V-Q) scan, especially to the lung ipsilateral to the hernia. Reduced exercise tolerance can be a lifelong problem. Intermittent wheezing requiring bronchodilator use is common in people with CDH, and they are at risk for respiratory decompensation with intercurrent illness.
Abnormal pulmonary vascular development and function is a significant problem in infants with CDH. Guidelines for the diagnosis of pediatric pulmonary hypertension were set forth by the American Heart Association and American Thoracic Society [
"Failure to thrive" with growth parameters lower than than the third centile of normal is common among infants with more significant pulmonary hypoplasia and/or a more prolonged hospitalization following surgical repair of CDH. Growth failure is caused, in large part, by oral aversion and feeding difficulties (often requiring gastrostomy tube insertion for the first few years of life) and gastroesophageal reflux (frequently requiring pharmacotherapy and/or surgical fundoplication). Some infants and children require long-term high-calorie nutritional supplements.
Reporting of neurodevelopmental outcomes is complicated by lack of standardization in terms of outcomes assessed, age of assessment, and metrics used (reviewed in
Chest asymmetry is found in as many as half of individuals with CDH. Pectus deformity, most often of the excavatum type, and scoliosis (≥10° Cobb's angle) are found in approximately 25% of individuals. These musculoskeletal abnormalities occur more often following repair of large diaphragmatic defects, possibly as a result of the extra tension exerted on the chest wall during surgical repair.
Sensorineural hearing loss (SNHL) has been found in 25% of individuals with CDH and as many as 100% of individuals treated with ECMO in some series [
## Respiratory Compromise
Infants with CDH often present in the neonatal period with severe respiratory distress, occasionally after a stable period of 24-48 hours followed by acute respiratory distress. Breath sounds are diminished ipsilateral to the hernia. Almost all individuals with CDH have some degree of pulmonary hypoplasia. The pathogenesis of the pulmonary hypoplasia associated with CDH appears to have both a primary component (i.e., the hypoplasia occurs independent of the diaphragm defect) and a secondary component (i.e., arising from competition for thoracic space particularly in the lung ipsilateral to the hernia). Evidence for the presence of a primary defect in lung development arises mostly from studies in animal models, some of which show that the lung hypoplasia precedes the herniation of abdominal viscera.
Infants with CDH typically require mechanical ventilation and sometimes extracorporeal membrane oxygenation (ECMO) in the newborn period. Major respiratory complications include tracheobronchomalacia, pneumothorax, and secondary lung infection (especially viral pneumonia) that could precipitate terminal respiratory failure even months after surgery. Many infants require ongoing oxygen supplementation and diuretics following surgical correction of CDH. Given the remarkable growth and recuperative capacity of the lung, these treatments can usually be discontinued within the first two years of life.
By early childhood, few children have respiratory symptoms at rest; however, formal testing in older children shows small airway obstruction and diminished blood flow on ventilation-perfusion (V-Q) scan, especially to the lung ipsilateral to the hernia. Reduced exercise tolerance can be a lifelong problem. Intermittent wheezing requiring bronchodilator use is common in people with CDH, and they are at risk for respiratory decompensation with intercurrent illness.
## Pulmonary Hypertension
Abnormal pulmonary vascular development and function is a significant problem in infants with CDH. Guidelines for the diagnosis of pediatric pulmonary hypertension were set forth by the American Heart Association and American Thoracic Society [
## Gastrointestinal
"Failure to thrive" with growth parameters lower than than the third centile of normal is common among infants with more significant pulmonary hypoplasia and/or a more prolonged hospitalization following surgical repair of CDH. Growth failure is caused, in large part, by oral aversion and feeding difficulties (often requiring gastrostomy tube insertion for the first few years of life) and gastroesophageal reflux (frequently requiring pharmacotherapy and/or surgical fundoplication). Some infants and children require long-term high-calorie nutritional supplements.
## Neurologic/Developmental
Reporting of neurodevelopmental outcomes is complicated by lack of standardization in terms of outcomes assessed, age of assessment, and metrics used (reviewed in
## Musculoskeletal
Chest asymmetry is found in as many as half of individuals with CDH. Pectus deformity, most often of the excavatum type, and scoliosis (≥10° Cobb's angle) are found in approximately 25% of individuals. These musculoskeletal abnormalities occur more often following repair of large diaphragmatic defects, possibly as a result of the extra tension exerted on the chest wall during surgical repair.
## Sensorineural Hearing Loss
Sensorineural hearing loss (SNHL) has been found in 25% of individuals with CDH and as many as 100% of individuals treated with ECMO in some series [
## Prognosis
## Differential Diagnosis
## Genetic Causes of Congenital Diaphragmatic Hernia
Older data using standard cytogenetic and molecular cytogenetic techniques showed that approximately 15%-20% of individuals with CDH were identified as having a genetic cause for their diaphragm defect [
Congenital Diaphragmatic Hernia: Monogenic Causes and Distinguishing Clinical Features
Enlarged anterior fontanelle, agenesis of the corpus callosum, hypertelorism, retinal anomalies, omphalocele or umbilical hernia
Sensorineural hearing loss, myopia, ID
Characteristic pattern of low-molecular-weight proteinuria
ID, behavioral difficulties
GU malformations, distal digital hypoplasia
Microphthalmia, sclerocornea, linear dermal hypoplasia, brain, cardiac, & GU anomalies, nail dystrophy
Hearing impairment
Characteristic facial appearance; short distal phalanges of fingers & toes; pulmonary hypoplasia; & assoc anomalies (polyhydramnios, cloudy corneas &/or microphthalmia, orofacial clefting, renal dysplasia / renal cortical cysts, &/or malformations involving brain, cardiovascular system, GI system, &/or genitalia)
Survival beyond neonatal period is rare.
Hypoplasia/absence of nail/phalanx of 5th digit (& occasionally of additional digits), scalp hypotrichosis, body hypertrichosis, facial dysmorphology (coarse face, wide mouth, full lips), brain & cardiac anomalies
Growth restriction
ID
Prenatal &/or postnatal overgrowth, macroglossia, visceromegaly, hemihypertrophy
Abdominal wall defects, earlobe creases or pits behind the upper ear
Embryonal tumors
Coloboma, ear anomalies, cranial nerve deficits, choanal atresia or stenosis, oral facial clefts, cardiac malformations, GU anomalies, tracheoesophageal atresia
Growth deficiency
Arterial & visceral fragility & rupture
Thin translucent skin, micrognathia, narrow nose, thin vermillion of lip, prominent eyes, acrogeria, joint hypermobility
Craniosynostosis, mid-face hypoplasia, hypertelorism, fusion of cervical vertebrae, soft tissue & bony syndactyly of hands & feet
ID
Congenital heart defects, pancreatic agenesis, gallbladder agenesis
DD
Macrosomia, macrocephaly, hypertelorism, umbilical hernia, omphalocele, ocular & renal anomalies
Embryonal tumors
ID
Long palpebral fissures, eversion of lower eyelids, arched/discontinuous eyebrows w/lateral thinning, prominent ears, oral clefts, fetal finger pads, short 5th finger, cardiovascular malformations
Postnatal growth deficiency
Mild-to-moderate ID
Microcephaly, synophrys, arched eyebrows, long eyelashes, small upturned nose, growth deficiency, hirsutism, upper limb anomalies
ID
DD, autism, ID
Hypotonia, facial dysmorphism, visual impairment
Asymmetry of the face, trunk, & extremities; skin atrophy w/fat herniation, hyper- & hypopigmentation, mucous & perioral papillomas, digit anomalies, dental anomalies, coloboma, microphthalmia; osteopathia striata
Mild ID
High frequency of male lethality
GU anomalies, typically undermasculinized 46,XY individuals, diffuse mesangial sclerosis
Wilms tumor
Early-onset kidney failure
46,XY males, undervirilization of external male genitalia, ambiguous or female external genitalia, retained müllerian structures w/double vagina
Pulmonary hypoplasia, complex cardiac malformations
AD = autosomal dominant; AR = autosomal recessive; GI = gastrointestinal; GU = genitourinary; MOI = mode of inheritance; XL = X-linked; DD = developmental delay; ID = intellectual disability
+++ = CDH is considered a core feature in this syndrome. For extensively reported syndromes, CDH is a common finding (i.e., >40%).
++ = CDH is a variable feature of this syndrome. For extensively reported syndromes, CDH is a less common finding (i.e., ~10%-40%). For less extensively characterized syndromes, multiple case reports of CDH are present in the published literature.
+ = CDH is a rare feature of this syndrome. For extensively reported syndromes (e.g., trisomy 21), many case reports of CDH are present in the literature, though the overall incidence of CDH in this syndrome is estimated at <10%. For less extensively characterized syndromes, few case reports are present in the literature; however, it is not generally considered to be a component of the syndrome.
Genes are listed alphabetically
The majority of Beckwith-Wiedemann syndrome (BWS) is caused by imprinting defects or uniparental disomy of 11p15.5 and is simplex (i.e., a single occurrence in a family). In a small number of affected individuals, BWS is caused by a maternally inherited pathogenic variant in
Genetic heterogeneity for Fryns syndrome remains highly probable, as some individuals clinically diagnosed with Fryns syndrome have not had
Congenital Diaphragmatic Hernia: Syndromic Causes of Unknown Genetic Etiology and Distinguishing Clinical Features
Characteristic facial appearance; short distal phalanges of fingers & toes; pulmonary hypoplasia; & assoc anomalies (polyhydramnios, cloudy corneas &/or microphthalmia, orofacial clefting, renal dysplasia / renal cortical cysts, &/or malformations involving brain, cardiovascular system, GI system, &/or genitalia)
Mild ID to severe DD in survivors
Survival beyond neonatal period is rare.
AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
+++ = CDH is considered a core feature in this syndrome. For extensively reported syndromes, CDH is a common component (i.e., >40%).
++ = CDH is a variable feature of this syndrome. For extensively reported syndromes, CDH is a less common finding (i.e., ~10%-40%). For less extensively characterized syndromes, multiple case reports of CDH are present in the published literature.
Genetic basis is unknown and inheritance pattern is predicted based on reports of sib recurrences, parental consanguinity, parental transmission, or increased severity in males.
Historically, cytogenetically detectable chromosome anomalies have been reported in approximately 10% of individuals with CDH (see
Chromosome Anomalies Associated with Congenital Diaphragmatic Hernia
Prenatal: short limbs, CNS anomalies, ventricular dilatation, nuchal edema &/or hydrops fetalis
Postnatal: bitemporal sparse hair, brachycephaly, high broad forehead, hypertelorism, low-set ears, broad nasal bridge, anteverted nostrils, long philtrum, progressively coarse features, short neck, nuchal skin redundancy, short broad hands, linear streaky hyperpigmentation, normal growth, seizures, ID, congenital heart defects (VSD)
Limb anomalies, CLP
Seizures
ID
Typical craniofacial features
Seizures
Growth deficiency
DD/ID
Cardiovascular malformations, mild facial dysmorphology, renal anomalies
ID
Typical craniofacial features, malformations of hands & feet
Growth deficiency
ID w/marked speech delay
Craniofacial anomalies, cardiovascular malformations, hypoplastic genitalia or cryptorchidism
Growth deficiency
ID
Malformations of the genitourinary tract (e.g., echogenic kidneys)
MODY
ID
Cardiovascular malformations, mild facial dysmorphology
ID
Cardiovascular malformations, craniofacial dysmorphology, congenital anomalies
Learning difficulties
Cardiovascular malformations, craniofacial anomalies (preauricular tags or sinuses, micrognathia, cleft palate)
Growth deficiency
ID
IUGR, holoprosencephaly, scalp defects, CLP, cardiac defects, polydactyly
High mortality
IUGR, cardiovascular malformations, craniofacial dysmorphology, clenched hands
High mortality
Characteristic facies, atrioventricular septal defects, gastrointestinal anomalies
Hypotonia
ID
Hemihypertrophy, congenital heart disease
Growth deficiency
ID
CLP = cleft lip and palate; DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth restriction; MODY = maturity-onset diabetes of the young; VSD = ventricular septal defect
++ CDH is a variable feature of this syndrome. For extensively reported syndromes, CDH is a less common finding (i.e., ~10%-40%). For less extensively characterized syndromes, multiple case reports of CDH are present in the published literature.
+ CDH is a rare feature of this syndrome. For extensively reported syndromes (e.g., trisomy 21), many case reports of CDH are present in the literature, though the overall incidence of CDH in this syndrome is estimated at <10%. For less extensively characterized syndromes, few case reports are present in the literature; however, it is not generally considered to be a component of the syndrome.
Mosaicism for tetrasomy 12 can be identified in amniocytes, chorionic villi, and skin fibroblasts.
• Enlarged anterior fontanelle, agenesis of the corpus callosum, hypertelorism, retinal anomalies, omphalocele or umbilical hernia
• Sensorineural hearing loss, myopia, ID
• Characteristic pattern of low-molecular-weight proteinuria
• ID, behavioral difficulties
• GU malformations, distal digital hypoplasia
• Microphthalmia, sclerocornea, linear dermal hypoplasia, brain, cardiac, & GU anomalies, nail dystrophy
• Hearing impairment
• Characteristic facial appearance; short distal phalanges of fingers & toes; pulmonary hypoplasia; & assoc anomalies (polyhydramnios, cloudy corneas &/or microphthalmia, orofacial clefting, renal dysplasia / renal cortical cysts, &/or malformations involving brain, cardiovascular system, GI system, &/or genitalia)
• Survival beyond neonatal period is rare.
• Hypoplasia/absence of nail/phalanx of 5th digit (& occasionally of additional digits), scalp hypotrichosis, body hypertrichosis, facial dysmorphology (coarse face, wide mouth, full lips), brain & cardiac anomalies
• Growth restriction
• ID
• Prenatal &/or postnatal overgrowth, macroglossia, visceromegaly, hemihypertrophy
• Abdominal wall defects, earlobe creases or pits behind the upper ear
• Embryonal tumors
• Coloboma, ear anomalies, cranial nerve deficits, choanal atresia or stenosis, oral facial clefts, cardiac malformations, GU anomalies, tracheoesophageal atresia
• Growth deficiency
• Arterial & visceral fragility & rupture
• Thin translucent skin, micrognathia, narrow nose, thin vermillion of lip, prominent eyes, acrogeria, joint hypermobility
• Craniosynostosis, mid-face hypoplasia, hypertelorism, fusion of cervical vertebrae, soft tissue & bony syndactyly of hands & feet
• ID
• Congenital heart defects, pancreatic agenesis, gallbladder agenesis
• DD
• Macrosomia, macrocephaly, hypertelorism, umbilical hernia, omphalocele, ocular & renal anomalies
• Embryonal tumors
• ID
• Long palpebral fissures, eversion of lower eyelids, arched/discontinuous eyebrows w/lateral thinning, prominent ears, oral clefts, fetal finger pads, short 5th finger, cardiovascular malformations
• Postnatal growth deficiency
• Mild-to-moderate ID
• Microcephaly, synophrys, arched eyebrows, long eyelashes, small upturned nose, growth deficiency, hirsutism, upper limb anomalies
• ID
• DD, autism, ID
• Hypotonia, facial dysmorphism, visual impairment
• Asymmetry of the face, trunk, & extremities; skin atrophy w/fat herniation, hyper- & hypopigmentation, mucous & perioral papillomas, digit anomalies, dental anomalies, coloboma, microphthalmia; osteopathia striata
• Mild ID
• High frequency of male lethality
• GU anomalies, typically undermasculinized 46,XY individuals, diffuse mesangial sclerosis
• Wilms tumor
• Early-onset kidney failure
• 46,XY males, undervirilization of external male genitalia, ambiguous or female external genitalia, retained müllerian structures w/double vagina
• Pulmonary hypoplasia, complex cardiac malformations
• Characteristic facial appearance; short distal phalanges of fingers & toes; pulmonary hypoplasia; & assoc anomalies (polyhydramnios, cloudy corneas &/or microphthalmia, orofacial clefting, renal dysplasia / renal cortical cysts, &/or malformations involving brain, cardiovascular system, GI system, &/or genitalia)
• Mild ID to severe DD in survivors
• Survival beyond neonatal period is rare.
• Prenatal: short limbs, CNS anomalies, ventricular dilatation, nuchal edema &/or hydrops fetalis
• Postnatal: bitemporal sparse hair, brachycephaly, high broad forehead, hypertelorism, low-set ears, broad nasal bridge, anteverted nostrils, long philtrum, progressively coarse features, short neck, nuchal skin redundancy, short broad hands, linear streaky hyperpigmentation, normal growth, seizures, ID, congenital heart defects (VSD)
• Limb anomalies, CLP
• Seizures
• ID
• Typical craniofacial features
• Seizures
• Growth deficiency
• DD/ID
• Cardiovascular malformations, mild facial dysmorphology, renal anomalies
• ID
• Typical craniofacial features, malformations of hands & feet
• Growth deficiency
• ID w/marked speech delay
• Craniofacial anomalies, cardiovascular malformations, hypoplastic genitalia or cryptorchidism
• Growth deficiency
• ID
• Malformations of the genitourinary tract (e.g., echogenic kidneys)
• MODY
• ID
• Cardiovascular malformations, mild facial dysmorphology
• ID
• Cardiovascular malformations, craniofacial dysmorphology, congenital anomalies
• Learning difficulties
• Cardiovascular malformations, craniofacial anomalies (preauricular tags or sinuses, micrognathia, cleft palate)
• Growth deficiency
• ID
• IUGR, holoprosencephaly, scalp defects, CLP, cardiac defects, polydactyly
• High mortality
• IUGR, cardiovascular malformations, craniofacial dysmorphology, clenched hands
• High mortality
• Characteristic facies, atrioventricular septal defects, gastrointestinal anomalies
• Hypotonia
• ID
• Hemihypertrophy, congenital heart disease
• Growth deficiency
• ID
## Chromosomal Causes of Congenital Diaphragmatic Hernia
Historically, cytogenetically detectable chromosome anomalies have been reported in approximately 10% of individuals with CDH (see
Chromosome Anomalies Associated with Congenital Diaphragmatic Hernia
Prenatal: short limbs, CNS anomalies, ventricular dilatation, nuchal edema &/or hydrops fetalis
Postnatal: bitemporal sparse hair, brachycephaly, high broad forehead, hypertelorism, low-set ears, broad nasal bridge, anteverted nostrils, long philtrum, progressively coarse features, short neck, nuchal skin redundancy, short broad hands, linear streaky hyperpigmentation, normal growth, seizures, ID, congenital heart defects (VSD)
Limb anomalies, CLP
Seizures
ID
Typical craniofacial features
Seizures
Growth deficiency
DD/ID
Cardiovascular malformations, mild facial dysmorphology, renal anomalies
ID
Typical craniofacial features, malformations of hands & feet
Growth deficiency
ID w/marked speech delay
Craniofacial anomalies, cardiovascular malformations, hypoplastic genitalia or cryptorchidism
Growth deficiency
ID
Malformations of the genitourinary tract (e.g., echogenic kidneys)
MODY
ID
Cardiovascular malformations, mild facial dysmorphology
ID
Cardiovascular malformations, craniofacial dysmorphology, congenital anomalies
Learning difficulties
Cardiovascular malformations, craniofacial anomalies (preauricular tags or sinuses, micrognathia, cleft palate)
Growth deficiency
ID
IUGR, holoprosencephaly, scalp defects, CLP, cardiac defects, polydactyly
High mortality
IUGR, cardiovascular malformations, craniofacial dysmorphology, clenched hands
High mortality
Characteristic facies, atrioventricular septal defects, gastrointestinal anomalies
Hypotonia
ID
Hemihypertrophy, congenital heart disease
Growth deficiency
ID
CLP = cleft lip and palate; DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth restriction; MODY = maturity-onset diabetes of the young; VSD = ventricular septal defect
++ CDH is a variable feature of this syndrome. For extensively reported syndromes, CDH is a less common finding (i.e., ~10%-40%). For less extensively characterized syndromes, multiple case reports of CDH are present in the published literature.
+ CDH is a rare feature of this syndrome. For extensively reported syndromes (e.g., trisomy 21), many case reports of CDH are present in the literature, though the overall incidence of CDH in this syndrome is estimated at <10%. For less extensively characterized syndromes, few case reports are present in the literature; however, it is not generally considered to be a component of the syndrome.
Mosaicism for tetrasomy 12 can be identified in amniocytes, chorionic villi, and skin fibroblasts.
• Prenatal: short limbs, CNS anomalies, ventricular dilatation, nuchal edema &/or hydrops fetalis
• Postnatal: bitemporal sparse hair, brachycephaly, high broad forehead, hypertelorism, low-set ears, broad nasal bridge, anteverted nostrils, long philtrum, progressively coarse features, short neck, nuchal skin redundancy, short broad hands, linear streaky hyperpigmentation, normal growth, seizures, ID, congenital heart defects (VSD)
• Limb anomalies, CLP
• Seizures
• ID
• Typical craniofacial features
• Seizures
• Growth deficiency
• DD/ID
• Cardiovascular malformations, mild facial dysmorphology, renal anomalies
• ID
• Typical craniofacial features, malformations of hands & feet
• Growth deficiency
• ID w/marked speech delay
• Craniofacial anomalies, cardiovascular malformations, hypoplastic genitalia or cryptorchidism
• Growth deficiency
• ID
• Malformations of the genitourinary tract (e.g., echogenic kidneys)
• MODY
• ID
• Cardiovascular malformations, mild facial dysmorphology
• ID
• Cardiovascular malformations, craniofacial dysmorphology, congenital anomalies
• Learning difficulties
• Cardiovascular malformations, craniofacial anomalies (preauricular tags or sinuses, micrognathia, cleft palate)
• Growth deficiency
• ID
• IUGR, holoprosencephaly, scalp defects, CLP, cardiac defects, polydactyly
• High mortality
• IUGR, cardiovascular malformations, craniofacial dysmorphology, clenched hands
• High mortality
• Characteristic facies, atrioventricular septal defects, gastrointestinal anomalies
• Hypotonia
• ID
• Hemihypertrophy, congenital heart disease
• Growth deficiency
• ID
## Evaluation Strategies to Identify the Genetic Cause of Congenital Diaphragmatic Hernia in a Proband
Establishing a specific genetic cause of congenital diaphragmatic hernia:
Can aid in discussions of prognosis (which are beyond the scope of this
Usually involves a medical history, physical examination, family history, imaging, and genomic/genetic testing;
Is complicated by the extreme genetic heterogeneity of the condition, which requires a tiered approach to genetic testing.
For an introduction to exome sequencing click
Genetic testing should be directed by the clinical evidence garnered by the interpretation of medical history, physical examination, and family history.
Note: (1) In an otherwise healthy individual with isolated CHD and a negative family history, currently available clinical genetic testing has a relatively low yield. However, the decision to proceed with testing should be made by an experienced geneticist on a case-by-case basis and should be regularly reevaluated in light of the individual’s developmental course, as well as advances in identifying genetic contributions to CDH. (2) Special attention must be paid when considering the diagnosis of isochromosome 12p (Pallister-Killian syndrome; see
For an introduction to comprehensive genomic testing click
• Can aid in discussions of prognosis (which are beyond the scope of this
• Usually involves a medical history, physical examination, family history, imaging, and genomic/genetic testing;
• Is complicated by the extreme genetic heterogeneity of the condition, which requires a tiered approach to genetic testing.
## Prenatal Evaluation Strategy
For an introduction to exome sequencing click
## Testing
For an introduction to exome sequencing click
## Postnatal Evaluation Strategy
Genetic testing should be directed by the clinical evidence garnered by the interpretation of medical history, physical examination, and family history.
Note: (1) In an otherwise healthy individual with isolated CHD and a negative family history, currently available clinical genetic testing has a relatively low yield. However, the decision to proceed with testing should be made by an experienced geneticist on a case-by-case basis and should be regularly reevaluated in light of the individual’s developmental course, as well as advances in identifying genetic contributions to CDH. (2) Special attention must be paid when considering the diagnosis of isochromosome 12p (Pallister-Killian syndrome; see
For an introduction to comprehensive genomic testing click
## Testing
Note: (1) In an otherwise healthy individual with isolated CHD and a negative family history, currently available clinical genetic testing has a relatively low yield. However, the decision to proceed with testing should be made by an experienced geneticist on a case-by-case basis and should be regularly reevaluated in light of the individual’s developmental course, as well as advances in identifying genetic contributions to CDH. (2) Special attention must be paid when considering the diagnosis of isochromosome 12p (Pallister-Killian syndrome; see
For an introduction to comprehensive genomic testing click
## Management
Proper management of newborns with CDH must start in the delivery room; recently, investigative therapies may start in the prenatal period. A standardized protocol for neonatal management and treatment of infants with CDH was proposed by the CDH EURO Consortium Consensus [
Complications of ECMO treatment include air embolism, neurologic complications (e.g., intracranial hemorrhage, infarct, and seizures), cannulation site bleeding, coagulation abnormalities including disseminated intravascular coagulation, left-to-right shunting through the patent ductus arteriosus due to rapid and dramatic decrease in pulmonary hypertension, kidney failure, systemic hypertension, and infection [
Since both pre- and postnatal advances in treatment have increased survival of high-risk individuals, it is important to provide close follow up and support for major complications and potential long-term morbidities. Long-term follow up for infants with CDH is ideally provided at a specialized center by a multidisciplinary team consisting of a pediatric surgeon, surgical nurse specialist, cardiologist, nutritionist, pulmonologist, and developmental pediatrician. This type of team can recognize, treat, and coordinate care for the many medical complications frequently found in long-term survivors with CDH.
See
Search
## Treatment of Manifestations
Proper management of newborns with CDH must start in the delivery room; recently, investigative therapies may start in the prenatal period. A standardized protocol for neonatal management and treatment of infants with CDH was proposed by the CDH EURO Consortium Consensus [
Complications of ECMO treatment include air embolism, neurologic complications (e.g., intracranial hemorrhage, infarct, and seizures), cannulation site bleeding, coagulation abnormalities including disseminated intravascular coagulation, left-to-right shunting through the patent ductus arteriosus due to rapid and dramatic decrease in pulmonary hypertension, kidney failure, systemic hypertension, and infection [
## Surveillance
Since both pre- and postnatal advances in treatment have increased survival of high-risk individuals, it is important to provide close follow up and support for major complications and potential long-term morbidities. Long-term follow up for infants with CDH is ideally provided at a specialized center by a multidisciplinary team consisting of a pediatric surgeon, surgical nurse specialist, cardiologist, nutritionist, pulmonologist, and developmental pediatrician. This type of team can recognize, treat, and coordinate care for the many medical complications frequently found in long-term survivors with CDH.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Congenital diaphragmatic hernia (CDH) may occur as an isolated finding, as part of a genetic syndrome or chromosome abnormality, or as part of a complex but nonsyndromic set of findings.
Kindreds representing both syndromic and nonsyndromic CDH consistent with autosomal dominant, autosomal recessive, and X-linked patterns of inheritance have been reported. Some published pedigrees suggest reduced penetrance and variable expressivity in individuals with heterozygous pathogenic variants associated with autosomal dominant CDH [
If a proband is found to have a specific genetic disorder, syndrome, or association with CDH (see
The majority of individuals with isolated CDH represent simplex cases (i.e., the only affected member of the family); however, a few families are multiplex (i.e., ≥2 relatives have isolated CDH).
The estimated risk for recurrence of isolated Bochdalek CDH in a sib is less than 2% [
Some cases of complex CDH are probably caused by dominant
Some are probably unrecognized syndromic conditions.
Some may be multifactorial disorders with a low recurrence risk.
Non-genetic causes including stochastic events, epigenetic modifications, or teratogenic/environmental exposures are possible as well.
Thus, counseling in this setting should be as for other multiple congenital anomaly disorders of unknown etiology. Specifically, the estimated recurrence risk to sibs is "low," but this estimate represents an averaging of a negligible, or very low, recurrence risk in the majority of families together with a higher recurrence risk (as high as 25%-50%) in the minority of families.
Among multiplex families with CDH, concordance is extremely high among affected relatives both for the specific type and the side of the diaphragm defect, although the size of the defect can vary. Very occasionally, one affected sib has unilateral CDH while a second affected sib has bilateral CDH, or one sib has an eventration while a second has a diaphragmatic hernia. Also, occasionally, one sib has CDH only while a second affected sib has CDH plus another common birth defect such as a cardiovascular malformation or polydactyly. Whether these latter cases represent differing manifestations of a monogenic condition influenced by genetic modifiers, environmental modifiers, or stochastic fluctuations, or even multifactorial inheritance is not yet known.
When CDH is found on routine prenatal ultrasound examination, both a high-resolution ultrasound examination and fetal MRI to determine the presence of additional structural anomalies are indicated. Chromosome analysis of fetal cells obtained by amniocentesis should be considered in all pregnancies while CMA should strongly be considered when CDH is present in conjunction with additional anomalies. (See
All fetuses with CDH should be evaluated for the presence of syndromes and/or additional major malformations given that they so commonly coexist and significantly affect the prognosis. Involvement of a clinical geneticist in the evaluation of these families can be helpful. The measurement of either the expected/observed LHR or the lung volume by fetal MRI have been useful to predict outcome; however, since the predictive value of these measurements varies from center to center, results must be interpreted with caution.
If the genetic cause of CDH has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Counseling should include a discussion of possible reduced penetrance in autosomal dominant forms of CDH [
• The majority of individuals with isolated CDH represent simplex cases (i.e., the only affected member of the family); however, a few families are multiplex (i.e., ≥2 relatives have isolated CDH).
• The estimated risk for recurrence of isolated Bochdalek CDH in a sib is less than 2% [
• Some cases of complex CDH are probably caused by dominant
• Some are probably unrecognized syndromic conditions.
• Some may be multifactorial disorders with a low recurrence risk.
• Non-genetic causes including stochastic events, epigenetic modifications, or teratogenic/environmental exposures are possible as well.
## Mode of Inheritance
Congenital diaphragmatic hernia (CDH) may occur as an isolated finding, as part of a genetic syndrome or chromosome abnormality, or as part of a complex but nonsyndromic set of findings.
Kindreds representing both syndromic and nonsyndromic CDH consistent with autosomal dominant, autosomal recessive, and X-linked patterns of inheritance have been reported. Some published pedigrees suggest reduced penetrance and variable expressivity in individuals with heterozygous pathogenic variants associated with autosomal dominant CDH [
## Risks to Family Members of a Proband With an Identified Genetic Etiology
If a proband is found to have a specific genetic disorder, syndrome, or association with CDH (see
## Empiric Risks to Family Members of a Proband Without an Identified Genetic Etiology
The majority of individuals with isolated CDH represent simplex cases (i.e., the only affected member of the family); however, a few families are multiplex (i.e., ≥2 relatives have isolated CDH).
The estimated risk for recurrence of isolated Bochdalek CDH in a sib is less than 2% [
Some cases of complex CDH are probably caused by dominant
Some are probably unrecognized syndromic conditions.
Some may be multifactorial disorders with a low recurrence risk.
Non-genetic causes including stochastic events, epigenetic modifications, or teratogenic/environmental exposures are possible as well.
Thus, counseling in this setting should be as for other multiple congenital anomaly disorders of unknown etiology. Specifically, the estimated recurrence risk to sibs is "low," but this estimate represents an averaging of a negligible, or very low, recurrence risk in the majority of families together with a higher recurrence risk (as high as 25%-50%) in the minority of families.
• The majority of individuals with isolated CDH represent simplex cases (i.e., the only affected member of the family); however, a few families are multiplex (i.e., ≥2 relatives have isolated CDH).
• The estimated risk for recurrence of isolated Bochdalek CDH in a sib is less than 2% [
• Some cases of complex CDH are probably caused by dominant
• Some are probably unrecognized syndromic conditions.
• Some may be multifactorial disorders with a low recurrence risk.
• Non-genetic causes including stochastic events, epigenetic modifications, or teratogenic/environmental exposures are possible as well.
## Related Genetic Counseling Issues
Among multiplex families with CDH, concordance is extremely high among affected relatives both for the specific type and the side of the diaphragm defect, although the size of the defect can vary. Very occasionally, one affected sib has unilateral CDH while a second affected sib has bilateral CDH, or one sib has an eventration while a second has a diaphragmatic hernia. Also, occasionally, one sib has CDH only while a second affected sib has CDH plus another common birth defect such as a cardiovascular malformation or polydactyly. Whether these latter cases represent differing manifestations of a monogenic condition influenced by genetic modifiers, environmental modifiers, or stochastic fluctuations, or even multifactorial inheritance is not yet known.
## Prenatal Testing and Preimplantation Genetic Testing
When CDH is found on routine prenatal ultrasound examination, both a high-resolution ultrasound examination and fetal MRI to determine the presence of additional structural anomalies are indicated. Chromosome analysis of fetal cells obtained by amniocentesis should be considered in all pregnancies while CMA should strongly be considered when CDH is present in conjunction with additional anomalies. (See
All fetuses with CDH should be evaluated for the presence of syndromes and/or additional major malformations given that they so commonly coexist and significantly affect the prognosis. Involvement of a clinical geneticist in the evaluation of these families can be helpful. The measurement of either the expected/observed LHR or the lung volume by fetal MRI have been useful to predict outcome; however, since the predictive value of these measurements varies from center to center, results must be interpreted with caution.
If the genetic cause of CDH has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Counseling should include a discussion of possible reduced penetrance in autosomal dominant forms of CDH [
## Resources
United Kingdom
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• United Kingdom
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•
## Chapter Notes
Kate Guernsey Ackerman, MD; University of Rochester (2006-2019)Frances A High, MD, PhD (2019-present)Mauro Longoni, MD (2019-present)Barbara R Pober, MD (2006-present)Meaghan K Russell, MPH; MassGeneral Hospital for Children (2006-2019)
17 July 2025 (ma) Chapter retired: phenotype is too broad
5 November 2020 (aa/sw) Revision: added
28 March 2019 (sw) Comprehensive update posted live
16 March 2010 (me) Comprehensive update posted live
1 February 2006 (me) Review posted live
6 June 2005 (brp) Original submission
• 17 July 2025 (ma) Chapter retired: phenotype is too broad
• 5 November 2020 (aa/sw) Revision: added
• 28 March 2019 (sw) Comprehensive update posted live
• 16 March 2010 (me) Comprehensive update posted live
• 1 February 2006 (me) Review posted live
• 6 June 2005 (brp) Original submission
## Author History
Kate Guernsey Ackerman, MD; University of Rochester (2006-2019)Frances A High, MD, PhD (2019-present)Mauro Longoni, MD (2019-present)Barbara R Pober, MD (2006-present)Meaghan K Russell, MPH; MassGeneral Hospital for Children (2006-2019)
## Revision History
17 July 2025 (ma) Chapter retired: phenotype is too broad
5 November 2020 (aa/sw) Revision: added
28 March 2019 (sw) Comprehensive update posted live
16 March 2010 (me) Comprehensive update posted live
1 February 2006 (me) Review posted live
6 June 2005 (brp) Original submission
• 17 July 2025 (ma) Chapter retired: phenotype is too broad
• 5 November 2020 (aa/sw) Revision: added
• 28 March 2019 (sw) Comprehensive update posted live
• 16 March 2010 (me) Comprehensive update posted live
• 1 February 2006 (me) Review posted live
• 6 June 2005 (brp) Original submission
## References
## Literature Cited
A. Normal diaphragm (for reference)
B. View of normal diaphragm from below
View of diaphragmatic defects from below
A. Bochdalek hernia
B. Morgnani hernia and other anterior hernias
C. Central hernia
|
[] |
1/2/2006
|
28/3/2019
|
5/11/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cdk13-dis
|
cdk13-dis
|
[
"CDK13-Related Congenital Heart Defects, Dysmorphic Facial Features, and Intellectual Developmental Disorder",
"CDK13-Related CHDFIDD",
"CDK13-Related CHDFIDD",
"CDK13-Related Congenital Heart Defects, Dysmorphic Facial Features and Intellectual Developmental Disorder",
"Cyclin-dependent kinase 13",
"CDK13",
"CDK13-Related Disorder"
] |
Bret Bostwick
|
Summary The diagnosis of
|
## Diagnosis
No formal clinical diagnostic criteria for
Developmental delay / intellectual disability
Structural cardiac defects
Atrial septal defects
Ventricular septal defects
Pulmonary valve abnormalities
Hypoplastic pulmonary artery
Suggestive facial dysmorphisms (See
Agenesis/hypogenesis of the corpus callosum (5 individuals)
Aplasia of the cerebellar vermis
Periventricular leukomalacia or periventricular gliosis (3)
Spinal cord syrinx (2)
Cerebellar tonsillar abnormalities (2)
Diminished white matter volume (1)
The diagnosis of
Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
For an introduction to multigene panels click
When the diagnosis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Developmental delay / intellectual disability
• Structural cardiac defects
• Atrial septal defects
• Ventricular septal defects
• Pulmonary valve abnormalities
• Hypoplastic pulmonary artery
• Atrial septal defects
• Ventricular septal defects
• Pulmonary valve abnormalities
• Hypoplastic pulmonary artery
• Suggestive facial dysmorphisms (See
• Atrial septal defects
• Ventricular septal defects
• Pulmonary valve abnormalities
• Hypoplastic pulmonary artery
• Agenesis/hypogenesis of the corpus callosum (5 individuals)
• Aplasia of the cerebellar vermis
• Periventricular leukomalacia or periventricular gliosis (3)
• Spinal cord syrinx (2)
• Cerebellar tonsillar abnormalities (2)
• Diminished white matter volume (1)
## Suggestive Findings
Developmental delay / intellectual disability
Structural cardiac defects
Atrial septal defects
Ventricular septal defects
Pulmonary valve abnormalities
Hypoplastic pulmonary artery
Suggestive facial dysmorphisms (See
Agenesis/hypogenesis of the corpus callosum (5 individuals)
Aplasia of the cerebellar vermis
Periventricular leukomalacia or periventricular gliosis (3)
Spinal cord syrinx (2)
Cerebellar tonsillar abnormalities (2)
Diminished white matter volume (1)
• Developmental delay / intellectual disability
• Structural cardiac defects
• Atrial septal defects
• Ventricular septal defects
• Pulmonary valve abnormalities
• Hypoplastic pulmonary artery
• Atrial septal defects
• Ventricular septal defects
• Pulmonary valve abnormalities
• Hypoplastic pulmonary artery
• Suggestive facial dysmorphisms (See
• Atrial septal defects
• Ventricular septal defects
• Pulmonary valve abnormalities
• Hypoplastic pulmonary artery
• Agenesis/hypogenesis of the corpus callosum (5 individuals)
• Aplasia of the cerebellar vermis
• Periventricular leukomalacia or periventricular gliosis (3)
• Spinal cord syrinx (2)
• Cerebellar tonsillar abnormalities (2)
• Diminished white matter volume (1)
## Establishing the Diagnosis
The diagnosis of
Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
For an introduction to multigene panels click
When the diagnosis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Option 1
For an introduction to multigene panels click
## Option 2
When the diagnosis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
To date 43 individuals with
The following are the most common clinical features of
All individuals reported to date have had developmental delay (DD) or intellectual disability (ID), with four reported in the mild range. Forty-one of 42 individuals on whom data were available had a degree of learning disability or DD. One individual was reported with formal IQ testing in the low-normal range.
Nearly all individuals reported older than age one year have impaired verbal language skills with either absent or restricted speech. Some discrepancy in language developmental is evident: some children have better receptive than expressive language skills.
Autism spectrum disorder has been reported in 11 individuals; two additional individuals displayed autistic traits or stereotypies. ADHD or hyperactivity alone has been reported in seven individuals. Pica has been reported in two.
Seizures have been reported in eight individuals with seizure types that include myoclonic, generalized tonic-clonic, and absence seizures. No correlation between the presence of structural brain abnormalities and seizure activity is apparent.
The majority of infants with
The overall prevalence of structural cardiac defects is approximately 46% (17 of 37 evaluated for cardiac abnormality). Although structural heart defects were present in all seven of the initially reported individuals with
A variety of cardiac defects have been reported in the 17 with known cardiac defects; the most common, seen alone or in combination, are atrial septal defect (in 10 individuals) and ventricular septal defect (in 5).
Hypoplastic pulmonary arteries, dilated pulmonary arteries, and/or pulmonary valve abnormalities were reported in six individuals. Ebstein's anomaly and tetralogy of Fallot have also been reported.
One of the oldest individuals reported to date had bicuspid aortic valve, aortic stenosis, and aortic insufficiency diagnosed in childhood; when last evaluated at age 38 years cardiac findings included left ventricular non-compaction and sick sinus syndrome requiring pacemaker implantation [
Short stature in childhood is present in about half of affected individuals. Endocrinologic evaluations of short stature have not been performed.
Microcephaly is more common in older individuals and, thus, may be acquired. Macrocephaly has been reported in three individuals to date [
Scoliosis in the absence of known vertebral abnormalities, hyperlordosis
Vertebral hemangiomas
Cervical spinal fusions
Sacral clefting
Spina bifida
Sacral bony prominence
Contractures at the Achilles tendons and knees were less severe.
The small number of published cases to date limits the statistical power for evaluating genotype-phenotype correlations.
A possible genotype-phenotype correlation is the observation that the greater the decrease in total kinase activity the more severe the phenotype [
Variants affecting the lysine residue at position 734 (
Variants affecting the asparagine residue at position 842 (
Two individuals harboring a stop codon at the end of the kinase domain may have shown a milder phenotype [
Penetrance based on 43 individuals reported to date appears to be complete: all reported variants have been
Forty-three individuals with
A
In another cohort (which included some individuals from the
• Scoliosis in the absence of known vertebral abnormalities, hyperlordosis
• Vertebral hemangiomas
• Cervical spinal fusions
• Sacral clefting
• Spina bifida
• Sacral bony prominence
• Variants affecting the lysine residue at position 734 (
• Variants affecting the asparagine residue at position 842 (
## Clinical Description
To date 43 individuals with
The following are the most common clinical features of
All individuals reported to date have had developmental delay (DD) or intellectual disability (ID), with four reported in the mild range. Forty-one of 42 individuals on whom data were available had a degree of learning disability or DD. One individual was reported with formal IQ testing in the low-normal range.
Nearly all individuals reported older than age one year have impaired verbal language skills with either absent or restricted speech. Some discrepancy in language developmental is evident: some children have better receptive than expressive language skills.
Autism spectrum disorder has been reported in 11 individuals; two additional individuals displayed autistic traits or stereotypies. ADHD or hyperactivity alone has been reported in seven individuals. Pica has been reported in two.
Seizures have been reported in eight individuals with seizure types that include myoclonic, generalized tonic-clonic, and absence seizures. No correlation between the presence of structural brain abnormalities and seizure activity is apparent.
The majority of infants with
The overall prevalence of structural cardiac defects is approximately 46% (17 of 37 evaluated for cardiac abnormality). Although structural heart defects were present in all seven of the initially reported individuals with
A variety of cardiac defects have been reported in the 17 with known cardiac defects; the most common, seen alone or in combination, are atrial septal defect (in 10 individuals) and ventricular septal defect (in 5).
Hypoplastic pulmonary arteries, dilated pulmonary arteries, and/or pulmonary valve abnormalities were reported in six individuals. Ebstein's anomaly and tetralogy of Fallot have also been reported.
One of the oldest individuals reported to date had bicuspid aortic valve, aortic stenosis, and aortic insufficiency diagnosed in childhood; when last evaluated at age 38 years cardiac findings included left ventricular non-compaction and sick sinus syndrome requiring pacemaker implantation [
Short stature in childhood is present in about half of affected individuals. Endocrinologic evaluations of short stature have not been performed.
Microcephaly is more common in older individuals and, thus, may be acquired. Macrocephaly has been reported in three individuals to date [
Scoliosis in the absence of known vertebral abnormalities, hyperlordosis
Vertebral hemangiomas
Cervical spinal fusions
Sacral clefting
Spina bifida
Sacral bony prominence
Contractures at the Achilles tendons and knees were less severe.
• Scoliosis in the absence of known vertebral abnormalities, hyperlordosis
• Vertebral hemangiomas
• Cervical spinal fusions
• Sacral clefting
• Spina bifida
• Sacral bony prominence
## Psychosocial and Cognitive Development
All individuals reported to date have had developmental delay (DD) or intellectual disability (ID), with four reported in the mild range. Forty-one of 42 individuals on whom data were available had a degree of learning disability or DD. One individual was reported with formal IQ testing in the low-normal range.
Nearly all individuals reported older than age one year have impaired verbal language skills with either absent or restricted speech. Some discrepancy in language developmental is evident: some children have better receptive than expressive language skills.
Autism spectrum disorder has been reported in 11 individuals; two additional individuals displayed autistic traits or stereotypies. ADHD or hyperactivity alone has been reported in seven individuals. Pica has been reported in two.
## Seizures
Seizures have been reported in eight individuals with seizure types that include myoclonic, generalized tonic-clonic, and absence seizures. No correlation between the presence of structural brain abnormalities and seizure activity is apparent.
## Gastrointestinal
The majority of infants with
## Cardiac
The overall prevalence of structural cardiac defects is approximately 46% (17 of 37 evaluated for cardiac abnormality). Although structural heart defects were present in all seven of the initially reported individuals with
A variety of cardiac defects have been reported in the 17 with known cardiac defects; the most common, seen alone or in combination, are atrial septal defect (in 10 individuals) and ventricular septal defect (in 5).
Hypoplastic pulmonary arteries, dilated pulmonary arteries, and/or pulmonary valve abnormalities were reported in six individuals. Ebstein's anomaly and tetralogy of Fallot have also been reported.
One of the oldest individuals reported to date had bicuspid aortic valve, aortic stenosis, and aortic insufficiency diagnosed in childhood; when last evaluated at age 38 years cardiac findings included left ventricular non-compaction and sick sinus syndrome requiring pacemaker implantation [
## Other
Short stature in childhood is present in about half of affected individuals. Endocrinologic evaluations of short stature have not been performed.
Microcephaly is more common in older individuals and, thus, may be acquired. Macrocephaly has been reported in three individuals to date [
Scoliosis in the absence of known vertebral abnormalities, hyperlordosis
Vertebral hemangiomas
Cervical spinal fusions
Sacral clefting
Spina bifida
Sacral bony prominence
Contractures at the Achilles tendons and knees were less severe.
• Scoliosis in the absence of known vertebral abnormalities, hyperlordosis
• Vertebral hemangiomas
• Cervical spinal fusions
• Sacral clefting
• Spina bifida
• Sacral bony prominence
## Genotype-Phenotype Correlations
The small number of published cases to date limits the statistical power for evaluating genotype-phenotype correlations.
A possible genotype-phenotype correlation is the observation that the greater the decrease in total kinase activity the more severe the phenotype [
Variants affecting the lysine residue at position 734 (
Variants affecting the asparagine residue at position 842 (
Two individuals harboring a stop codon at the end of the kinase domain may have shown a milder phenotype [
• Variants affecting the lysine residue at position 734 (
• Variants affecting the asparagine residue at position 842 (
## Penetrance
Penetrance based on 43 individuals reported to date appears to be complete: all reported variants have been
## Prevalence
Forty-three individuals with
A
In another cohort (which included some individuals from the
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders with Developmental Delay / Intellectual Disability and other Anomalies to Consider in the Differential Diagnosis of
Congenital heart defects
Agenesis of corpus callosum
Dental anomalies (hypoplastic teeth &/or delayed eruption of teeth)
Hypotonia
Syndrome-specific facial features
Patellar hypoplasia/agenesis
Flexion contractures at hips/knees
Long thumbs / great toes
Immobile mask-like face
Sacral & vertebral abnormalities
Pulmonary artery hypoplasia
Pulmonary valve abnormalities
Congenital heart defects
Dental anomalies, widely spaced teeth
Sagittal cleft vertebrae
Scoliosis
Syndrome-specific facial features
Brachydactyly
Ear pits
Coarctation of the aorta
Pulmonary artery hypoplasia
Pulmonary valve abnormalities
Congenital heart defects incl pulmonary artery involvement
Agenesis or hypogenesis of corpus callosum
Constipation, anal stenosis
Syndrome-specific facial features
Hirschsprung disease
Axenfeld eye anomaly
Uplifted earlobes
Broad medial eyebrows
Sacral & vertebral abnormalities
AD = autosomal dominant; MOI = mode of inheritance; XL = X-linked
• Congenital heart defects
• Agenesis of corpus callosum
• Dental anomalies (hypoplastic teeth &/or delayed eruption of teeth)
• Hypotonia
• Syndrome-specific facial features
• Patellar hypoplasia/agenesis
• Flexion contractures at hips/knees
• Long thumbs / great toes
• Immobile mask-like face
• Sacral & vertebral abnormalities
• Pulmonary artery hypoplasia
• Pulmonary valve abnormalities
• Congenital heart defects
• Dental anomalies, widely spaced teeth
• Sagittal cleft vertebrae
• Scoliosis
• Syndrome-specific facial features
• Brachydactyly
• Ear pits
• Coarctation of the aorta
• Pulmonary artery hypoplasia
• Pulmonary valve abnormalities
• Congenital heart defects incl pulmonary artery involvement
• Agenesis or hypogenesis of corpus callosum
• Constipation, anal stenosis
• Syndrome-specific facial features
• Hirschsprung disease
• Axenfeld eye anomaly
• Uplifted earlobes
• Broad medial eyebrows
• Sacral & vertebral abnormalities
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations for
Assess swallowing, feeding, nutritional status, weight gain.
Assess for severe constipation / anal stenosis.
Assess for need for tube feeding.
Determine if constipation requires specialized care.
Brain MRI
EEG if seizure activity is suspected
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
Standardized treatment with anti-seizure medication (ASM) by an experienced neurologist is indicated. No particular ASMs have shown increased efficacy in
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial, vocation/employment if feasible, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of ASD, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat ADHD, when necessary.
Recommended Surveillance for Individuals with
EKG to detect electrical disturbances
Echocardiogram to evaluate structural defects
See
Search
• Assess swallowing, feeding, nutritional status, weight gain.
• Assess for severe constipation / anal stenosis.
• Assess for need for tube feeding.
• Determine if constipation requires specialized care.
• Brain MRI
• EEG if seizure activity is suspected
• Standardized treatment with anti-seizure medication (ASM) by an experienced neurologist is indicated. No particular ASMs have shown increased efficacy in
• Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
• In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial, vocation/employment if feasible, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• EKG to detect electrical disturbances
• Echocardiogram to evaluate structural defects
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations for
Assess swallowing, feeding, nutritional status, weight gain.
Assess for severe constipation / anal stenosis.
Assess for need for tube feeding.
Determine if constipation requires specialized care.
Brain MRI
EEG if seizure activity is suspected
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
• Assess swallowing, feeding, nutritional status, weight gain.
• Assess for severe constipation / anal stenosis.
• Assess for need for tube feeding.
• Determine if constipation requires specialized care.
• Brain MRI
• EEG if seizure activity is suspected
## Treatment of Manifestations
Standardized treatment with anti-seizure medication (ASM) by an experienced neurologist is indicated. No particular ASMs have shown increased efficacy in
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial, vocation/employment if feasible, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of ASD, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat ADHD, when necessary.
• Standardized treatment with anti-seizure medication (ASM) by an experienced neurologist is indicated. No particular ASMs have shown increased efficacy in
• Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
• In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial, vocation/employment if feasible, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial, vocation/employment if feasible, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial, vocation/employment if feasible, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of ASD, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat ADHD, when necessary.
## Surveillance
Recommended Surveillance for Individuals with
EKG to detect electrical disturbances
Echocardiogram to evaluate structural defects
• EKG to detect electrical disturbances
• Echocardiogram to evaluate structural defects
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
All probands reported to date with
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
Risk to future pregnancies is presumed to be low as the proband most likely has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• All probands reported to date with
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
## Risk to Family Members
All probands reported to date with
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
• All probands reported to date with
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Risk to future pregnancies is presumed to be low as the proband most likely has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
CDK13-Related Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CDK13-Related Disorder (
See
Pathogenic variants reported to date have included missense substitutions and splice site, frameshift, and nonsense variants [
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
## Molecular Pathogenesis
See
Pathogenic variants reported to date have included missense substitutions and splice site, frameshift, and nonsense variants [
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
## Chapter Notes
Bret L Bostwick, MD is an assistant professor in the Department of Molecular and Human Genetics at Baylor College of Medicine in Houston, Texas. As a clinician and clinical researcher he has special interest in
The author gratefully acknowledges the
31 January 2019 (bp) Review posted live
29 January 2018 (bb) Original submission
• 31 January 2019 (bp) Review posted live
• 29 January 2018 (bb) Original submission
## Author Notes
Bret L Bostwick, MD is an assistant professor in the Department of Molecular and Human Genetics at Baylor College of Medicine in Houston, Texas. As a clinician and clinical researcher he has special interest in
## Acknowledgments
The author gratefully acknowledges the
## Revision History
31 January 2019 (bp) Review posted live
29 January 2018 (bb) Original submission
• 31 January 2019 (bp) Review posted live
• 29 January 2018 (bb) Original submission
## References
## Literature Cited
Characteristic facial dysmorphisms in
Figure modified from
|
[
"D Blazek, J Kohoutek, K Bartholomeeusen, E Johansen, P Hulinkova, Z Luo, P Cimermancic, J Ule, BM Peterlin. The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes.. Genes Dev. 2011;25:2158-72",
"BL Bostwick, S McLean, JE Posey, H Streff, KW Gripp, A Blesson, N Powell-Hamilton, J Tusi, DA. Stevenson, E Farrelly, L Hudgins, Y Yang, F Xia, X Wang, P Liu, M Walkiewicz, M McGuire, DK Grange, MV Andrews, M Hummel, S Madan-Khetarpal, E Infante, Z Coban-Akdemir, K Miszalski-Jamka, JL Jefferies, JA Rosenfeld, L Emrick, KM Nugent, JR Lupski, JW Belmont, B Lee, SR Lalani. Phenotypic and molecular characterisation of CDK13-related congenital heart defects dysmorphic facial features and intellectual developmental disorders.. Genome Med. 2017;9:73",
"HH Chen, YH Wong, AM Geneviere, MJ Fann. CDK13/CDC2L5 interacts with L-type cyclins and regulates alternative splicing.. Biochem Biophys Res Commun. 2007;354:735-40",
"HR Chen, GT Lin, CK Huang, MJ Fann. Cdk12 and Cdk13 regulate axonal elongation through a common signaling pathway that modulates Cdk5 expression.. Exp Neurol. 2014;261:10-21",
"MJ Hamilton, RC Caswell, N Canham, T Cole, HV Firth, N Foulds, K Heimdal, E Hobson, G Houge, S Joss, D Kumar, AK Lampe, I Maystadt, V McKay, K Metcalfe, R Newbury-Ecob, SM Park, L Robert, CF Rustad, E Wakeling, AOM Wilkie, TDDD Study, SRF Twigg, M Suri. Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability.. J Med Genet. 2018;55:28-38",
"J Kohoutek, D. Blazek. Cyclin K goes with Cdk12 and Cdk13.. Cell Div. 2012;7:12",
"K Liang, X Gao, JM Gilmore, L Florens, MP Washburn, E Smith, A Shilatifard. Characterization of human cyclin-dependent kinase 12 (CDK12) and CDK13 complexes in C-terminal domain phosphorylation, gene transcription, and RNA processing.. Mol Cell Biol. 2015;35:928-38",
"JF McRae, S Clayton, TW Fitzgerald, J Kaplanis, E Prigmore, D Rajan, A Sifrim, S Aitken, N Akawi, M Alvi. Prevalence and architecture of de novo mutations in developmental disorders.. Nature. 2017;542:433-8",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"A Sifrim, MP Hitz, A Wilsdon, J Breckpot, SH Turki, B Thienpont, J McRae, TW Fitzgerald, T Singh, GJ Swaminathan, E Prigmore, D Rajan, H Abdul-Khaliq, S Banka, UM Bauer, J Bentham, F Berger, S Bhattacharya. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.. Nat Genet. 2016;48:1060-5",
"T Uehara, T Takenouchi, R Kosaki, K Kurosawa, S Mizuno, K Kosaki. Redefining the phenotypic spectrum of de novo heterozygous CDK13 variants: three patients without cardiac defects.. Eur J Med Genet. 2018;61:243-7",
"WM van den Akker, I Brummelman, LM Martis, R Timmermans, R Pfundt, T Kleefstra, MH Willemsen, EH Gerkes. Herkert JC2, van Essen A, Rump P, Vansenne F, Terhal PA, van Haelst MM, Cristian I, Turner CE, Cho MT, Begtrup A, Willaert R, Fassi E, van Gassen K, Stegmann A, de Vries B, Schuurs-Hoeijmakers J. De novo variants in CDK13 associated with syndromic ID/DD; molecular and clinical delineation of 15 individuals and a further review.. Clin Genet. 2018;93:1000-7",
"T Zhang, N Kwiatkowski, CM Olson, SE Dixon-Clarke, BJ Abraham, AK Greifenberg, S B Ficarro, JM Elkins, Y Liang, NM Hannett, T Manz, M Hao, B Bartkowiak, AL Greenleaf, JA Marto, M Geyer, AN Bullock, RA Young, NS Gray. Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors.. Nat Chem Biol. 2016;12:876-84"
] |
31/1/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
cdkl5-def
|
cdkl5-def
|
[
"Cyclin-Dependent Kinase-Like 5 (CDKL5) Deficiency Disorder (CDD)",
"CDKL5-Related Developmental and Epileptic Encephalopathy",
"Cyclin-Dependent Kinase-Like 5 (CDKL5) Deficiency Disorder (CDD)",
"CDKL5-Related Developmental and Epileptic Encephalopathy",
"Cyclin-dependent kinase-like 5",
"CDKL5",
"CDKL5 Deficiency Disorder"
] |
CDKL5 Deficiency Disorder
|
Tim A Benke, Scott Demarest, Katie Angione, Jenny Downs, Helen Leonard, Jacinta Saldaris, Eric D Marsh, Heather Olson, Isabel Haviland
|
Summary CDKL5 deficiency disorder (CDD) is a developmental and epileptic encephalopathy (DEE) characterized by severe early-onset intractable epilepsy and motor, cognitive, visual, and autonomic disturbances. Movement disorders include chorea, dystonia, and stereotypical hand and leg movements. Although females are more commonly affected than males (female-to-male ratio is approximately 4:1), the severity of manifestations in heterozygous females and hemizygous males can be equivalent. However, the severity of the phenotype can vary depending on the type and position of the The diagnosis of CDD is established in a female proband with suggestive clinical findings and a heterozygous The diagnosis of CDD is established in a male proband with suggestive clinical findings and a hemizygous CDD is inherited in an X-linked manner. Approximately 99% of affected individuals represent simplex cases (i.e., a single occurrence in the family). The majority of individuals who represent simplex cases have the disorder as the result of a
|
## Diagnosis
For the purposes of this
Diagnostic criteria for CDKL5 deficiency disorder (CDD) have been proposed [
CDD
Typically beginning within the first two months of life (up to age 12 months)
Usually severe, with multiple episodes per day
Seizure types vary over time. Epileptic spasms (without hypsarrhythmia in 50%) are the initial seizure type in nearly 25% of individuals; other seizure types include tonic, focal, myoclonic, and generalized tonic-clonic; and mixed types that include features of spasms, tonic seizures, and hypermotor seizures. EEG findings may be normal in early infancy.
Refractory to anti-seizure medications (ASMs)
Cerebral visual impairment manifesting as:
Abnormal eye movements that include esotropia, exotropia, and horizontal and rotatory nystagmus
Abnormal fixation and responsiveness to bright lights
Tone abnormalities, including generalized hypotonia
Sleep disturbances
Inability to maintain nighttime sleep for extended periods
Excessive daytime sleepiness
Movement abnormalities
Stereotypies of hands (e.g., putting hands in mouth), arms (e.g., flapping, waving), or legs (e.g., leg crossing)
Generalized chorea
Dystonia
Autonomic dysfunction
Constipation
Gastroesophageal reflux disease
Abnormal breathing pattern
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making. Reference to "pathogenic variants" in this
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in CDKL5 Deficiency Disorder
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Intronic
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications and array comparative genomic hybridization (CGH). Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Mosaic deletions and inversions disrupting
•
• Typically beginning within the first two months of life (up to age 12 months)
• Usually severe, with multiple episodes per day
• Seizure types vary over time. Epileptic spasms (without hypsarrhythmia in 50%) are the initial seizure type in nearly 25% of individuals; other seizure types include tonic, focal, myoclonic, and generalized tonic-clonic; and mixed types that include features of spasms, tonic seizures, and hypermotor seizures. EEG findings may be normal in early infancy.
• Refractory to anti-seizure medications (ASMs)
• Typically beginning within the first two months of life (up to age 12 months)
• Usually severe, with multiple episodes per day
• Seizure types vary over time. Epileptic spasms (without hypsarrhythmia in 50%) are the initial seizure type in nearly 25% of individuals; other seizure types include tonic, focal, myoclonic, and generalized tonic-clonic; and mixed types that include features of spasms, tonic seizures, and hypermotor seizures. EEG findings may be normal in early infancy.
• Refractory to anti-seizure medications (ASMs)
• Cerebral visual impairment manifesting as:
• Abnormal eye movements that include esotropia, exotropia, and horizontal and rotatory nystagmus
• Abnormal fixation and responsiveness to bright lights
• Abnormal eye movements that include esotropia, exotropia, and horizontal and rotatory nystagmus
• Abnormal fixation and responsiveness to bright lights
• Tone abnormalities, including generalized hypotonia
• Sleep disturbances
• Inability to maintain nighttime sleep for extended periods
• Excessive daytime sleepiness
• Inability to maintain nighttime sleep for extended periods
• Excessive daytime sleepiness
• Movement abnormalities
• Stereotypies of hands (e.g., putting hands in mouth), arms (e.g., flapping, waving), or legs (e.g., leg crossing)
• Generalized chorea
• Dystonia
• Stereotypies of hands (e.g., putting hands in mouth), arms (e.g., flapping, waving), or legs (e.g., leg crossing)
• Generalized chorea
• Dystonia
• Autonomic dysfunction
• Constipation
• Gastroesophageal reflux disease
• Abnormal breathing pattern
• Constipation
• Gastroesophageal reflux disease
• Abnormal breathing pattern
• Typically beginning within the first two months of life (up to age 12 months)
• Usually severe, with multiple episodes per day
• Seizure types vary over time. Epileptic spasms (without hypsarrhythmia in 50%) are the initial seizure type in nearly 25% of individuals; other seizure types include tonic, focal, myoclonic, and generalized tonic-clonic; and mixed types that include features of spasms, tonic seizures, and hypermotor seizures. EEG findings may be normal in early infancy.
• Refractory to anti-seizure medications (ASMs)
• Abnormal eye movements that include esotropia, exotropia, and horizontal and rotatory nystagmus
• Abnormal fixation and responsiveness to bright lights
• Inability to maintain nighttime sleep for extended periods
• Excessive daytime sleepiness
• Stereotypies of hands (e.g., putting hands in mouth), arms (e.g., flapping, waving), or legs (e.g., leg crossing)
• Generalized chorea
• Dystonia
• Constipation
• Gastroesophageal reflux disease
• Abnormal breathing pattern
## Suggestive Findings
CDD
Typically beginning within the first two months of life (up to age 12 months)
Usually severe, with multiple episodes per day
Seizure types vary over time. Epileptic spasms (without hypsarrhythmia in 50%) are the initial seizure type in nearly 25% of individuals; other seizure types include tonic, focal, myoclonic, and generalized tonic-clonic; and mixed types that include features of spasms, tonic seizures, and hypermotor seizures. EEG findings may be normal in early infancy.
Refractory to anti-seizure medications (ASMs)
Cerebral visual impairment manifesting as:
Abnormal eye movements that include esotropia, exotropia, and horizontal and rotatory nystagmus
Abnormal fixation and responsiveness to bright lights
Tone abnormalities, including generalized hypotonia
Sleep disturbances
Inability to maintain nighttime sleep for extended periods
Excessive daytime sleepiness
Movement abnormalities
Stereotypies of hands (e.g., putting hands in mouth), arms (e.g., flapping, waving), or legs (e.g., leg crossing)
Generalized chorea
Dystonia
Autonomic dysfunction
Constipation
Gastroesophageal reflux disease
Abnormal breathing pattern
•
• Typically beginning within the first two months of life (up to age 12 months)
• Usually severe, with multiple episodes per day
• Seizure types vary over time. Epileptic spasms (without hypsarrhythmia in 50%) are the initial seizure type in nearly 25% of individuals; other seizure types include tonic, focal, myoclonic, and generalized tonic-clonic; and mixed types that include features of spasms, tonic seizures, and hypermotor seizures. EEG findings may be normal in early infancy.
• Refractory to anti-seizure medications (ASMs)
• Typically beginning within the first two months of life (up to age 12 months)
• Usually severe, with multiple episodes per day
• Seizure types vary over time. Epileptic spasms (without hypsarrhythmia in 50%) are the initial seizure type in nearly 25% of individuals; other seizure types include tonic, focal, myoclonic, and generalized tonic-clonic; and mixed types that include features of spasms, tonic seizures, and hypermotor seizures. EEG findings may be normal in early infancy.
• Refractory to anti-seizure medications (ASMs)
• Cerebral visual impairment manifesting as:
• Abnormal eye movements that include esotropia, exotropia, and horizontal and rotatory nystagmus
• Abnormal fixation and responsiveness to bright lights
• Abnormal eye movements that include esotropia, exotropia, and horizontal and rotatory nystagmus
• Abnormal fixation and responsiveness to bright lights
• Tone abnormalities, including generalized hypotonia
• Sleep disturbances
• Inability to maintain nighttime sleep for extended periods
• Excessive daytime sleepiness
• Inability to maintain nighttime sleep for extended periods
• Excessive daytime sleepiness
• Movement abnormalities
• Stereotypies of hands (e.g., putting hands in mouth), arms (e.g., flapping, waving), or legs (e.g., leg crossing)
• Generalized chorea
• Dystonia
• Stereotypies of hands (e.g., putting hands in mouth), arms (e.g., flapping, waving), or legs (e.g., leg crossing)
• Generalized chorea
• Dystonia
• Autonomic dysfunction
• Constipation
• Gastroesophageal reflux disease
• Abnormal breathing pattern
• Constipation
• Gastroesophageal reflux disease
• Abnormal breathing pattern
• Typically beginning within the first two months of life (up to age 12 months)
• Usually severe, with multiple episodes per day
• Seizure types vary over time. Epileptic spasms (without hypsarrhythmia in 50%) are the initial seizure type in nearly 25% of individuals; other seizure types include tonic, focal, myoclonic, and generalized tonic-clonic; and mixed types that include features of spasms, tonic seizures, and hypermotor seizures. EEG findings may be normal in early infancy.
• Refractory to anti-seizure medications (ASMs)
• Abnormal eye movements that include esotropia, exotropia, and horizontal and rotatory nystagmus
• Abnormal fixation and responsiveness to bright lights
• Inability to maintain nighttime sleep for extended periods
• Excessive daytime sleepiness
• Stereotypies of hands (e.g., putting hands in mouth), arms (e.g., flapping, waving), or legs (e.g., leg crossing)
• Generalized chorea
• Dystonia
• Constipation
• Gastroesophageal reflux disease
• Abnormal breathing pattern
## Establishing the Diagnosis
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making. Reference to "pathogenic variants" in this
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in CDKL5 Deficiency Disorder
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Intronic
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications and array comparative genomic hybridization (CGH). Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Mosaic deletions and inversions disrupting
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in CDKL5 Deficiency Disorder
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Intronic
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications and array comparative genomic hybridization (CGH). Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Mosaic deletions and inversions disrupting
## Clinical Characteristics
CDKL5 deficiency disorder (CDD) is a developmental and epileptic encephalopathy (DEE) characterized by severe early-onset epilepsy and motor, cognitive, visual, and autonomic disturbances [
Because the full spectrum of phenotypic severity is still emerging, especially given the possibility of mosaicism (in males and females) and the potential for skewed X-chromosome inactivation (in females), an individual with a
To date, approximately 500 individuals have been identified with CDD [
Although females are more commonly affected than males (female-to-male ratio is approximately 4:1 [
CDKL5 Deficiency Disorder: Frequency of Select Features
Based on
Families who care for children with CDD rank seizures as a top concern, followed closely by communication, sleep disorders, and vision issues [
Fewer than 1% of individuals with CDD do not have epilepsy [
Gross motor abnormalities are accompanied by generalized hypotonia. Approximately 60% of individuals achieve sitting and approximately 20% achieve independent walking.
Approximately 40%-70% of individuals cannot grasp and hold objects.
Approximately 20% of individuals have spoken language. Most children can use some simple nonverbal communication methods.
Cerebral visual impairment, which affects 80% of individuals, may affect development in each of these areas.
In general, epilepsy is medically refractory throughout life but shows some improvements with age. In up to 40% of individuals there may be a relative temporary improvement in seizures ("honeymoon period") around ages one to two years [
EEG features may be normal in early infancy but subsequently evolve to abnormal background activity that can include a Lennox-Gastaut pattern.
In one study, brain MRIs in 64% (n=14/22) of individuals were normal in the first year of life. Follow-up MRIs showed progressive cortical and cerebellar atrophy. These findings, which can be seen in other DEEs, were hypothesized to be due to either CDD pathogenesis or severe intractable epilepsy [
While genotype-phenotype correlations are emerging [
Phenotypes associated with nonsense alterations throughout the protein appear equally severe, suggesting that truncating variants located within the terminal region of the gene may be less severe [
CDKL5 deficiency disorder (CDD) was previously referred to as an early-onset seizure variant (Hanefeld variant) of Rett syndrome [
The prevalence of CDD in the general population is unknown. An incidence of 2.36 in 100,000 live births (95% CI: 0.805-5.59) was estimated based on identification of CDD in four of 333 Scottish children with epilepsy tested over three years using an epilepsy multigene panel [
## Clinical Description
CDKL5 deficiency disorder (CDD) is a developmental and epileptic encephalopathy (DEE) characterized by severe early-onset epilepsy and motor, cognitive, visual, and autonomic disturbances [
Because the full spectrum of phenotypic severity is still emerging, especially given the possibility of mosaicism (in males and females) and the potential for skewed X-chromosome inactivation (in females), an individual with a
To date, approximately 500 individuals have been identified with CDD [
Although females are more commonly affected than males (female-to-male ratio is approximately 4:1 [
CDKL5 Deficiency Disorder: Frequency of Select Features
Based on
Families who care for children with CDD rank seizures as a top concern, followed closely by communication, sleep disorders, and vision issues [
Fewer than 1% of individuals with CDD do not have epilepsy [
Gross motor abnormalities are accompanied by generalized hypotonia. Approximately 60% of individuals achieve sitting and approximately 20% achieve independent walking.
Approximately 40%-70% of individuals cannot grasp and hold objects.
Approximately 20% of individuals have spoken language. Most children can use some simple nonverbal communication methods.
Cerebral visual impairment, which affects 80% of individuals, may affect development in each of these areas.
In general, epilepsy is medically refractory throughout life but shows some improvements with age. In up to 40% of individuals there may be a relative temporary improvement in seizures ("honeymoon period") around ages one to two years [
EEG features may be normal in early infancy but subsequently evolve to abnormal background activity that can include a Lennox-Gastaut pattern.
In one study, brain MRIs in 64% (n=14/22) of individuals were normal in the first year of life. Follow-up MRIs showed progressive cortical and cerebellar atrophy. These findings, which can be seen in other DEEs, were hypothesized to be due to either CDD pathogenesis or severe intractable epilepsy [
## Genotype-Phenotype Correlations
While genotype-phenotype correlations are emerging [
Phenotypes associated with nonsense alterations throughout the protein appear equally severe, suggesting that truncating variants located within the terminal region of the gene may be less severe [
## Nomenclature
CDKL5 deficiency disorder (CDD) was previously referred to as an early-onset seizure variant (Hanefeld variant) of Rett syndrome [
## Prevalence
The prevalence of CDD in the general population is unknown. An incidence of 2.36 in 100,000 live births (95% CI: 0.805-5.59) was estimated based on identification of CDD in four of 333 Scottish children with epilepsy tested over three years using an epilepsy multigene panel [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Developmental and Epileptic Encephalopathies in the Differential Diagnosis of CDKL5 Deficiency Disorder
Adapted from
AD = autosomal dominant; AR = autosomal recessive; DEE = developmental and epileptic encephalopathy; MOI = mode of inheritance; XL = X-linked
Glucose transporter type 1 deficiency syndrome (Glut1 DS) is most commonly inherited in an autosomal dominant manner. Rarely, Glut1 DS is inherited in an autosomal recessive manner.
Individuals with Angelman syndrome (AS) typically have the disorder as the result of a
## Management
International consensus recommendations for the assessment and management of individuals with CDKL5 deficiency disorder (CDD) have been published [
The management of individuals with CDD is complex and requires multiple specialty appointments; referral to a
To establish the extent of disease and needs in an individual diagnosed with CDD, the evaluations summarized in
CDKL5 Deficiency Disorder: Recommended Evaluations Following Initial Diagnosis
Smaller OFC is assoc w/↑ severity of disorder.
Poor weight gain can reflect nutritional status.
EEG to assess EEG background, epileptiform activity, & seizure type & correlate w/clinical semiology
Prolonged video EEGs may be required to characterize spells of unclear etiology or rule out subclinical status epilepticus.
Motor, adaptive, cognitive, & speech-language delays
Early intervention program / IEP or 504 plan
Issues assoc w/sleep initiation &/or maintenance;
Presence of snoring, apnea, &/or excessive limb movements.
Incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia, poor weight gain, excessive feeding times (greater than 30 minutes per meal), &/or ↑ aspiration risk.
Aspiration pneumonia
Excessive or chronic cough
Need for mgmt of oral secretions
Annual assessments of nutritional status & bone health, incl 25-hydroxyvitamin D intake
Clinical eval of spine; spine radiograph for baseline or to compare w/previous studies for presence of progressive scoliosis; referral to orthopedist if Cobb angle >45 degrees for consideration of surgical correction
Annual assessments of large joint hypo- & hypermobility that may affect function; referral for radiographs & further interventions if indicated
Gross motor & fine motor skills
Contractures, clubfoot, & kypho-scoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or online
Social work involvement to connect families w/parental support, respite, & assistance w/establishing guardianship (see
Palliative care involvement &/or home nursing referral
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; CDD = CDKL5 deficiency disorder; IEP = individual education plan; MOI = mode of inheritance; OFC = occipital frontal circumference; OT = occupational therapy/therapist; PCP = primary care physician; PT = physical therapy/therapist
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
There is no cure for CDD to date [
Ztalmy
CDKL5 Deficiency Disorder: Targeted Therapy
Overall, treatment is assoc w/modest reduction in seizure burden.
Primary side effect is somnolence.
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
CDKL5 Deficiency Disorder: Treatment of Manifestations
An approach to seizure mgmt that balances seizure control w/side effects & attempts to limit number of ASMs to ideally ≤2.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Interventions (e.g., CPAP or supplemental oxygen) that address central &/or obstructive sleep apnea
Pharmacologic therapy to address disorders of sleep initiation & sleep maintenance
Therapies to address features of ASD such as applied behavioral analysis
Pharmacologic therapies for anxiety
Vitamin D supplementation if indicated
PT/OT
Referral for orthopedic surveillance & correction
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
Referral to community or online family support
Based on
ASD = autism spectrum disorder; ASM = anti-seizure medication; CPAP = continuous positive airway pressure; OT = occupational therapy; PT = physical therapy
See
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants, including a teacher of the visually impaired (TVI), should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. This includes access to assistive and augmentative communication [
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
This is in accordance with the Free Appropriate Public Education (FAPE) federal rules. FAPE is an educational right of children with disabilities in the United States that is guaranteed by the Rehabilitation Act of 1973 and the Individuals with Disabilities Education Act (IDEA). The US Supreme Court has determined that services must be provided that will allow children to learn and make progress. Families should work with schools to develop an IEP that recognizes this.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
CDKL5 Deficiency Disorder: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Eval of feeding time
Physical medicine, OT/PT assessment of mobility, self-help skills
Assessment of large joint mobility (e.g., hip surveillance)
Clinical eval of spine
Spine radiograph as needed to identify progressive scoliosis
Referral to orthopedist if Cobb angle >45 degrees for consideration of surgical correction
GERD = gastroesophageal reflux disease; OFC = occipital frontal circumference; OT = occupational therapy; PT = physical therapy
See
Several therapies have been investigated or are ongoing for CDD [
Soticlestat/TAK935 (
Ataluren (
Fenfluramine (
Canabidiol [
Ketogenic diet [
Vagal nerve stimulation [
Protein and gene replacement therapies have been proposed.
Clinical trials and registries assessing natural history and outcome measures are ongoing (
Search
• Smaller OFC is assoc w/↑ severity of disorder.
• Poor weight gain can reflect nutritional status.
• EEG to assess EEG background, epileptiform activity, & seizure type & correlate w/clinical semiology
• Prolonged video EEGs may be required to characterize spells of unclear etiology or rule out subclinical status epilepticus.
• Motor, adaptive, cognitive, & speech-language delays
• Early intervention program / IEP or 504 plan
• Issues assoc w/sleep initiation &/or maintenance;
• Presence of snoring, apnea, &/or excessive limb movements.
• Incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia, poor weight gain, excessive feeding times (greater than 30 minutes per meal), &/or ↑ aspiration risk.
• Aspiration pneumonia
• Excessive or chronic cough
• Need for mgmt of oral secretions
• Annual assessments of nutritional status & bone health, incl 25-hydroxyvitamin D intake
• Clinical eval of spine; spine radiograph for baseline or to compare w/previous studies for presence of progressive scoliosis; referral to orthopedist if Cobb angle >45 degrees for consideration of surgical correction
• Annual assessments of large joint hypo- & hypermobility that may affect function; referral for radiographs & further interventions if indicated
• Gross motor & fine motor skills
• Contractures, clubfoot, & kypho-scoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or online
• Social work involvement to connect families w/parental support, respite, & assistance w/establishing guardianship (see
• Palliative care involvement &/or home nursing referral
• Overall, treatment is assoc w/modest reduction in seizure burden.
• Primary side effect is somnolence.
• An approach to seizure mgmt that balances seizure control w/side effects & attempts to limit number of ASMs to ideally ≤2.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Interventions (e.g., CPAP or supplemental oxygen) that address central &/or obstructive sleep apnea
• Pharmacologic therapy to address disorders of sleep initiation & sleep maintenance
• Therapies to address features of ASD such as applied behavioral analysis
• Pharmacologic therapies for anxiety
• Vitamin D supplementation if indicated
• PT/OT
• Referral for orthopedic surveillance & correction
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• Referral to community or online family support
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants, including a teacher of the visually impaired (TVI), should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. This includes access to assistive and augmentative communication [
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• This is in accordance with the Free Appropriate Public Education (FAPE) federal rules. FAPE is an educational right of children with disabilities in the United States that is guaranteed by the Rehabilitation Act of 1973 and the Individuals with Disabilities Education Act (IDEA). The US Supreme Court has determined that services must be provided that will allow children to learn and make progress. Families should work with schools to develop an IEP that recognizes this.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants, including a teacher of the visually impaired (TVI), should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. This includes access to assistive and augmentative communication [
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• This is in accordance with the Free Appropriate Public Education (FAPE) federal rules. FAPE is an educational right of children with disabilities in the United States that is guaranteed by the Rehabilitation Act of 1973 and the Individuals with Disabilities Education Act (IDEA). The US Supreme Court has determined that services must be provided that will allow children to learn and make progress. Families should work with schools to develop an IEP that recognizes this.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants, including a teacher of the visually impaired (TVI), should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. This includes access to assistive and augmentative communication [
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• This is in accordance with the Free Appropriate Public Education (FAPE) federal rules. FAPE is an educational right of children with disabilities in the United States that is guaranteed by the Rehabilitation Act of 1973 and the Individuals with Disabilities Education Act (IDEA). The US Supreme Court has determined that services must be provided that will allow children to learn and make progress. Families should work with schools to develop an IEP that recognizes this.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Eval of feeding time
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Assessment of large joint mobility (e.g., hip surveillance)
• Clinical eval of spine
• Spine radiograph as needed to identify progressive scoliosis
• Referral to orthopedist if Cobb angle >45 degrees for consideration of surgical correction
• Soticlestat/TAK935 (
• Ataluren (
• Fenfluramine (
• Canabidiol [
• Ketogenic diet [
• Vagal nerve stimulation [
• Protein and gene replacement therapies have been proposed.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CDD, the evaluations summarized in
CDKL5 Deficiency Disorder: Recommended Evaluations Following Initial Diagnosis
Smaller OFC is assoc w/↑ severity of disorder.
Poor weight gain can reflect nutritional status.
EEG to assess EEG background, epileptiform activity, & seizure type & correlate w/clinical semiology
Prolonged video EEGs may be required to characterize spells of unclear etiology or rule out subclinical status epilepticus.
Motor, adaptive, cognitive, & speech-language delays
Early intervention program / IEP or 504 plan
Issues assoc w/sleep initiation &/or maintenance;
Presence of snoring, apnea, &/or excessive limb movements.
Incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia, poor weight gain, excessive feeding times (greater than 30 minutes per meal), &/or ↑ aspiration risk.
Aspiration pneumonia
Excessive or chronic cough
Need for mgmt of oral secretions
Annual assessments of nutritional status & bone health, incl 25-hydroxyvitamin D intake
Clinical eval of spine; spine radiograph for baseline or to compare w/previous studies for presence of progressive scoliosis; referral to orthopedist if Cobb angle >45 degrees for consideration of surgical correction
Annual assessments of large joint hypo- & hypermobility that may affect function; referral for radiographs & further interventions if indicated
Gross motor & fine motor skills
Contractures, clubfoot, & kypho-scoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or online
Social work involvement to connect families w/parental support, respite, & assistance w/establishing guardianship (see
Palliative care involvement &/or home nursing referral
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; CDD = CDKL5 deficiency disorder; IEP = individual education plan; MOI = mode of inheritance; OFC = occipital frontal circumference; OT = occupational therapy/therapist; PCP = primary care physician; PT = physical therapy/therapist
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Smaller OFC is assoc w/↑ severity of disorder.
• Poor weight gain can reflect nutritional status.
• EEG to assess EEG background, epileptiform activity, & seizure type & correlate w/clinical semiology
• Prolonged video EEGs may be required to characterize spells of unclear etiology or rule out subclinical status epilepticus.
• Motor, adaptive, cognitive, & speech-language delays
• Early intervention program / IEP or 504 plan
• Issues assoc w/sleep initiation &/or maintenance;
• Presence of snoring, apnea, &/or excessive limb movements.
• Incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia, poor weight gain, excessive feeding times (greater than 30 minutes per meal), &/or ↑ aspiration risk.
• Aspiration pneumonia
• Excessive or chronic cough
• Need for mgmt of oral secretions
• Annual assessments of nutritional status & bone health, incl 25-hydroxyvitamin D intake
• Clinical eval of spine; spine radiograph for baseline or to compare w/previous studies for presence of progressive scoliosis; referral to orthopedist if Cobb angle >45 degrees for consideration of surgical correction
• Annual assessments of large joint hypo- & hypermobility that may affect function; referral for radiographs & further interventions if indicated
• Gross motor & fine motor skills
• Contractures, clubfoot, & kypho-scoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or online
• Social work involvement to connect families w/parental support, respite, & assistance w/establishing guardianship (see
• Palliative care involvement &/or home nursing referral
## Treatment of Manifestations
There is no cure for CDD to date [
Ztalmy
CDKL5 Deficiency Disorder: Targeted Therapy
Overall, treatment is assoc w/modest reduction in seizure burden.
Primary side effect is somnolence.
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
CDKL5 Deficiency Disorder: Treatment of Manifestations
An approach to seizure mgmt that balances seizure control w/side effects & attempts to limit number of ASMs to ideally ≤2.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Interventions (e.g., CPAP or supplemental oxygen) that address central &/or obstructive sleep apnea
Pharmacologic therapy to address disorders of sleep initiation & sleep maintenance
Therapies to address features of ASD such as applied behavioral analysis
Pharmacologic therapies for anxiety
Vitamin D supplementation if indicated
PT/OT
Referral for orthopedic surveillance & correction
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
Referral to community or online family support
Based on
ASD = autism spectrum disorder; ASM = anti-seizure medication; CPAP = continuous positive airway pressure; OT = occupational therapy; PT = physical therapy
See
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants, including a teacher of the visually impaired (TVI), should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. This includes access to assistive and augmentative communication [
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
This is in accordance with the Free Appropriate Public Education (FAPE) federal rules. FAPE is an educational right of children with disabilities in the United States that is guaranteed by the Rehabilitation Act of 1973 and the Individuals with Disabilities Education Act (IDEA). The US Supreme Court has determined that services must be provided that will allow children to learn and make progress. Families should work with schools to develop an IEP that recognizes this.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Overall, treatment is assoc w/modest reduction in seizure burden.
• Primary side effect is somnolence.
• An approach to seizure mgmt that balances seizure control w/side effects & attempts to limit number of ASMs to ideally ≤2.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Interventions (e.g., CPAP or supplemental oxygen) that address central &/or obstructive sleep apnea
• Pharmacologic therapy to address disorders of sleep initiation & sleep maintenance
• Therapies to address features of ASD such as applied behavioral analysis
• Pharmacologic therapies for anxiety
• Vitamin D supplementation if indicated
• PT/OT
• Referral for orthopedic surveillance & correction
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• Referral to community or online family support
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants, including a teacher of the visually impaired (TVI), should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. This includes access to assistive and augmentative communication [
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• This is in accordance with the Free Appropriate Public Education (FAPE) federal rules. FAPE is an educational right of children with disabilities in the United States that is guaranteed by the Rehabilitation Act of 1973 and the Individuals with Disabilities Education Act (IDEA). The US Supreme Court has determined that services must be provided that will allow children to learn and make progress. Families should work with schools to develop an IEP that recognizes this.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants, including a teacher of the visually impaired (TVI), should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. This includes access to assistive and augmentative communication [
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• This is in accordance with the Free Appropriate Public Education (FAPE) federal rules. FAPE is an educational right of children with disabilities in the United States that is guaranteed by the Rehabilitation Act of 1973 and the Individuals with Disabilities Education Act (IDEA). The US Supreme Court has determined that services must be provided that will allow children to learn and make progress. Families should work with schools to develop an IEP that recognizes this.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants, including a teacher of the visually impaired (TVI), should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. This includes access to assistive and augmentative communication [
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• This is in accordance with the Free Appropriate Public Education (FAPE) federal rules. FAPE is an educational right of children with disabilities in the United States that is guaranteed by the Rehabilitation Act of 1973 and the Individuals with Disabilities Education Act (IDEA). The US Supreme Court has determined that services must be provided that will allow children to learn and make progress. Families should work with schools to develop an IEP that recognizes this.
## Targeted Therapy
Ztalmy
CDKL5 Deficiency Disorder: Targeted Therapy
Overall, treatment is assoc w/modest reduction in seizure burden.
Primary side effect is somnolence.
• Overall, treatment is assoc w/modest reduction in seizure burden.
• Primary side effect is somnolence.
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
CDKL5 Deficiency Disorder: Treatment of Manifestations
An approach to seizure mgmt that balances seizure control w/side effects & attempts to limit number of ASMs to ideally ≤2.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Interventions (e.g., CPAP or supplemental oxygen) that address central &/or obstructive sleep apnea
Pharmacologic therapy to address disorders of sleep initiation & sleep maintenance
Therapies to address features of ASD such as applied behavioral analysis
Pharmacologic therapies for anxiety
Vitamin D supplementation if indicated
PT/OT
Referral for orthopedic surveillance & correction
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
Referral to community or online family support
Based on
ASD = autism spectrum disorder; ASM = anti-seizure medication; CPAP = continuous positive airway pressure; OT = occupational therapy; PT = physical therapy
See
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants, including a teacher of the visually impaired (TVI), should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. This includes access to assistive and augmentative communication [
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
This is in accordance with the Free Appropriate Public Education (FAPE) federal rules. FAPE is an educational right of children with disabilities in the United States that is guaranteed by the Rehabilitation Act of 1973 and the Individuals with Disabilities Education Act (IDEA). The US Supreme Court has determined that services must be provided that will allow children to learn and make progress. Families should work with schools to develop an IEP that recognizes this.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An approach to seizure mgmt that balances seizure control w/side effects & attempts to limit number of ASMs to ideally ≤2.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Interventions (e.g., CPAP or supplemental oxygen) that address central &/or obstructive sleep apnea
• Pharmacologic therapy to address disorders of sleep initiation & sleep maintenance
• Therapies to address features of ASD such as applied behavioral analysis
• Pharmacologic therapies for anxiety
• Vitamin D supplementation if indicated
• PT/OT
• Referral for orthopedic surveillance & correction
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• Referral to community or online family support
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants, including a teacher of the visually impaired (TVI), should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. This includes access to assistive and augmentative communication [
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• This is in accordance with the Free Appropriate Public Education (FAPE) federal rules. FAPE is an educational right of children with disabilities in the United States that is guaranteed by the Rehabilitation Act of 1973 and the Individuals with Disabilities Education Act (IDEA). The US Supreme Court has determined that services must be provided that will allow children to learn and make progress. Families should work with schools to develop an IEP that recognizes this.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants, including a teacher of the visually impaired (TVI), should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. This includes access to assistive and augmentative communication [
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• This is in accordance with the Free Appropriate Public Education (FAPE) federal rules. FAPE is an educational right of children with disabilities in the United States that is guaranteed by the Rehabilitation Act of 1973 and the Individuals with Disabilities Education Act (IDEA). The US Supreme Court has determined that services must be provided that will allow children to learn and make progress. Families should work with schools to develop an IEP that recognizes this.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants, including a teacher of the visually impaired (TVI), should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. This includes access to assistive and augmentative communication [
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• This is in accordance with the Free Appropriate Public Education (FAPE) federal rules. FAPE is an educational right of children with disabilities in the United States that is guaranteed by the Rehabilitation Act of 1973 and the Individuals with Disabilities Education Act (IDEA). The US Supreme Court has determined that services must be provided that will allow children to learn and make progress. Families should work with schools to develop an IEP that recognizes this.
##
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants, including a teacher of the visually impaired (TVI), should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. This includes access to assistive and augmentative communication [
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
This is in accordance with the Free Appropriate Public Education (FAPE) federal rules. FAPE is an educational right of children with disabilities in the United States that is guaranteed by the Rehabilitation Act of 1973 and the Individuals with Disabilities Education Act (IDEA). The US Supreme Court has determined that services must be provided that will allow children to learn and make progress. Families should work with schools to develop an IEP that recognizes this.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants, including a teacher of the visually impaired (TVI), should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. This includes access to assistive and augmentative communication [
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• This is in accordance with the Free Appropriate Public Education (FAPE) federal rules. FAPE is an educational right of children with disabilities in the United States that is guaranteed by the Rehabilitation Act of 1973 and the Individuals with Disabilities Education Act (IDEA). The US Supreme Court has determined that services must be provided that will allow children to learn and make progress. Families should work with schools to develop an IEP that recognizes this.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants, including a teacher of the visually impaired (TVI), should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. This includes access to assistive and augmentative communication [
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• This is in accordance with the Free Appropriate Public Education (FAPE) federal rules. FAPE is an educational right of children with disabilities in the United States that is guaranteed by the Rehabilitation Act of 1973 and the Individuals with Disabilities Education Act (IDEA). The US Supreme Court has determined that services must be provided that will allow children to learn and make progress. Families should work with schools to develop an IEP that recognizes this.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants, including a teacher of the visually impaired (TVI), should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. This includes access to assistive and augmentative communication [
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• This is in accordance with the Free Appropriate Public Education (FAPE) federal rules. FAPE is an educational right of children with disabilities in the United States that is guaranteed by the Rehabilitation Act of 1973 and the Individuals with Disabilities Education Act (IDEA). The US Supreme Court has determined that services must be provided that will allow children to learn and make progress. Families should work with schools to develop an IEP that recognizes this.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
CDKL5 Deficiency Disorder: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Eval of feeding time
Physical medicine, OT/PT assessment of mobility, self-help skills
Assessment of large joint mobility (e.g., hip surveillance)
Clinical eval of spine
Spine radiograph as needed to identify progressive scoliosis
Referral to orthopedist if Cobb angle >45 degrees for consideration of surgical correction
GERD = gastroesophageal reflux disease; OFC = occipital frontal circumference; OT = occupational therapy; PT = physical therapy
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Eval of feeding time
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Assessment of large joint mobility (e.g., hip surveillance)
• Clinical eval of spine
• Spine radiograph as needed to identify progressive scoliosis
• Referral to orthopedist if Cobb angle >45 degrees for consideration of surgical correction
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Several therapies have been investigated or are ongoing for CDD [
Soticlestat/TAK935 (
Ataluren (
Fenfluramine (
Canabidiol [
Ketogenic diet [
Vagal nerve stimulation [
Protein and gene replacement therapies have been proposed.
Clinical trials and registries assessing natural history and outcome measures are ongoing (
Search
• Soticlestat/TAK935 (
• Ataluren (
• Fenfluramine (
• Canabidiol [
• Ketogenic diet [
• Vagal nerve stimulation [
• Protein and gene replacement therapies have been proposed.
## Genetic Counseling
CDKL5 deficiency disorder (CDD) is inherited in an X-linked manner.
Approximately 99% of affected individuals represent simplex cases (i.e., a single occurrence in the family). The majority of individuals who represent simplex cases have the disorder as the result of a
Rarely, an individual with CDD has the disorder as the result of a
Evaluation/testing of the father of the proband is not required. If the proband is female, it is presumed that the father is not hemizygous for the
Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in germ (gonadal) cells only.
If the
If the mother of the proband has a CDKL5 pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
Females who inherit the pathogenic variant will be heterozygous and are at high risk of being affected, although skewed X-chromosome inactivation and the possibility of other attenuating factors may result in a variable phenotype.
Males who inherit the pathogenic variant will be hemizygous and will most likely be severely affected [
If the proband represents a simplex case and if the
Each child of a female proband with CDD has a 50% chance of inheriting the
Males with CDD are not known to reproduce.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a
Once the
Note: Because presumed maternal germline mosaicism for a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Approximately 99% of affected individuals represent simplex cases (i.e., a single occurrence in the family). The majority of individuals who represent simplex cases have the disorder as the result of a
• Rarely, an individual with CDD has the disorder as the result of a
• Evaluation/testing of the father of the proband is not required. If the proband is female, it is presumed that the father is not hemizygous for the
• Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in germ (gonadal) cells only.
• If the
• If the mother of the proband has a CDKL5 pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
• Females who inherit the pathogenic variant will be heterozygous and are at high risk of being affected, although skewed X-chromosome inactivation and the possibility of other attenuating factors may result in a variable phenotype.
• Males who inherit the pathogenic variant will be hemizygous and will most likely be severely affected [
• Females who inherit the pathogenic variant will be heterozygous and are at high risk of being affected, although skewed X-chromosome inactivation and the possibility of other attenuating factors may result in a variable phenotype.
• Males who inherit the pathogenic variant will be hemizygous and will most likely be severely affected [
• If the proband represents a simplex case and if the
• Females who inherit the pathogenic variant will be heterozygous and are at high risk of being affected, although skewed X-chromosome inactivation and the possibility of other attenuating factors may result in a variable phenotype.
• Males who inherit the pathogenic variant will be hemizygous and will most likely be severely affected [
• Each child of a female proband with CDD has a 50% chance of inheriting the
• Males with CDD are not known to reproduce.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a
## Mode of Inheritance
CDKL5 deficiency disorder (CDD) is inherited in an X-linked manner.
## Risk to Family Members
Approximately 99% of affected individuals represent simplex cases (i.e., a single occurrence in the family). The majority of individuals who represent simplex cases have the disorder as the result of a
Rarely, an individual with CDD has the disorder as the result of a
Evaluation/testing of the father of the proband is not required. If the proband is female, it is presumed that the father is not hemizygous for the
Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in germ (gonadal) cells only.
If the
If the mother of the proband has a CDKL5 pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
Females who inherit the pathogenic variant will be heterozygous and are at high risk of being affected, although skewed X-chromosome inactivation and the possibility of other attenuating factors may result in a variable phenotype.
Males who inherit the pathogenic variant will be hemizygous and will most likely be severely affected [
If the proband represents a simplex case and if the
Each child of a female proband with CDD has a 50% chance of inheriting the
Males with CDD are not known to reproduce.
• Approximately 99% of affected individuals represent simplex cases (i.e., a single occurrence in the family). The majority of individuals who represent simplex cases have the disorder as the result of a
• Rarely, an individual with CDD has the disorder as the result of a
• Evaluation/testing of the father of the proband is not required. If the proband is female, it is presumed that the father is not hemizygous for the
• Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in germ (gonadal) cells only.
• If the
• If the mother of the proband has a CDKL5 pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
• Females who inherit the pathogenic variant will be heterozygous and are at high risk of being affected, although skewed X-chromosome inactivation and the possibility of other attenuating factors may result in a variable phenotype.
• Males who inherit the pathogenic variant will be hemizygous and will most likely be severely affected [
• Females who inherit the pathogenic variant will be heterozygous and are at high risk of being affected, although skewed X-chromosome inactivation and the possibility of other attenuating factors may result in a variable phenotype.
• Males who inherit the pathogenic variant will be hemizygous and will most likely be severely affected [
• If the proband represents a simplex case and if the
• Females who inherit the pathogenic variant will be heterozygous and are at high risk of being affected, although skewed X-chromosome inactivation and the possibility of other attenuating factors may result in a variable phenotype.
• Males who inherit the pathogenic variant will be hemizygous and will most likely be severely affected [
• Each child of a female proband with CDD has a 50% chance of inheriting the
• Males with CDD are not known to reproduce.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Note: Because presumed maternal germline mosaicism for a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
International Foundation for CDKL5 Research
•
•
•
• International Foundation for CDKL5 Research
•
•
•
•
•
•
•
•
## Molecular Genetics
CDKL5 Deficiency Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CDKL5 Deficiency Disorder (
CDKL5, an X-linked gene, encodes cyclin-dependent kinase-like 5 (CDKL5), a 115-kD serine-threonine kinase and member of the CMGC family, which includes cyclin-dependent kinases (
CDKL5 interacts with PSD-95 [
Loss of CDKL5 leads to a global reduction in excitatory synapse numbers [
Analysis of
Note: Duplications [
See
• See
## Molecular Pathogenesis
CDKL5, an X-linked gene, encodes cyclin-dependent kinase-like 5 (CDKL5), a 115-kD serine-threonine kinase and member of the CMGC family, which includes cyclin-dependent kinases (
CDKL5 interacts with PSD-95 [
Loss of CDKL5 leads to a global reduction in excitatory synapse numbers [
Analysis of
Note: Duplications [
See
• See
## Chapter Notes
Tim Benke, MD, PhDPonzio Family Endowed Chair in Neurology ResearchMedical Director, Rett ClinicResearch Director, Neuroscience InstituteChildren's Hospital ColoradoProfessor of Pediatrics, Neurology, Pharmacology & OtolaryngologyUniversity of Colorado School of Medicine
Tim Benke (
Eric Marsh (
Contact Drs Tim Benke, Scott Demarest, Jenny Downs, Helen Leonard, Heather Olson, and Isa Haviland to inquire about individuals with
The authors recognize the following support: NIH-NINDS: R21 NS112770 (Benke), U01NS114312 (PD/Benke); NIH-NICHD: U54 HD061222 (PD/Percy), Rocky Mountain Rett Association (Benke), International Foundation for CDKL5 Research (all), Children's Hospital Colorado Foundation: Ponzio Family Chair in Neurology Research (Benke), NIH-NINDS: 5K23NS107646 (Olson), Loulou Foundation (Olson, Haviland), NIH-NIMH: 2T32MH112510 (Haviland).
1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines
11 April 2024 (bp) Review posted live
22 August 2023 (tb) Original submission
• 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines
• 11 April 2024 (bp) Review posted live
• 22 August 2023 (tb) Original submission
## Author Notes
Tim Benke, MD, PhDPonzio Family Endowed Chair in Neurology ResearchMedical Director, Rett ClinicResearch Director, Neuroscience InstituteChildren's Hospital ColoradoProfessor of Pediatrics, Neurology, Pharmacology & OtolaryngologyUniversity of Colorado School of Medicine
Tim Benke (
Eric Marsh (
Contact Drs Tim Benke, Scott Demarest, Jenny Downs, Helen Leonard, Heather Olson, and Isa Haviland to inquire about individuals with
## Acknowledgments
The authors recognize the following support: NIH-NINDS: R21 NS112770 (Benke), U01NS114312 (PD/Benke); NIH-NICHD: U54 HD061222 (PD/Percy), Rocky Mountain Rett Association (Benke), International Foundation for CDKL5 Research (all), Children's Hospital Colorado Foundation: Ponzio Family Chair in Neurology Research (Benke), NIH-NINDS: 5K23NS107646 (Olson), Loulou Foundation (Olson, Haviland), NIH-NIMH: 2T32MH112510 (Haviland).
## Revision History
1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines
11 April 2024 (bp) Review posted live
22 August 2023 (tb) Original submission
• 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines
• 11 April 2024 (bp) Review posted live
• 22 August 2023 (tb) Original submission
## Key Sections in this
## References
## Literature Cited
|
[] |
11/4/2024
|
1/5/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
cdkn2a-cpd
|
cdkn2a-cpd
|
[
"CDKN2A-Related Melanoma-Astrocytoma Syndrome (MAS)",
"Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM)",
"Melanoma-Pancreatic Cancer Syndrome",
"CDKN2A-Related Melanoma-Astrocytoma Syndrome (MAS)",
"Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM)",
"Melanoma-Pancreatic Cancer Syndrome",
"Cyclin-dependent kinase inhibitor 2A",
"CDKN2A",
"CDKN2A Cancer Predisposition"
] |
Michelle F Jacobs, Andrea M Murad, Nicole D Cho, Kelly B Cha, Elena M Stoffel, Tobias Else
|
Summary The diagnosis of
|
## Diagnosis
≥3 cutaneous melanomas at any age
Pancreatic cancer and melanoma at any age
≥1 melanoma AND multiple melanocytic nevi (>50)
Astrocytoma and melanoma in the same individual at any age
Astrocytoma and family history of melanoma in two first-degree relatives at any age
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision-making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
• ≥3 cutaneous melanomas at any age
• Pancreatic cancer and melanoma at any age
• ≥1 melanoma AND multiple melanocytic nevi (>50)
• Astrocytoma and melanoma in the same individual at any age
• Astrocytoma and family history of melanoma in two first-degree relatives at any age
## Suggestive Findings
≥3 cutaneous melanomas at any age
Pancreatic cancer and melanoma at any age
≥1 melanoma AND multiple melanocytic nevi (>50)
Astrocytoma and melanoma in the same individual at any age
Astrocytoma and family history of melanoma in two first-degree relatives at any age
• ≥3 cutaneous melanomas at any age
• Pancreatic cancer and melanoma at any age
• ≥1 melanoma AND multiple melanocytic nevi (>50)
• Astrocytoma and melanoma in the same individual at any age
• Astrocytoma and family history of melanoma in two first-degree relatives at any age
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision-making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
## Clinical Characteristics
Pathogenic variants in
The penetrance for
The true prevalence of
The prevalence of
## Clinical Description
## Genotype-Phenotype Correlations
Pathogenic variants in
## Penetrance
The penetrance for
## Prevalence
The true prevalence of
The prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Other cancer/tumor predisposition syndromes associated with melanoma and/or pancreatic cancer are listed in
Hereditary Cancer Syndromes of Interest in the Differential Diagnosis of
Uveal melanoma
Malignant mesothelioma
Renal cell carcinoma
Basal cell carcinoma
Breast
Ovarian
Prostate
Cutaneous melanoma
Pancreatic
Breast
Ovarian
Prostate
Colorectal
Endometrium
Ovarian
Gastric
Small bowel
Urinary tract
Biliary tract
Brain
Skin (sebaceous adenomas, sebaceous carcinomas, & keratoacanthomas)
Prostate
Breast
Male breast cancer
Ovarian
Chronic lymphocytic leukemia
Angiosarcoma
Glioma
Thyroid
Breast
Kidney
Endometrium
Brain/CNS tumors
Colorectal
Gastric
Breast
Ovarian
Cutaneous melanoma
Pancreatic
Adrenocortical carcinoma
Breast
CNS tumors
Osteosarcoma
Soft-tissue sarcoma
Leukemia
Gastrointestinal cancers
Lung
AD = autosomal dominant; CNS = central nervous system; MOI = mode of inheritance
See linked
• Uveal melanoma
• Malignant mesothelioma
• Renal cell carcinoma
• Basal cell carcinoma
• Breast
• Ovarian
• Prostate
• Cutaneous melanoma
• Pancreatic
• Breast
• Ovarian
• Prostate
• Colorectal
• Endometrium
• Ovarian
• Gastric
• Small bowel
• Urinary tract
• Biliary tract
• Brain
• Skin (sebaceous adenomas, sebaceous carcinomas, & keratoacanthomas)
• Prostate
• Breast
• Male breast cancer
• Ovarian
• Chronic lymphocytic leukemia
• Angiosarcoma
• Glioma
• Thyroid
• Breast
• Kidney
• Endometrium
• Brain/CNS tumors
• Colorectal
• Gastric
• Breast
• Ovarian
• Cutaneous melanoma
• Pancreatic
• Adrenocortical carcinoma
• Breast
• CNS tumors
• Osteosarcoma
• Soft-tissue sarcoma
• Leukemia
• Gastrointestinal cancers
• Lung
## Management
The National Comprehensive Cancer Network has clinical practice guidelines for the care of individuals with
To establish the extent of disease and needs in an individual diagnosed with
MOI = mode of inheritance
Published clinical practice guidelines do not provide a starting age. Melanoma has been reported as young as age nine years [
It is recommended that screening be performed in experienced high-volume centers. Screening should only take place after an in-depth discussion about the potential limitations to screening, including cost, the high incidence of benign or indeterminate pancreatic abnormalities, and uncertainties about the potential benefits of pancreatic cancer screening.
See NCCN Guidelines,
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
The treatments for
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Every 6 mos beginning at diagnosis
Note: Individuals at risk but whose genetic status is unknown should undergo skin exams at their well child / health maintenance visits.
Annually (alternating)
Starting at age 40 yrs or 10 yrs younger than earliest exocrine pancreatic cancer diagnosis in family, whichever is earlier
Published clinical practice guidelines do not provide a starting age. Melanoma has been reported as young as age nine years [
Screening should be performed in experienced high-volume centers. Screening should only take place after an in-depth discussion about the potential limitations to screening, including cost, the high incidence of benign or indeterminate pancreatic abnormalities, and uncertainties about the potential benefits of pancreatic cancer screening.
See NCCN Guidelines,
Avoid the following:
Ultraviolet light exposure, particularly sunburns and tanning booths
Tobacco use
Molecular genetic testing for the familial
In general, genetic testing for
See
Other clinical trials available for individuals with
Ilorasertib (
Milademetan in combination with atezolizumab (
Abemaciclib when administered with bevacizumab (
AZD1775 monotherapy (
Palbociclib and cetuximab in comparison with cetuximab monotherapy (
Search
• Every 6 mos beginning at diagnosis
• Note: Individuals at risk but whose genetic status is unknown should undergo skin exams at their well child / health maintenance visits.
• Annually (alternating)
• Starting at age 40 yrs or 10 yrs younger than earliest exocrine pancreatic cancer diagnosis in family, whichever is earlier
• Ultraviolet light exposure, particularly sunburns and tanning booths
• Tobacco use
• Ilorasertib (
• Milademetan in combination with atezolizumab (
• Abemaciclib when administered with bevacizumab (
• AZD1775 monotherapy (
• Palbociclib and cetuximab in comparison with cetuximab monotherapy (
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
MOI = mode of inheritance
Published clinical practice guidelines do not provide a starting age. Melanoma has been reported as young as age nine years [
It is recommended that screening be performed in experienced high-volume centers. Screening should only take place after an in-depth discussion about the potential limitations to screening, including cost, the high incidence of benign or indeterminate pancreatic abnormalities, and uncertainties about the potential benefits of pancreatic cancer screening.
See NCCN Guidelines,
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
## Treatment of Manifestations
The treatments for
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Every 6 mos beginning at diagnosis
Note: Individuals at risk but whose genetic status is unknown should undergo skin exams at their well child / health maintenance visits.
Annually (alternating)
Starting at age 40 yrs or 10 yrs younger than earliest exocrine pancreatic cancer diagnosis in family, whichever is earlier
Published clinical practice guidelines do not provide a starting age. Melanoma has been reported as young as age nine years [
Screening should be performed in experienced high-volume centers. Screening should only take place after an in-depth discussion about the potential limitations to screening, including cost, the high incidence of benign or indeterminate pancreatic abnormalities, and uncertainties about the potential benefits of pancreatic cancer screening.
See NCCN Guidelines,
• Every 6 mos beginning at diagnosis
• Note: Individuals at risk but whose genetic status is unknown should undergo skin exams at their well child / health maintenance visits.
• Annually (alternating)
• Starting at age 40 yrs or 10 yrs younger than earliest exocrine pancreatic cancer diagnosis in family, whichever is earlier
## Agents/Circumstances to Avoid
Avoid the following:
Ultraviolet light exposure, particularly sunburns and tanning booths
Tobacco use
• Ultraviolet light exposure, particularly sunburns and tanning booths
• Tobacco use
## Evaluation of Relatives at Risk
Molecular genetic testing for the familial
In general, genetic testing for
See
## Therapies Under Investigation
Other clinical trials available for individuals with
Ilorasertib (
Milademetan in combination with atezolizumab (
Abemaciclib when administered with bevacizumab (
AZD1775 monotherapy (
Palbociclib and cetuximab in comparison with cetuximab monotherapy (
Search
• Ilorasertib (
• Milademetan in combination with atezolizumab (
• Abemaciclib when administered with bevacizumab (
• AZD1775 monotherapy (
• Palbociclib and cetuximab in comparison with cetuximab monotherapy (
## Genetic Counseling
The majority of individuals diagnosed with
Individuals with
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the gonadal cells only.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the
The risk of developing cancer in a sib who inherits the familial
If the
If the proband is the only family member known to have
See Management,
Predictive testing for at-risk relatives is possible once the
Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
In a family with an established diagnosis of
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The majority of individuals diagnosed with
• Individuals with
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the gonadal cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the gonadal cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the gonadal cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the
• The risk of developing cancer in a sib who inherits the familial
• If the
• If the proband is the only family member known to have
• Predictive testing for at-risk relatives is possible once the
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
## Risk to Family Members
The majority of individuals diagnosed with
Individuals with
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the gonadal cells only.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the
The risk of developing cancer in a sib who inherits the familial
If the
If the proband is the only family member known to have
• The majority of individuals diagnosed with
• Individuals with
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the gonadal cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the gonadal cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the gonadal cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the
• The risk of developing cancer in a sib who inherits the familial
• If the
• If the proband is the only family member known to have
## Related Genetic Counseling Issues
See Management,
Predictive testing for at-risk relatives is possible once the
Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
In a family with an established diagnosis of
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Predictive testing for at-risk relatives is possible once the
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Facing Hereditary Cancer Empowered
•
•
•
•
•
•
• Facing Hereditary Cancer Empowered
•
## Molecular Genetics
CDKN2A Cancer Predisposition: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CDKN2A Cancer Predisposition (
Swedish founder variant; accounts for 90% of pathogenic variants in this population [
See
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• Swedish founder variant; accounts for 90% of pathogenic variants in this population [
• See
## Molecular Pathogenesis
Swedish founder variant; accounts for 90% of pathogenic variants in this population [
See
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• Swedish founder variant; accounts for 90% of pathogenic variants in this population [
• See
## Chapter Notes
17 July 2025 (sw) Review posted live
1 November 2024 (te) Original submission
• 17 July 2025 (sw) Review posted live
• 1 November 2024 (te) Original submission
## Revision History
17 July 2025 (sw) Review posted live
1 November 2024 (te) Original submission
• 17 July 2025 (sw) Review posted live
• 1 November 2024 (te) Original submission
## References
## Literature Cited
|
[] |
17/7/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
cdls
|
cdls
|
[
"BDLS",
"Brachmann-de Lange Syndrome",
"CdLS",
"de Lange Syndrome",
"BDLS",
"Brachmann-de Lange Syndrome",
"CdLS",
"de Lange Syndrome",
"Bromodomain-containing protein 4",
"Double-strand-break repair protein rad21 homolog",
"Histone deacetylase 8",
"Nipped-B-like protein",
"Structural maintenance of chromosomes protein 1A",
"Structural maintenance of chromosomes protein 3",
"BRD4",
"HDAC8",
"NIPBL",
"RAD21",
"SMC1A",
"SMC3",
"Cornelia de Lange Syndrome"
] |
Cornelia de Lange Syndrome
|
Matthew A Deardorff, Sarah E Noon, Ian D Krantz
|
Summary Cornelia de Lange syndrome (CdLS) encompasses a spectrum of findings from mild to severe. Severe (classic) CdLS is characterized by distinctive facial features, growth restriction (prenatal onset; <5th centile throughout life), hypertrichosis, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nasal bridge with anteverted nares, small widely spaced teeth, and microcephaly. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS. Across the CdLS spectrum IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Other frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia. The diagnosis of CdLS is established in a proband with suggestive clinical features and/or by identification of a heterozygous pathogenic variant in
|
## Diagnosis
Cornelia de Lange syndrome (CdLS) constitutes a clinical spectrum, with some individuals having milder features and others displaying more severe, classic features. An international consensus statement has defined both cardinal and suggestive features, as well as a scoring system to define classic and non-classic CdLS to assist with clinical genetic testing decisions [
Cornelia de Lange syndrome (CdLS)
Microcephaly (mean occipital frontal circumference <2nd centile)
Synophrys with highly arched and/or thick eyebrows
Long, thick eyelashes
Short nasal bridge, upturned nasal tip with anteverted nares
Long and/or smooth philtrum, thin vermilion of the upper lip, downturned corners of the mouth
Highly arched palate with or without cleft palate
Small widely spaced teeth
Micrognathia with or without mandibular spurs
The diagnosis of CdLS
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Cornelia de Lange syndrome can be broad, individuals with distinctive features described in
When the phenotypic findings suggest the diagnosis of Cornelia de Lange syndrome, molecular genetic testing approaches include use of a
This approach is most likely to identify the genetic cause of the condition while limiting identification pathogenic variants and of variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
For an introduction to multigene panels click
For individuals with features strongly suggestive of CdLS who score highly on the international consensus scoring criteria or for whom multigene panel testing is not available,
If no
If no
When the diagnosis of Cornelia de Lange syndrome is not strongly considered due to atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cornelia de Lange Syndrome
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Somatic mosaicism for
Gene-targeted deletion/duplication analysis of
Cytogenetic testing or chromosomal microarray (CMA) may also be considered in those with classic features of CdLS but normal molecular genetic testing because a few individuals with large deletions of 5p13 that include
• Microcephaly (mean occipital frontal circumference <2nd centile)
• Synophrys with highly arched and/or thick eyebrows
• Long, thick eyelashes
• Short nasal bridge, upturned nasal tip with anteverted nares
• Long and/or smooth philtrum, thin vermilion of the upper lip, downturned corners of the mouth
• Highly arched palate with or without cleft palate
• Small widely spaced teeth
• Micrognathia with or without mandibular spurs
• Microcephaly (mean occipital frontal circumference <2nd centile)
• Synophrys with highly arched and/or thick eyebrows
• Long, thick eyelashes
• Short nasal bridge, upturned nasal tip with anteverted nares
• Long and/or smooth philtrum, thin vermilion of the upper lip, downturned corners of the mouth
• Highly arched palate with or without cleft palate
• Small widely spaced teeth
• Micrognathia with or without mandibular spurs
• Microcephaly (mean occipital frontal circumference <2nd centile)
• Synophrys with highly arched and/or thick eyebrows
• Long, thick eyelashes
• Short nasal bridge, upturned nasal tip with anteverted nares
• Long and/or smooth philtrum, thin vermilion of the upper lip, downturned corners of the mouth
• Highly arched palate with or without cleft palate
• Small widely spaced teeth
• Micrognathia with or without mandibular spurs
• For individuals with features strongly suggestive of CdLS who score highly on the international consensus scoring criteria or for whom multigene panel testing is not available,
• If no
• If no
## Suggestive Findings
Cornelia de Lange syndrome (CdLS)
Microcephaly (mean occipital frontal circumference <2nd centile)
Synophrys with highly arched and/or thick eyebrows
Long, thick eyelashes
Short nasal bridge, upturned nasal tip with anteverted nares
Long and/or smooth philtrum, thin vermilion of the upper lip, downturned corners of the mouth
Highly arched palate with or without cleft palate
Small widely spaced teeth
Micrognathia with or without mandibular spurs
• Microcephaly (mean occipital frontal circumference <2nd centile)
• Synophrys with highly arched and/or thick eyebrows
• Long, thick eyelashes
• Short nasal bridge, upturned nasal tip with anteverted nares
• Long and/or smooth philtrum, thin vermilion of the upper lip, downturned corners of the mouth
• Highly arched palate with or without cleft palate
• Small widely spaced teeth
• Micrognathia with or without mandibular spurs
• Microcephaly (mean occipital frontal circumference <2nd centile)
• Synophrys with highly arched and/or thick eyebrows
• Long, thick eyelashes
• Short nasal bridge, upturned nasal tip with anteverted nares
• Long and/or smooth philtrum, thin vermilion of the upper lip, downturned corners of the mouth
• Highly arched palate with or without cleft palate
• Small widely spaced teeth
• Micrognathia with or without mandibular spurs
• Microcephaly (mean occipital frontal circumference <2nd centile)
• Synophrys with highly arched and/or thick eyebrows
• Long, thick eyelashes
• Short nasal bridge, upturned nasal tip with anteverted nares
• Long and/or smooth philtrum, thin vermilion of the upper lip, downturned corners of the mouth
• Highly arched palate with or without cleft palate
• Small widely spaced teeth
• Micrognathia with or without mandibular spurs
## Establishing the Diagnosis
The diagnosis of CdLS
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Cornelia de Lange syndrome can be broad, individuals with distinctive features described in
When the phenotypic findings suggest the diagnosis of Cornelia de Lange syndrome, molecular genetic testing approaches include use of a
This approach is most likely to identify the genetic cause of the condition while limiting identification pathogenic variants and of variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
For an introduction to multigene panels click
For individuals with features strongly suggestive of CdLS who score highly on the international consensus scoring criteria or for whom multigene panel testing is not available,
If no
If no
When the diagnosis of Cornelia de Lange syndrome is not strongly considered due to atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cornelia de Lange Syndrome
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Somatic mosaicism for
Gene-targeted deletion/duplication analysis of
Cytogenetic testing or chromosomal microarray (CMA) may also be considered in those with classic features of CdLS but normal molecular genetic testing because a few individuals with large deletions of 5p13 that include
• For individuals with features strongly suggestive of CdLS who score highly on the international consensus scoring criteria or for whom multigene panel testing is not available,
• If no
• If no
## Option 1
When the phenotypic findings suggest the diagnosis of Cornelia de Lange syndrome, molecular genetic testing approaches include use of a
This approach is most likely to identify the genetic cause of the condition while limiting identification pathogenic variants and of variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
For an introduction to multigene panels click
For individuals with features strongly suggestive of CdLS who score highly on the international consensus scoring criteria or for whom multigene panel testing is not available,
If no
If no
• For individuals with features strongly suggestive of CdLS who score highly on the international consensus scoring criteria or for whom multigene panel testing is not available,
• If no
• If no
## Option 2
When the diagnosis of Cornelia de Lange syndrome is not strongly considered due to atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cornelia de Lange Syndrome
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Somatic mosaicism for
Gene-targeted deletion/duplication analysis of
Cytogenetic testing or chromosomal microarray (CMA) may also be considered in those with classic features of CdLS but normal molecular genetic testing because a few individuals with large deletions of 5p13 that include
## Clinical Characteristics
While classic Cornelia de Lange syndrome (CdLS) was formally characterized more than 70 years ago and well delineated clinically [
Features of Cornelia de Lange Syndrome
Features and frequencies are largely derived from
ASD = atrial septal defect; GERD = gastroesophageal disease; SNHL = sensorineural hearing loss; VSD = ventricular septal defect
CdLS-specific growth charts have been developed. See
Expressive language is often more compromised than receptive language, and receptive language more compromised than cognition [
Effective verbal and nonverbal communication skills can facilitate quality of life enormously [
Half of children walk by 24 months and 95% by age ten. Half of children are able to feed themselves by age three years and 95% by age ten [
Behavior problems are often directly related to frustration from an inability to communicate (see
Difficulties in sensory processing can lead to hyposensitivity, hypersensitivity, disorientation, and fixation.
Autistic behavior may lead to avoidance or rejection of social interaction and physical contact.
Repetitive behaviors, which can be exacerbated by anxiety, are common and are associated with more marked intellectual disability and autistic features.
Clinically significant self-injurious behavior occurs in 56% of individuals, with hand-directed self-injurious behavior the most common.
Upper-extremity deficiencies ranging from severe reduction defects with complete absence of the forearms to various forms of oligodactyly (missing digits) are present in about one third of those with classic features.
In the absence of limb deficiency, micromelia (small hands), proximally placed thumbs, and fifth-finger clinodactyly occur in nearly all individuals (see
Radioulnar synostosis is common and may result in flexion contractures of the elbows.
The lower extremities are less involved than the upper extremities. The feet are often small and syndactyly of the second and third toes occurs in more than 80% of affected individuals [
Pyloric stenosis (4%), the most frequent cause of persistent vomiting in the newborn period
Intestinal malrotation (2%)
Congenital diaphragmatic hernia (CDH) (1%)
CDH has been diagnosed both pre- and postnatally, but may be underascertained, especially in infants who die in the perinatal period.
Nasolacrimal duct stenosis
Glaucoma
Microcornea
Astigmatism
Optic atrophy
Coloboma of the optic nerve
Strabismus
Proptosis
Kidney abnormalities, primarily vesicoureteral reflux, have been reported in 12% of affected individuals.
Cryptorchidism occurs in 73% of males with CdLS
Hypoplastic (small) genitalia occur in 57% and hypospadias in 9% of males [
Bicornuate uterus, which can cause abdominal pain, has been observed in five (25%) of 20 affected females [
Pulmonic or peripheral pulmonic stenosis
Ventricular septal defects
Atrial septal defects
Coarctation or hypoplastic aortic arch
Aortic valve anomaly
Tetralogy of Fallot
Double-outlet right ventricle
Atrioventricular canal defect
A characteristic low-pitched cry that tends to disappear in late infancy has been described in 75% of children with CdLS and is associated with more severe cases [
Hypoplastic nipples and umbilicus are seen in 50%.
Individuals with classic findings of CdLS, including characteristic facial features and limb anomalies, are more likely to have a pathogenic variant in
Milder phenotypes that retain some of the characteristic facial features but with variable cognitive and limb or structural involvement compared to individuals with a pathogenic variant in
Individuals with
Compared to individuals with a heterozygous
Those with pathogenic variants in
Cardiac malformations, although typically mild, are also observed (~56%) in individuals with
Typically do not have major structural differences.
Have milder cognitive impairment compared to those with classic CdLS.
Specifically, 10% have normal cognition, 45% have mild cognitive impairment and none have severe or profound cognitive disability [
Often display growth restriction, minor skeletal anomalies, and facial features that overlap with CdLS [
Cornelia de Lange syndrome (CdLS) was first described by Vrolik in 1849, who reported a case as an extreme example of oligodactyly [
In the 1930s, Cornelia de Lange, a Dutch pediatrician, described two unrelated girls with similar features and named the condition after the city in which she worked:
The prevalence of CdLS is difficult to estimate as individuals with milder or variable features are likely under-recognized. Published estimates for the prevalence range from 1:100,000 [
• Expressive language is often more compromised than receptive language, and receptive language more compromised than cognition [
• Effective verbal and nonverbal communication skills can facilitate quality of life enormously [
• Half of children walk by 24 months and 95% by age ten. Half of children are able to feed themselves by age three years and 95% by age ten [
• Behavior problems are often directly related to frustration from an inability to communicate (see
• Difficulties in sensory processing can lead to hyposensitivity, hypersensitivity, disorientation, and fixation.
• Autistic behavior may lead to avoidance or rejection of social interaction and physical contact.
• Repetitive behaviors, which can be exacerbated by anxiety, are common and are associated with more marked intellectual disability and autistic features.
• Clinically significant self-injurious behavior occurs in 56% of individuals, with hand-directed self-injurious behavior the most common.
• Upper-extremity deficiencies ranging from severe reduction defects with complete absence of the forearms to various forms of oligodactyly (missing digits) are present in about one third of those with classic features.
• In the absence of limb deficiency, micromelia (small hands), proximally placed thumbs, and fifth-finger clinodactyly occur in nearly all individuals (see
• Radioulnar synostosis is common and may result in flexion contractures of the elbows.
• The lower extremities are less involved than the upper extremities. The feet are often small and syndactyly of the second and third toes occurs in more than 80% of affected individuals [
• Pyloric stenosis (4%), the most frequent cause of persistent vomiting in the newborn period
• Intestinal malrotation (2%)
• Congenital diaphragmatic hernia (CDH) (1%)
• CDH has been diagnosed both pre- and postnatally, but may be underascertained, especially in infants who die in the perinatal period.
• Nasolacrimal duct stenosis
• Glaucoma
• Microcornea
• Astigmatism
• Optic atrophy
• Coloboma of the optic nerve
• Strabismus
• Proptosis
• Kidney abnormalities, primarily vesicoureteral reflux, have been reported in 12% of affected individuals.
• Cryptorchidism occurs in 73% of males with CdLS
• Hypoplastic (small) genitalia occur in 57% and hypospadias in 9% of males [
• Bicornuate uterus, which can cause abdominal pain, has been observed in five (25%) of 20 affected females [
• Pulmonic or peripheral pulmonic stenosis
• Ventricular septal defects
• Atrial septal defects
• Coarctation or hypoplastic aortic arch
• Aortic valve anomaly
• Tetralogy of Fallot
• Double-outlet right ventricle
• Atrioventricular canal defect
• A characteristic low-pitched cry that tends to disappear in late infancy has been described in 75% of children with CdLS and is associated with more severe cases [
• Hypoplastic nipples and umbilicus are seen in 50%.
• Individuals with
• Compared to individuals with a heterozygous
• Those with pathogenic variants in
• Cardiac malformations, although typically mild, are also observed (~56%) in individuals with
• Typically do not have major structural differences.
• Have milder cognitive impairment compared to those with classic CdLS.
• Specifically, 10% have normal cognition, 45% have mild cognitive impairment and none have severe or profound cognitive disability [
• Often display growth restriction, minor skeletal anomalies, and facial features that overlap with CdLS [
## Clinical Description
While classic Cornelia de Lange syndrome (CdLS) was formally characterized more than 70 years ago and well delineated clinically [
Features of Cornelia de Lange Syndrome
Features and frequencies are largely derived from
ASD = atrial septal defect; GERD = gastroesophageal disease; SNHL = sensorineural hearing loss; VSD = ventricular septal defect
CdLS-specific growth charts have been developed. See
Expressive language is often more compromised than receptive language, and receptive language more compromised than cognition [
Effective verbal and nonverbal communication skills can facilitate quality of life enormously [
Half of children walk by 24 months and 95% by age ten. Half of children are able to feed themselves by age three years and 95% by age ten [
Behavior problems are often directly related to frustration from an inability to communicate (see
Difficulties in sensory processing can lead to hyposensitivity, hypersensitivity, disorientation, and fixation.
Autistic behavior may lead to avoidance or rejection of social interaction and physical contact.
Repetitive behaviors, which can be exacerbated by anxiety, are common and are associated with more marked intellectual disability and autistic features.
Clinically significant self-injurious behavior occurs in 56% of individuals, with hand-directed self-injurious behavior the most common.
Upper-extremity deficiencies ranging from severe reduction defects with complete absence of the forearms to various forms of oligodactyly (missing digits) are present in about one third of those with classic features.
In the absence of limb deficiency, micromelia (small hands), proximally placed thumbs, and fifth-finger clinodactyly occur in nearly all individuals (see
Radioulnar synostosis is common and may result in flexion contractures of the elbows.
The lower extremities are less involved than the upper extremities. The feet are often small and syndactyly of the second and third toes occurs in more than 80% of affected individuals [
Pyloric stenosis (4%), the most frequent cause of persistent vomiting in the newborn period
Intestinal malrotation (2%)
Congenital diaphragmatic hernia (CDH) (1%)
CDH has been diagnosed both pre- and postnatally, but may be underascertained, especially in infants who die in the perinatal period.
Nasolacrimal duct stenosis
Glaucoma
Microcornea
Astigmatism
Optic atrophy
Coloboma of the optic nerve
Strabismus
Proptosis
Kidney abnormalities, primarily vesicoureteral reflux, have been reported in 12% of affected individuals.
Cryptorchidism occurs in 73% of males with CdLS
Hypoplastic (small) genitalia occur in 57% and hypospadias in 9% of males [
Bicornuate uterus, which can cause abdominal pain, has been observed in five (25%) of 20 affected females [
Pulmonic or peripheral pulmonic stenosis
Ventricular septal defects
Atrial septal defects
Coarctation or hypoplastic aortic arch
Aortic valve anomaly
Tetralogy of Fallot
Double-outlet right ventricle
Atrioventricular canal defect
A characteristic low-pitched cry that tends to disappear in late infancy has been described in 75% of children with CdLS and is associated with more severe cases [
Hypoplastic nipples and umbilicus are seen in 50%.
• Expressive language is often more compromised than receptive language, and receptive language more compromised than cognition [
• Effective verbal and nonverbal communication skills can facilitate quality of life enormously [
• Half of children walk by 24 months and 95% by age ten. Half of children are able to feed themselves by age three years and 95% by age ten [
• Behavior problems are often directly related to frustration from an inability to communicate (see
• Difficulties in sensory processing can lead to hyposensitivity, hypersensitivity, disorientation, and fixation.
• Autistic behavior may lead to avoidance or rejection of social interaction and physical contact.
• Repetitive behaviors, which can be exacerbated by anxiety, are common and are associated with more marked intellectual disability and autistic features.
• Clinically significant self-injurious behavior occurs in 56% of individuals, with hand-directed self-injurious behavior the most common.
• Upper-extremity deficiencies ranging from severe reduction defects with complete absence of the forearms to various forms of oligodactyly (missing digits) are present in about one third of those with classic features.
• In the absence of limb deficiency, micromelia (small hands), proximally placed thumbs, and fifth-finger clinodactyly occur in nearly all individuals (see
• Radioulnar synostosis is common and may result in flexion contractures of the elbows.
• The lower extremities are less involved than the upper extremities. The feet are often small and syndactyly of the second and third toes occurs in more than 80% of affected individuals [
• Pyloric stenosis (4%), the most frequent cause of persistent vomiting in the newborn period
• Intestinal malrotation (2%)
• Congenital diaphragmatic hernia (CDH) (1%)
• CDH has been diagnosed both pre- and postnatally, but may be underascertained, especially in infants who die in the perinatal period.
• Nasolacrimal duct stenosis
• Glaucoma
• Microcornea
• Astigmatism
• Optic atrophy
• Coloboma of the optic nerve
• Strabismus
• Proptosis
• Kidney abnormalities, primarily vesicoureteral reflux, have been reported in 12% of affected individuals.
• Cryptorchidism occurs in 73% of males with CdLS
• Hypoplastic (small) genitalia occur in 57% and hypospadias in 9% of males [
• Bicornuate uterus, which can cause abdominal pain, has been observed in five (25%) of 20 affected females [
• Pulmonic or peripheral pulmonic stenosis
• Ventricular septal defects
• Atrial septal defects
• Coarctation or hypoplastic aortic arch
• Aortic valve anomaly
• Tetralogy of Fallot
• Double-outlet right ventricle
• Atrioventricular canal defect
• A characteristic low-pitched cry that tends to disappear in late infancy has been described in 75% of children with CdLS and is associated with more severe cases [
• Hypoplastic nipples and umbilicus are seen in 50%.
## Phenotype Correlations by Gene
Individuals with classic findings of CdLS, including characteristic facial features and limb anomalies, are more likely to have a pathogenic variant in
Milder phenotypes that retain some of the characteristic facial features but with variable cognitive and limb or structural involvement compared to individuals with a pathogenic variant in
Individuals with
Compared to individuals with a heterozygous
Those with pathogenic variants in
Cardiac malformations, although typically mild, are also observed (~56%) in individuals with
Typically do not have major structural differences.
Have milder cognitive impairment compared to those with classic CdLS.
Specifically, 10% have normal cognition, 45% have mild cognitive impairment and none have severe or profound cognitive disability [
Often display growth restriction, minor skeletal anomalies, and facial features that overlap with CdLS [
• Individuals with
• Compared to individuals with a heterozygous
• Those with pathogenic variants in
• Cardiac malformations, although typically mild, are also observed (~56%) in individuals with
• Typically do not have major structural differences.
• Have milder cognitive impairment compared to those with classic CdLS.
• Specifically, 10% have normal cognition, 45% have mild cognitive impairment and none have severe or profound cognitive disability [
• Often display growth restriction, minor skeletal anomalies, and facial features that overlap with CdLS [
##
Individuals with classic findings of CdLS, including characteristic facial features and limb anomalies, are more likely to have a pathogenic variant in
## Other Genes
Milder phenotypes that retain some of the characteristic facial features but with variable cognitive and limb or structural involvement compared to individuals with a pathogenic variant in
Individuals with
Compared to individuals with a heterozygous
Those with pathogenic variants in
Cardiac malformations, although typically mild, are also observed (~56%) in individuals with
Typically do not have major structural differences.
Have milder cognitive impairment compared to those with classic CdLS.
Specifically, 10% have normal cognition, 45% have mild cognitive impairment and none have severe or profound cognitive disability [
Often display growth restriction, minor skeletal anomalies, and facial features that overlap with CdLS [
• Individuals with
• Compared to individuals with a heterozygous
• Those with pathogenic variants in
• Cardiac malformations, although typically mild, are also observed (~56%) in individuals with
• Typically do not have major structural differences.
• Have milder cognitive impairment compared to those with classic CdLS.
• Specifically, 10% have normal cognition, 45% have mild cognitive impairment and none have severe or profound cognitive disability [
• Often display growth restriction, minor skeletal anomalies, and facial features that overlap with CdLS [
## Genotype-Phenotype Correlations
## Nomenclature
Cornelia de Lange syndrome (CdLS) was first described by Vrolik in 1849, who reported a case as an extreme example of oligodactyly [
In the 1930s, Cornelia de Lange, a Dutch pediatrician, described two unrelated girls with similar features and named the condition after the city in which she worked:
## Prevalence
The prevalence of CdLS is difficult to estimate as individuals with milder or variable features are likely under-recognized. Published estimates for the prevalence range from 1:100,000 [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Allelic Disorders (not in the Differential Diagnosis of Cornelia de Lange Syndrome)
## Differential Diagnosis
Phenotypic overlap with CdLS may be observed in monogenic disorders (see
Genes of Interest in the Differential Diagnosis of Cornelia de Lange Syndrome
AD = autosomal dominant; AR = autosomal recessive; CdLS = Cornelia de Lange syndrome; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
KBG syndrome is caused by either a heterozygous pathogenic variant in
Individuals with Bohring-Opitz syndrome (BOS) can have a specific limb posture termed "BOS posture," described as an external rotation or adduction of the shoulders with flexion of the wrists and fingers at the metacarpophalangeal joint.
## Management
Clinical management guidelines for Cornelia de Lange syndrome have been published [
To establish the extent of disease and needs in an individual diagnosed with Cornelia de Lange syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Cornelia de Lange Syndrome
Motor, adaptive, cognitive, & speech-language eval. Speech therapy is highly recommended to optimize communication skills & should be implemented in 1st 18 mos of life.
Eval for early intervention / special education
Gross motor & fine motor skills
Limb deficiencies
Scoliosis
Mobility, activities of daily living, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Consider upper GI series to evaluate for malrotation.
Consider endoscopy, pH probe for severe or refractory GERD.
Eval of aspiration risk
Eval of nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Examination of palate by both inspection & palpation at diagnosis
In case of symptoms of a (submucous) cleft palate, referral for specialist assessment is indicated.
Community or
Social work involvement for parental support;
Home nursing referral.
ASD = autism spectrum disorder; GERD = gastrointestinal reflux disease; OT = occupational therapy; PT = physical therapy; VCUG = vesicoureterogram
To include auditory brain stem response testing and otoacoustic emissions testing
Quantitative immunoglobulins; antibodies to tetanus, diptheria, and pneumococcus; B-cell panel; T-cell panel
Treatment of Manifestations in Individuals with Cornelia de Lange Syndrome
Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
Referral to a nutritionist may be considered.
Proactive mgmt of GERD w/very ↓ threshold for medical therapy
Standard medication & postprandial positioning
Many ASMs may be effective; none has been demonstrated effective specifically for CdLS.
Education of parents/caregivers
Preoperative eval for thrombocytopenia & cardiac disease
Sedation &/or operative procedures w/anesthesiologists experienced in mgmt of small airways present in CdLS
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Recommended Surveillance for Individuals with Cornelia de Lange Syndrome
Measure growth parameters.
Evaluate nutritional status & safety of oral intake.
GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
See
Search
• Motor, adaptive, cognitive, & speech-language eval. Speech therapy is highly recommended to optimize communication skills & should be implemented in 1st 18 mos of life.
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Limb deficiencies
• Scoliosis
• Mobility, activities of daily living, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Consider upper GI series to evaluate for malrotation.
• Consider endoscopy, pH probe for severe or refractory GERD.
• Eval of aspiration risk
• Eval of nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Examination of palate by both inspection & palpation at diagnosis
• In case of symptoms of a (submucous) cleft palate, referral for specialist assessment is indicated.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
• Referral to a nutritionist may be considered.
• Proactive mgmt of GERD w/very ↓ threshold for medical therapy
• Standard medication & postprandial positioning
• Many ASMs may be effective; none has been demonstrated effective specifically for CdLS.
• Education of parents/caregivers
• Preoperative eval for thrombocytopenia & cardiac disease
• Sedation &/or operative procedures w/anesthesiologists experienced in mgmt of small airways present in CdLS
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Measure growth parameters.
• Evaluate nutritional status & safety of oral intake.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Cornelia de Lange syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Cornelia de Lange Syndrome
Motor, adaptive, cognitive, & speech-language eval. Speech therapy is highly recommended to optimize communication skills & should be implemented in 1st 18 mos of life.
Eval for early intervention / special education
Gross motor & fine motor skills
Limb deficiencies
Scoliosis
Mobility, activities of daily living, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Consider upper GI series to evaluate for malrotation.
Consider endoscopy, pH probe for severe or refractory GERD.
Eval of aspiration risk
Eval of nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Examination of palate by both inspection & palpation at diagnosis
In case of symptoms of a (submucous) cleft palate, referral for specialist assessment is indicated.
Community or
Social work involvement for parental support;
Home nursing referral.
ASD = autism spectrum disorder; GERD = gastrointestinal reflux disease; OT = occupational therapy; PT = physical therapy; VCUG = vesicoureterogram
To include auditory brain stem response testing and otoacoustic emissions testing
Quantitative immunoglobulins; antibodies to tetanus, diptheria, and pneumococcus; B-cell panel; T-cell panel
• Motor, adaptive, cognitive, & speech-language eval. Speech therapy is highly recommended to optimize communication skills & should be implemented in 1st 18 mos of life.
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Limb deficiencies
• Scoliosis
• Mobility, activities of daily living, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Consider upper GI series to evaluate for malrotation.
• Consider endoscopy, pH probe for severe or refractory GERD.
• Eval of aspiration risk
• Eval of nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Examination of palate by both inspection & palpation at diagnosis
• In case of symptoms of a (submucous) cleft palate, referral for specialist assessment is indicated.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Cornelia de Lange Syndrome
Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
Referral to a nutritionist may be considered.
Proactive mgmt of GERD w/very ↓ threshold for medical therapy
Standard medication & postprandial positioning
Many ASMs may be effective; none has been demonstrated effective specifically for CdLS.
Education of parents/caregivers
Preoperative eval for thrombocytopenia & cardiac disease
Sedation &/or operative procedures w/anesthesiologists experienced in mgmt of small airways present in CdLS
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
• Referral to a nutritionist may be considered.
• Proactive mgmt of GERD w/very ↓ threshold for medical therapy
• Standard medication & postprandial positioning
• Many ASMs may be effective; none has been demonstrated effective specifically for CdLS.
• Education of parents/caregivers
• Preoperative eval for thrombocytopenia & cardiac disease
• Sedation &/or operative procedures w/anesthesiologists experienced in mgmt of small airways present in CdLS
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Recommended Surveillance for Individuals with Cornelia de Lange Syndrome
Measure growth parameters.
Evaluate nutritional status & safety of oral intake.
GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
• Measure growth parameters.
• Evaluate nutritional status & safety of oral intake.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Approximately 99% of individuals with autosomal dominant CdLS have the disorder as the result of a
Fewer than 1% of individuals diagnosed with CdLS have an affected parent.
Recommendations for the evaluation of parents of a proband who appears to represent a simplex case (i.e., a single occurrence in a family) include clinical examination for features of CdLS, complete with plotting of growth parameters, and molecular genetic testing if the causative pathogenic variant has been identified in the proband.
If a pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the recurrence risk to the sibs is 50%.
If the proband has a known CdLS-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent and/or the parents are clinically unaffected, the risk to the sibs of a proband has been estimated at 1.5% because of the possibility of germline mosaicism [
Each child of an individual with autosomal dominant CdLS has a 50% chance of inheriting the pathogenic variant.
While most familial recurrences of CdLS are the result of germline mosaicism in a phenotypically normal parent, rare cases of mildly affected individuals with CdLS having children with CdLS have been reported.
The predominance of individuals with X-linked CdLS have the disorder as the result of a
The father of an affected male will not have CdLS nor will he be hemizygous for the pathogenic variant.
In a family with more than one affected individual, the mother of an affected male is typically heterozygous for the causative variant; alternatively, if she has no other affected relatives and the causative variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
Note: Unlike a typical X-linked gene,
A female proband may have inherited the causative variant from either her mother or her father, or the pathogenic variant may be
Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
Germline mosaicism for an
If the mother of the proband has an
Male sibs who inherit the pathogenic variant will be affected;
Female sibs who inherit the pathogenic variant will be heterozygous. Females who are heterozygous for an
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is approximately 1% because of the possibility of maternal germline mosaicism.
If the mother of the proband has an
If the father of the proband has a pathogenic variant, he will transmit it to all his daughters and none of his sons.
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is approximately 1% because of the possibility of parental germline mosaicism.
Although individuals with severe CdLS do not typically reproduce, mildly affected individuals may have children.
Males with X-linked CdLS would transmit the pathogenic variant to all of their daughters and none of their sons.
Females with X-linked CdLS would have a 50% chance of transmitting the pathogenic variant to each child.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Increased nuchal translucency in the first trimester [
Growth failure, which typically presents in the second trimester
The typical in utero facial profile of a fetus with CdLS consisting of micrognathia, a prominent upper lip, and a depressed nasal bridge with somewhat anteverted nares [
• Approximately 99% of individuals with autosomal dominant CdLS have the disorder as the result of a
• Fewer than 1% of individuals diagnosed with CdLS have an affected parent.
• Recommendations for the evaluation of parents of a proband who appears to represent a simplex case (i.e., a single occurrence in a family) include clinical examination for features of CdLS, complete with plotting of growth parameters, and molecular genetic testing if the causative pathogenic variant has been identified in the proband.
• If a pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the recurrence risk to the sibs is 50%.
• If the proband has a known CdLS-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent and/or the parents are clinically unaffected, the risk to the sibs of a proband has been estimated at 1.5% because of the possibility of germline mosaicism [
• Each child of an individual with autosomal dominant CdLS has a 50% chance of inheriting the pathogenic variant.
• While most familial recurrences of CdLS are the result of germline mosaicism in a phenotypically normal parent, rare cases of mildly affected individuals with CdLS having children with CdLS have been reported.
• The predominance of individuals with X-linked CdLS have the disorder as the result of a
• The father of an affected male will not have CdLS nor will he be hemizygous for the pathogenic variant.
• In a family with more than one affected individual, the mother of an affected male is typically heterozygous for the causative variant; alternatively, if she has no other affected relatives and the causative variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• Note: Unlike a typical X-linked gene,
• A female proband may have inherited the causative variant from either her mother or her father, or the pathogenic variant may be
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
• Germline mosaicism for an
• If the mother of the proband has an
• Male sibs who inherit the pathogenic variant will be affected;
• Female sibs who inherit the pathogenic variant will be heterozygous. Females who are heterozygous for an
• Male sibs who inherit the pathogenic variant will be affected;
• Female sibs who inherit the pathogenic variant will be heterozygous. Females who are heterozygous for an
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is approximately 1% because of the possibility of maternal germline mosaicism.
• Male sibs who inherit the pathogenic variant will be affected;
• Female sibs who inherit the pathogenic variant will be heterozygous. Females who are heterozygous for an
• If the mother of the proband has an
• If the father of the proband has a pathogenic variant, he will transmit it to all his daughters and none of his sons.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is approximately 1% because of the possibility of parental germline mosaicism.
• Although individuals with severe CdLS do not typically reproduce, mildly affected individuals may have children.
• Males with X-linked CdLS would transmit the pathogenic variant to all of their daughters and none of their sons.
• Females with X-linked CdLS would have a 50% chance of transmitting the pathogenic variant to each child.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Increased nuchal translucency in the first trimester [
• Growth failure, which typically presents in the second trimester
• The typical in utero facial profile of a fetus with CdLS consisting of micrognathia, a prominent upper lip, and a depressed nasal bridge with somewhat anteverted nares [
## Mode of Inheritance
## Autosomal Dominant Inheritance – Risk to Family Members
Approximately 99% of individuals with autosomal dominant CdLS have the disorder as the result of a
Fewer than 1% of individuals diagnosed with CdLS have an affected parent.
Recommendations for the evaluation of parents of a proband who appears to represent a simplex case (i.e., a single occurrence in a family) include clinical examination for features of CdLS, complete with plotting of growth parameters, and molecular genetic testing if the causative pathogenic variant has been identified in the proband.
If a pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the recurrence risk to the sibs is 50%.
If the proband has a known CdLS-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent and/or the parents are clinically unaffected, the risk to the sibs of a proband has been estimated at 1.5% because of the possibility of germline mosaicism [
Each child of an individual with autosomal dominant CdLS has a 50% chance of inheriting the pathogenic variant.
While most familial recurrences of CdLS are the result of germline mosaicism in a phenotypically normal parent, rare cases of mildly affected individuals with CdLS having children with CdLS have been reported.
• Approximately 99% of individuals with autosomal dominant CdLS have the disorder as the result of a
• Fewer than 1% of individuals diagnosed with CdLS have an affected parent.
• Recommendations for the evaluation of parents of a proband who appears to represent a simplex case (i.e., a single occurrence in a family) include clinical examination for features of CdLS, complete with plotting of growth parameters, and molecular genetic testing if the causative pathogenic variant has been identified in the proband.
• If a pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the recurrence risk to the sibs is 50%.
• If the proband has a known CdLS-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent and/or the parents are clinically unaffected, the risk to the sibs of a proband has been estimated at 1.5% because of the possibility of germline mosaicism [
• Each child of an individual with autosomal dominant CdLS has a 50% chance of inheriting the pathogenic variant.
• While most familial recurrences of CdLS are the result of germline mosaicism in a phenotypically normal parent, rare cases of mildly affected individuals with CdLS having children with CdLS have been reported.
## X-Linked Inheritance – Risk to Family Members
The predominance of individuals with X-linked CdLS have the disorder as the result of a
The father of an affected male will not have CdLS nor will he be hemizygous for the pathogenic variant.
In a family with more than one affected individual, the mother of an affected male is typically heterozygous for the causative variant; alternatively, if she has no other affected relatives and the causative variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
Note: Unlike a typical X-linked gene,
A female proband may have inherited the causative variant from either her mother or her father, or the pathogenic variant may be
Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
Germline mosaicism for an
If the mother of the proband has an
Male sibs who inherit the pathogenic variant will be affected;
Female sibs who inherit the pathogenic variant will be heterozygous. Females who are heterozygous for an
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is approximately 1% because of the possibility of maternal germline mosaicism.
If the mother of the proband has an
If the father of the proband has a pathogenic variant, he will transmit it to all his daughters and none of his sons.
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is approximately 1% because of the possibility of parental germline mosaicism.
Although individuals with severe CdLS do not typically reproduce, mildly affected individuals may have children.
Males with X-linked CdLS would transmit the pathogenic variant to all of their daughters and none of their sons.
Females with X-linked CdLS would have a 50% chance of transmitting the pathogenic variant to each child.
• The predominance of individuals with X-linked CdLS have the disorder as the result of a
• The father of an affected male will not have CdLS nor will he be hemizygous for the pathogenic variant.
• In a family with more than one affected individual, the mother of an affected male is typically heterozygous for the causative variant; alternatively, if she has no other affected relatives and the causative variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• Note: Unlike a typical X-linked gene,
• A female proband may have inherited the causative variant from either her mother or her father, or the pathogenic variant may be
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
• Germline mosaicism for an
• If the mother of the proband has an
• Male sibs who inherit the pathogenic variant will be affected;
• Female sibs who inherit the pathogenic variant will be heterozygous. Females who are heterozygous for an
• Male sibs who inherit the pathogenic variant will be affected;
• Female sibs who inherit the pathogenic variant will be heterozygous. Females who are heterozygous for an
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is approximately 1% because of the possibility of maternal germline mosaicism.
• Male sibs who inherit the pathogenic variant will be affected;
• Female sibs who inherit the pathogenic variant will be heterozygous. Females who are heterozygous for an
• If the mother of the proband has an
• If the father of the proband has a pathogenic variant, he will transmit it to all his daughters and none of his sons.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is approximately 1% because of the possibility of parental germline mosaicism.
• Although individuals with severe CdLS do not typically reproduce, mildly affected individuals may have children.
• Males with X-linked CdLS would transmit the pathogenic variant to all of their daughters and none of their sons.
• Females with X-linked CdLS would have a 50% chance of transmitting the pathogenic variant to each child.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Increased nuchal translucency in the first trimester [
Growth failure, which typically presents in the second trimester
The typical in utero facial profile of a fetus with CdLS consisting of micrognathia, a prominent upper lip, and a depressed nasal bridge with somewhat anteverted nares [
• Increased nuchal translucency in the first trimester [
• Growth failure, which typically presents in the second trimester
• The typical in utero facial profile of a fetus with CdLS consisting of micrognathia, a prominent upper lip, and a depressed nasal bridge with somewhat anteverted nares [
## Resources
302 West Main Street
#100
Avon CT 06001
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• 302 West Main Street
• #100
• Avon CT 06001
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## Molecular Genetics
Cornelia de Lange Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Cornelia de Lange Syndrome (
Pathogenic variants that result in Cornelia de Lange syndrome disrupt genes that regulate chromatin, most commonly the cohesin complex. Cohesin is a bracelet-like structure that regulates many elements of chromatin biology, including chromosome segregation, genomic stability, genome organization, and transcriptional regulation. The core proteins of the cohesin complex include SMC1A, SMC3, and RAD21. The regulatory proteins NIPBL and MAU2 play key roles in loading cohesin onto chromatin, while HDAC8 is important in enabling the loading and stabilization of cohesin on chromatin. Quite interestingly, some of the key roles of cohesin that enable looping of chromatin to facilitate enhancer regulation of promoters and promote RNA polymerase activity, are also regulated by ANKRD11, EP300, BRD4, and AFF4, suggesting that functional overlap in how pathogenic variants in these genes can result in CdLS-like presentations. For these reasons, CdLS has been termed a "cohesinopathy" and a "transcriptomopathy."
Cornelia de Lange Syndrome: Mechanism of Disease Causation
Genes from
Cornelia de Lange Syndrome: Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Pathogenic variants that result in Cornelia de Lange syndrome disrupt genes that regulate chromatin, most commonly the cohesin complex. Cohesin is a bracelet-like structure that regulates many elements of chromatin biology, including chromosome segregation, genomic stability, genome organization, and transcriptional regulation. The core proteins of the cohesin complex include SMC1A, SMC3, and RAD21. The regulatory proteins NIPBL and MAU2 play key roles in loading cohesin onto chromatin, while HDAC8 is important in enabling the loading and stabilization of cohesin on chromatin. Quite interestingly, some of the key roles of cohesin that enable looping of chromatin to facilitate enhancer regulation of promoters and promote RNA polymerase activity, are also regulated by ANKRD11, EP300, BRD4, and AFF4, suggesting that functional overlap in how pathogenic variants in these genes can result in CdLS-like presentations. For these reasons, CdLS has been termed a "cohesinopathy" and a "transcriptomopathy."
Cornelia de Lange Syndrome: Mechanism of Disease Causation
Genes from
Cornelia de Lange Syndrome: Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
We would like to acknowledge the continued support of the families we follow with CdLS as well as the CdLS-USA Foundation.
Dinah M Clark, MS; The Children's Hospital of Philadelphia (2005-2016)Matthew A Deardorff, MD, PhD (2005-present)Ian D Krantz, MD (2005-present)Sarah E Noon, MS (2016-present)
15 October 2020 (ma) Comprehensive update posted live
28 January 2016 (me) Comprehensive update posted live
27 October 2011 (me) Comprehensive update posted live
16 September 2005 (me) Review posted live
12 January 2005 (ik) Original submission
• 15 October 2020 (ma) Comprehensive update posted live
• 28 January 2016 (me) Comprehensive update posted live
• 27 October 2011 (me) Comprehensive update posted live
• 16 September 2005 (me) Review posted live
• 12 January 2005 (ik) Original submission
## Acknowledgments
We would like to acknowledge the continued support of the families we follow with CdLS as well as the CdLS-USA Foundation.
## Author History
Dinah M Clark, MS; The Children's Hospital of Philadelphia (2005-2016)Matthew A Deardorff, MD, PhD (2005-present)Ian D Krantz, MD (2005-present)Sarah E Noon, MS (2016-present)
## Revision History
15 October 2020 (ma) Comprehensive update posted live
28 January 2016 (me) Comprehensive update posted live
27 October 2011 (me) Comprehensive update posted live
16 September 2005 (me) Review posted live
12 January 2005 (ik) Original submission
• 15 October 2020 (ma) Comprehensive update posted live
• 28 January 2016 (me) Comprehensive update posted live
• 27 October 2011 (me) Comprehensive update posted live
• 16 September 2005 (me) Review posted live
• 12 January 2005 (ik) Original submission
## References
## Literature Cited
Classic CdLS craniofacial features
Affected individual with a pathogenic variant in
Range of limb anomalies in CdLS
|
[] |
16/9/2005
|
15/10/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
cdp1-xlr
|
cdp1-xlr
|
[
"Arylsulfatase E Deficiency",
"Arylsulfatase E Deficiency",
"Arylsulfatase L",
"ARSL",
"Chondrodysplasia Punctata 1, X-Linked"
] |
Chondrodysplasia Punctata 1, X-Linked
|
Nancy E Braverman, Michael B Bober, Nicola Brunetti-Pierri, Sharon F Suchy
|
Summary X-linked chondrodysplasia punctata 1 (CDPX1) is characterized by chondrodysplasia punctata (stippled epiphyses), brachytelephalangy (shortening of the distal phalanges), and nasomaxillary hypoplasia. Although most affected males have minimal morbidity and skeletal findings that improve by adulthood, some have significant medical problems including respiratory involvement, cervical spine stenosis and instability, mixed conductive and sensorineural hearing loss, and intellectual disability. The diagnosis of CDPX1 is established in a male proband with typical clinical and radiographic findings and a hemizygous CDPX1 is inherited in an X-linked manner. If the mother of a proband has the
|
## Diagnosis
X-linked chondrodysplasia punctata 1 (CDPX1) should be
Brachytelephalangy (shortening of the distal phalanges)
Nasomaxillary hypoplasia
Hypoplasia of the anterior nasal spine
Flattened nasal base
Reduced nasal tip protrusion with short columella
Crescent-shaped nostrils
Vertical grooves within the alae nasi (in some individuals)
Postnatal short stature
Chondrodysplasia punctata (stippled epiphyses) are observed on skeletal x-rays in infancy, usually of the ankle and distal phalanges, although they can be more generalized to include epiphyses of long bones, vertebrae, hips, costochondral junctions, and hyoid bone. An inverted triangular shape of the distal phalanges with lateral stippling at the apex is characteristic. Stippling is usually symmetric and age dependent and cannot be seen after normal epiphyseal ossification at age two to three years.
Calcifications can also occur in the larynx, trachea, and main stem bronchi (structures that do not normally ossify) and cause stenosis.
Vertebral abnormalities are common and include dysplastic and hypoplastic vertebrae and coronal or sagittal clefts. Cervical vertebral abnormalities can cause cervical kyphosis, cervical stenosis, and atlantoaxial instability.
The diagnosis of CDPX1 is
Note: (1) Identification of a hemizygous
Molecular genetic testing approaches can include the following:
If an Xp deletion syndrome is suspected (see
For an introduction to multigene panels click
Molecular Genetic Testing Used in Chondrodysplasia Punctata 1, X-Linked
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Brachytelephalangy (shortening of the distal phalanges)
• Nasomaxillary hypoplasia
• Hypoplasia of the anterior nasal spine
• Flattened nasal base
• Reduced nasal tip protrusion with short columella
• Crescent-shaped nostrils
• Vertical grooves within the alae nasi (in some individuals)
• Hypoplasia of the anterior nasal spine
• Flattened nasal base
• Reduced nasal tip protrusion with short columella
• Crescent-shaped nostrils
• Vertical grooves within the alae nasi (in some individuals)
• Postnatal short stature
• Hypoplasia of the anterior nasal spine
• Flattened nasal base
• Reduced nasal tip protrusion with short columella
• Crescent-shaped nostrils
• Vertical grooves within the alae nasi (in some individuals)
• Chondrodysplasia punctata (stippled epiphyses) are observed on skeletal x-rays in infancy, usually of the ankle and distal phalanges, although they can be more generalized to include epiphyses of long bones, vertebrae, hips, costochondral junctions, and hyoid bone. An inverted triangular shape of the distal phalanges with lateral stippling at the apex is characteristic. Stippling is usually symmetric and age dependent and cannot be seen after normal epiphyseal ossification at age two to three years.
• Calcifications can also occur in the larynx, trachea, and main stem bronchi (structures that do not normally ossify) and cause stenosis.
• Vertebral abnormalities are common and include dysplastic and hypoplastic vertebrae and coronal or sagittal clefts. Cervical vertebral abnormalities can cause cervical kyphosis, cervical stenosis, and atlantoaxial instability.
• If an Xp deletion syndrome is suspected (see
• For an introduction to multigene panels click
## Suggestive Findings
X-linked chondrodysplasia punctata 1 (CDPX1) should be
Brachytelephalangy (shortening of the distal phalanges)
Nasomaxillary hypoplasia
Hypoplasia of the anterior nasal spine
Flattened nasal base
Reduced nasal tip protrusion with short columella
Crescent-shaped nostrils
Vertical grooves within the alae nasi (in some individuals)
Postnatal short stature
Chondrodysplasia punctata (stippled epiphyses) are observed on skeletal x-rays in infancy, usually of the ankle and distal phalanges, although they can be more generalized to include epiphyses of long bones, vertebrae, hips, costochondral junctions, and hyoid bone. An inverted triangular shape of the distal phalanges with lateral stippling at the apex is characteristic. Stippling is usually symmetric and age dependent and cannot be seen after normal epiphyseal ossification at age two to three years.
Calcifications can also occur in the larynx, trachea, and main stem bronchi (structures that do not normally ossify) and cause stenosis.
Vertebral abnormalities are common and include dysplastic and hypoplastic vertebrae and coronal or sagittal clefts. Cervical vertebral abnormalities can cause cervical kyphosis, cervical stenosis, and atlantoaxial instability.
• Brachytelephalangy (shortening of the distal phalanges)
• Nasomaxillary hypoplasia
• Hypoplasia of the anterior nasal spine
• Flattened nasal base
• Reduced nasal tip protrusion with short columella
• Crescent-shaped nostrils
• Vertical grooves within the alae nasi (in some individuals)
• Hypoplasia of the anterior nasal spine
• Flattened nasal base
• Reduced nasal tip protrusion with short columella
• Crescent-shaped nostrils
• Vertical grooves within the alae nasi (in some individuals)
• Postnatal short stature
• Hypoplasia of the anterior nasal spine
• Flattened nasal base
• Reduced nasal tip protrusion with short columella
• Crescent-shaped nostrils
• Vertical grooves within the alae nasi (in some individuals)
• Chondrodysplasia punctata (stippled epiphyses) are observed on skeletal x-rays in infancy, usually of the ankle and distal phalanges, although they can be more generalized to include epiphyses of long bones, vertebrae, hips, costochondral junctions, and hyoid bone. An inverted triangular shape of the distal phalanges with lateral stippling at the apex is characteristic. Stippling is usually symmetric and age dependent and cannot be seen after normal epiphyseal ossification at age two to three years.
• Calcifications can also occur in the larynx, trachea, and main stem bronchi (structures that do not normally ossify) and cause stenosis.
• Vertebral abnormalities are common and include dysplastic and hypoplastic vertebrae and coronal or sagittal clefts. Cervical vertebral abnormalities can cause cervical kyphosis, cervical stenosis, and atlantoaxial instability.
## Establishing the Diagnosis
The diagnosis of CDPX1 is
Note: (1) Identification of a hemizygous
Molecular genetic testing approaches can include the following:
If an Xp deletion syndrome is suspected (see
For an introduction to multigene panels click
Molecular Genetic Testing Used in Chondrodysplasia Punctata 1, X-Linked
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• If an Xp deletion syndrome is suspected (see
• For an introduction to multigene panels click
## Clinical Characteristics
The most consistent clinical features of X-linked chondrodysplasia punctata 1 (CDPX1) in affected males are chondrodysplasia punctata (CDP), brachytelephalangy, and nasomaxillary hypoplasia. Most affected males have minimal morbidity, and skeletal findings improve by adulthood; however, some have significant medical problems including airway stenosis and cervical spine instability.
To date, approximately 50 individuals with a pathogenic variant in
Chondrodysplasia Punctata 1, X-Linked: Frequency of Select Features
From
A child with brachytelephalangy, nasomaxillary hypoplasia, and tracheobronchial calcifications did not have CDP at age 14 months [
Ophthalmologic abnormalities (e.g., cataracts, optic disc atrophy, small optic nerves)
Cardiac anomalies (e.g., patent ductus arteriosus, ventricular septal defect, atrial septal defect, pulmonary artery stenosis)
Gastroesophageal reflux
Feeding difficulties
Affected carrier females have not been described, presumably because they have sufficient levels of ARSE enzyme activity expressed from both X chromosomes. Some heterozygous females may have smaller-than-expected stature [
No genotype-phenotype correlations have been identified.
Penetrance may be incomplete.
CDPX1 refers specifically to a deficiency of ARSL enzyme activity.
Brachytelephalangic chondrodysplasia punctata (BCDP) is a descriptive term associated with CDPX1 and its non-genetic phenocopies.
The prevalence of CDPX1 is unknown; in one study it was estimated at 1:500,000 [
• Ophthalmologic abnormalities (e.g., cataracts, optic disc atrophy, small optic nerves)
• Cardiac anomalies (e.g., patent ductus arteriosus, ventricular septal defect, atrial septal defect, pulmonary artery stenosis)
• Gastroesophageal reflux
• Feeding difficulties
## Clinical Description
The most consistent clinical features of X-linked chondrodysplasia punctata 1 (CDPX1) in affected males are chondrodysplasia punctata (CDP), brachytelephalangy, and nasomaxillary hypoplasia. Most affected males have minimal morbidity, and skeletal findings improve by adulthood; however, some have significant medical problems including airway stenosis and cervical spine instability.
To date, approximately 50 individuals with a pathogenic variant in
Chondrodysplasia Punctata 1, X-Linked: Frequency of Select Features
From
A child with brachytelephalangy, nasomaxillary hypoplasia, and tracheobronchial calcifications did not have CDP at age 14 months [
Ophthalmologic abnormalities (e.g., cataracts, optic disc atrophy, small optic nerves)
Cardiac anomalies (e.g., patent ductus arteriosus, ventricular septal defect, atrial septal defect, pulmonary artery stenosis)
Gastroesophageal reflux
Feeding difficulties
Affected carrier females have not been described, presumably because they have sufficient levels of ARSE enzyme activity expressed from both X chromosomes. Some heterozygous females may have smaller-than-expected stature [
• Ophthalmologic abnormalities (e.g., cataracts, optic disc atrophy, small optic nerves)
• Cardiac anomalies (e.g., patent ductus arteriosus, ventricular septal defect, atrial septal defect, pulmonary artery stenosis)
• Gastroesophageal reflux
• Feeding difficulties
## Affected Males
The most consistent clinical features of X-linked chondrodysplasia punctata 1 (CDPX1) in affected males are chondrodysplasia punctata (CDP), brachytelephalangy, and nasomaxillary hypoplasia. Most affected males have minimal morbidity, and skeletal findings improve by adulthood; however, some have significant medical problems including airway stenosis and cervical spine instability.
To date, approximately 50 individuals with a pathogenic variant in
Chondrodysplasia Punctata 1, X-Linked: Frequency of Select Features
From
A child with brachytelephalangy, nasomaxillary hypoplasia, and tracheobronchial calcifications did not have CDP at age 14 months [
Ophthalmologic abnormalities (e.g., cataracts, optic disc atrophy, small optic nerves)
Cardiac anomalies (e.g., patent ductus arteriosus, ventricular septal defect, atrial septal defect, pulmonary artery stenosis)
Gastroesophageal reflux
Feeding difficulties
• Ophthalmologic abnormalities (e.g., cataracts, optic disc atrophy, small optic nerves)
• Cardiac anomalies (e.g., patent ductus arteriosus, ventricular septal defect, atrial septal defect, pulmonary artery stenosis)
• Gastroesophageal reflux
• Feeding difficulties
## Heterozygotes
Affected carrier females have not been described, presumably because they have sufficient levels of ARSE enzyme activity expressed from both X chromosomes. Some heterozygous females may have smaller-than-expected stature [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Penetrance
Penetrance may be incomplete.
## Nomenclature
CDPX1 refers specifically to a deficiency of ARSL enzyme activity.
Brachytelephalangic chondrodysplasia punctata (BCDP) is a descriptive term associated with CDPX1 and its non-genetic phenocopies.
## Prevalence
The prevalence of CDPX1 is unknown; in one study it was estimated at 1:500,000 [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders with Brachytelephalangic Chondrodysplasia Punctata (BCDP) in the Differential Diagnosis of CDPX1
AR = autosomal recessive; CDPX1 = chondrodysplasia punctata 1, X-linked; MOI = mode of inheritance
Disorders with Non-Brachytelephalangic Chondrodysplasia Punctata and Cervical Spine Anomalies in the Differential Diagnosis of CDPX1
Rhizomelia, profound growth restriction, congenital cataract
Absence of nasal hypoplasia
Asymmetric rhizomesomelia, sectorial cataracts, patchy alopecia, ichthyosis, & atrophoderma
Affected individuals are typically female
Absence of nasal hypoplasia
Male lethal, unilateral CDP, rhizomelia, polydactyly, skin findings; one side of the body affected
Absence of nasal hypoplasia
AR = autosomal recessive; CDP = chondrodysplasia punctata; CDPX = X-linked chondrodysplasia punctata; CHILD = congenital hemidysplasia, ichthyosis, limb defects; MOI = mode of inheritance; RCDP = rhizomelic chondrodysplasia punctata; XL = X-linked
Also referred to as Conradi-Hünermann syndrome and Happle syndrome.
Warfarin embryopathy and other vitamin K deficiencies (including vitamin K epoxide reductase deficiency) are phenotypically similar to CDPX1 with especially severe hypoplasia of the nasal bone ("Binder anomaly"), distal phalangeal abnormalities, and punctata of the axial skeleton.
BCDP was reported in infants whose mothers had presumed vitamin K deficiency as a result of severe hyperemesis gravidarum [
Maternal autoimmune disease (systemic lupus erythematosus) [
• Rhizomelia, profound growth restriction, congenital cataract
• Absence of nasal hypoplasia
• Asymmetric rhizomesomelia, sectorial cataracts, patchy alopecia, ichthyosis, & atrophoderma
• Affected individuals are typically female
• Absence of nasal hypoplasia
• Male lethal, unilateral CDP, rhizomelia, polydactyly, skin findings; one side of the body affected
• Absence of nasal hypoplasia
## Genetic Disorders
Disorders with Brachytelephalangic Chondrodysplasia Punctata (BCDP) in the Differential Diagnosis of CDPX1
AR = autosomal recessive; CDPX1 = chondrodysplasia punctata 1, X-linked; MOI = mode of inheritance
Disorders with Non-Brachytelephalangic Chondrodysplasia Punctata and Cervical Spine Anomalies in the Differential Diagnosis of CDPX1
Rhizomelia, profound growth restriction, congenital cataract
Absence of nasal hypoplasia
Asymmetric rhizomesomelia, sectorial cataracts, patchy alopecia, ichthyosis, & atrophoderma
Affected individuals are typically female
Absence of nasal hypoplasia
Male lethal, unilateral CDP, rhizomelia, polydactyly, skin findings; one side of the body affected
Absence of nasal hypoplasia
AR = autosomal recessive; CDP = chondrodysplasia punctata; CDPX = X-linked chondrodysplasia punctata; CHILD = congenital hemidysplasia, ichthyosis, limb defects; MOI = mode of inheritance; RCDP = rhizomelic chondrodysplasia punctata; XL = X-linked
Also referred to as Conradi-Hünermann syndrome and Happle syndrome.
• Rhizomelia, profound growth restriction, congenital cataract
• Absence of nasal hypoplasia
• Asymmetric rhizomesomelia, sectorial cataracts, patchy alopecia, ichthyosis, & atrophoderma
• Affected individuals are typically female
• Absence of nasal hypoplasia
• Male lethal, unilateral CDP, rhizomelia, polydactyly, skin findings; one side of the body affected
• Absence of nasal hypoplasia
## Teratogen Exposures
Warfarin embryopathy and other vitamin K deficiencies (including vitamin K epoxide reductase deficiency) are phenotypically similar to CDPX1 with especially severe hypoplasia of the nasal bone ("Binder anomaly"), distal phalangeal abnormalities, and punctata of the axial skeleton.
BCDP was reported in infants whose mothers had presumed vitamin K deficiency as a result of severe hyperemesis gravidarum [
Maternal autoimmune disease (systemic lupus erythematosus) [
## Management
To establish the extent of disease and needs in an individual diagnosed with X-linked chondrodysplasia punctata 1 (CDPX1), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Chondrodysplasia Punctata 1, X-Linked
Growth assessment
Skeletal survey
Assessment for scoliosis
Cervical spine MRI if clinical evidence of cervical myelopathy or significant instability on radiographs
Special consideration when performing this study in flexion & extension positions as spinal cord compression may only occur w/these movements (i.e., normal neutral cervical spine MRI does not rule out dynamic compression).
Consider brain MRI at time of cervical spine MRI.
Community or
Social work involvement for parental support;
Home nursing referral.
CDP = chondrodysplasia punctata; CDPX1 = chondrodysplasia punctata 1, X-linked; MOI = mode of inheritance
Although not reported in individuals with CDPX1, cortical dysplasia was reported in two infants with brachytelephalangic chondrodysplasia punctata due to maternal vitamin K deficiency [
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with Chondrodysplasia Punctata 1, X-Linked
Hearing aids
Pressure equalization tube placement as needed
Adjuvant therapies incl PT, OT, & speech therapy for persons w/identified developmental delays
Individualized education plans for learning disorders & school performance issues
OT = occupational therapy; PT = physical therapy
Recommended Surveillance for Individuals with Chondrodysplasia Punctata 1, X-Linked
Flexion-extension radiograph
Flexion-extension MRI if instability & compression on radiographs or limited interpretation on radiographs
Every 6-12 mos until growth is completed & prior to anesthesia to assess for cervical spine instability
Note: Some individuals have developed cervical spine instability later in the disease course [
In individuals with cervical spine instability, extreme neck extension and neck flexion and contact sports should be avoided.
In case of general anesthesia, the cervical spine should be assessed by imaging prior to the procedure.
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk male relatives of an individual with CDPX1 in order to identify as early as possible those who would benefit from evaluation for cervical spine instability and early screening for cardiac anomalies, ophthalmologic abnormalities, and hearing loss.
See
Search
• Growth assessment
• Skeletal survey
• Assessment for scoliosis
• Cervical spine MRI if clinical evidence of cervical myelopathy or significant instability on radiographs
• Special consideration when performing this study in flexion & extension positions as spinal cord compression may only occur w/these movements (i.e., normal neutral cervical spine MRI does not rule out dynamic compression).
• Consider brain MRI at time of cervical spine MRI.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Hearing aids
• Pressure equalization tube placement as needed
• Adjuvant therapies incl PT, OT, & speech therapy for persons w/identified developmental delays
• Individualized education plans for learning disorders & school performance issues
• Flexion-extension radiograph
• Flexion-extension MRI if instability & compression on radiographs or limited interpretation on radiographs
• Every 6-12 mos until growth is completed & prior to anesthesia to assess for cervical spine instability
• Note: Some individuals have developed cervical spine instability later in the disease course [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with X-linked chondrodysplasia punctata 1 (CDPX1), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Chondrodysplasia Punctata 1, X-Linked
Growth assessment
Skeletal survey
Assessment for scoliosis
Cervical spine MRI if clinical evidence of cervical myelopathy or significant instability on radiographs
Special consideration when performing this study in flexion & extension positions as spinal cord compression may only occur w/these movements (i.e., normal neutral cervical spine MRI does not rule out dynamic compression).
Consider brain MRI at time of cervical spine MRI.
Community or
Social work involvement for parental support;
Home nursing referral.
CDP = chondrodysplasia punctata; CDPX1 = chondrodysplasia punctata 1, X-linked; MOI = mode of inheritance
Although not reported in individuals with CDPX1, cortical dysplasia was reported in two infants with brachytelephalangic chondrodysplasia punctata due to maternal vitamin K deficiency [
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Growth assessment
• Skeletal survey
• Assessment for scoliosis
• Cervical spine MRI if clinical evidence of cervical myelopathy or significant instability on radiographs
• Special consideration when performing this study in flexion & extension positions as spinal cord compression may only occur w/these movements (i.e., normal neutral cervical spine MRI does not rule out dynamic compression).
• Consider brain MRI at time of cervical spine MRI.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Chondrodysplasia Punctata 1, X-Linked
Hearing aids
Pressure equalization tube placement as needed
Adjuvant therapies incl PT, OT, & speech therapy for persons w/identified developmental delays
Individualized education plans for learning disorders & school performance issues
OT = occupational therapy; PT = physical therapy
• Hearing aids
• Pressure equalization tube placement as needed
• Adjuvant therapies incl PT, OT, & speech therapy for persons w/identified developmental delays
• Individualized education plans for learning disorders & school performance issues
## Surveillance
Recommended Surveillance for Individuals with Chondrodysplasia Punctata 1, X-Linked
Flexion-extension radiograph
Flexion-extension MRI if instability & compression on radiographs or limited interpretation on radiographs
Every 6-12 mos until growth is completed & prior to anesthesia to assess for cervical spine instability
Note: Some individuals have developed cervical spine instability later in the disease course [
• Flexion-extension radiograph
• Flexion-extension MRI if instability & compression on radiographs or limited interpretation on radiographs
• Every 6-12 mos until growth is completed & prior to anesthesia to assess for cervical spine instability
• Note: Some individuals have developed cervical spine instability later in the disease course [
## Agents/Circumstances to Avoid
In individuals with cervical spine instability, extreme neck extension and neck flexion and contact sports should be avoided.
In case of general anesthesia, the cervical spine should be assessed by imaging prior to the procedure.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk male relatives of an individual with CDPX1 in order to identify as early as possible those who would benefit from evaluation for cervical spine instability and early screening for cardiac anomalies, ophthalmologic abnormalities, and hearing loss.
See
## Therapies Under Investigation
Search
## Genetic Counseling
X-linked chondrodysplasia punctata 1 (CDPX1) is inherited in an X-linked manner.
The father of an affected male will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a
To date, CDPX1 caused by a
If the mother of the proband has an
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
All of their daughters, who will be carriers (heterozygotes) and will not be expected to have clinical manifestations of CDPX1 (affected carrier females have not been reported to date);
None of their sons.
Note: Molecular genetic testing may be able to identify the family member in whom a
Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the
Note: (1) Females who are heterozygous (carriers) for this X-linked disorder will usually not be affected. (2) Identification of female heterozygotes requires either (a) prior identification of the
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a
• To date, CDPX1 caused by a
• If the mother of the proband has an
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• All of their daughters, who will be carriers (heterozygotes) and will not be expected to have clinical manifestations of CDPX1 (affected carrier females have not been reported to date);
• None of their sons.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
X-linked chondrodysplasia punctata 1 (CDPX1) is inherited in an X-linked manner.
## Risk to Family Members
The father of an affected male will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a
To date, CDPX1 caused by a
If the mother of the proband has an
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
All of their daughters, who will be carriers (heterozygotes) and will not be expected to have clinical manifestations of CDPX1 (affected carrier females have not been reported to date);
None of their sons.
Note: Molecular genetic testing may be able to identify the family member in whom a
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a
• To date, CDPX1 caused by a
• If the mother of the proband has an
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• All of their daughters, who will be carriers (heterozygotes) and will not be expected to have clinical manifestations of CDPX1 (affected carrier females have not been reported to date);
• None of their sons.
## Carrier Detection
Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the
Note: (1) Females who are heterozygous (carriers) for this X-linked disorder will usually not be affected. (2) Identification of female heterozygotes requires either (a) prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
•
•
•
•
•
## Molecular Genetics
Chondrodysplasia Punctata 1, X-Linked: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Chondrodysplasia Punctata 1, X-Linked (
Although its physiologic substrate has not yet been identified, ARSE enzyme activity is inhibited in vitro by the anticoagulant warfarin [
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Although its physiologic substrate has not yet been identified, ARSE enzyme activity is inhibited in vitro by the anticoagulant warfarin [
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
Michael B Bober, MD, PhD (2008-present)Nancy E Braverman, MS, MD (2008-present)Nicola Brunetti-Pierri, MD (2008-present)Gretchen L Oswald, MS, CGC; Johns Hopkins Medical Center (2008-2020)Sharon F Suchy, PhD (2020-present)
15 October 2020 (sw) Comprehensive update posted live
20 November 2014 (me) Comprehensive update posted live
3 November 2011 (me) Comprehensive update posted live
22 April 2008 (me) Review posted live
16 November 2007 (nb) Original submission
• 15 October 2020 (sw) Comprehensive update posted live
• 20 November 2014 (me) Comprehensive update posted live
• 3 November 2011 (me) Comprehensive update posted live
• 22 April 2008 (me) Review posted live
• 16 November 2007 (nb) Original submission
## Author History
Michael B Bober, MD, PhD (2008-present)Nancy E Braverman, MS, MD (2008-present)Nicola Brunetti-Pierri, MD (2008-present)Gretchen L Oswald, MS, CGC; Johns Hopkins Medical Center (2008-2020)Sharon F Suchy, PhD (2020-present)
## Revision History
15 October 2020 (sw) Comprehensive update posted live
20 November 2014 (me) Comprehensive update posted live
3 November 2011 (me) Comprehensive update posted live
22 April 2008 (me) Review posted live
16 November 2007 (nb) Original submission
• 15 October 2020 (sw) Comprehensive update posted live
• 20 November 2014 (me) Comprehensive update posted live
• 3 November 2011 (me) Comprehensive update posted live
• 22 April 2008 (me) Review posted live
• 16 November 2007 (nb) Original submission
## References
## Literature Cited
|
[
"E Alkhunaizi, S Unger, P Shannon, G Nishimura, S Blaser, D. Chitayat. Maternal SLE and brachytelephalangic chondrodysplasia punctata in a patient with unrelated de novo RAF1 and SIX2 variants.. Am J Med Genet A. 2020;182:1807-11",
"JL Alessandri, D Ramful, F Cuillier. Binder phenotype and brachytelephalangic chondrodysplasia punctata secondary to maternal vitamin K deficiency.. Clin Dysmorphol. 2010;19:85-7",
"E Bhoj, H Dubbs, D McDonald-McGinn, E Zackai. Late-onset partial complex seizures secondary to cortical dysplasia in a patient with maternal vitamin K deficient embryopathy: comments on the article by Toriello et al [2013] and first report of the natural history.. Am J Med Genet A. 2013;161A:2396-8",
"AR Blask, EI Rubio, KA Chapman, AK Lawrence, DI Bulas. Severe nasomaxillary hypoplasia (Binder phenotype) on prenatal US/MRI: an important marker for the prenatal diagnosis of chondrodysplasia punctata.. Pediatr Radiol. 2018;48:979-91",
"N Brunetti-Pierri, MV Andreucci, R Tuzzi, GR Vega, G Gray, C McKeown, A Ballabio, G Andria, G Meroni, G Parenti. X-linked recessive chondrodysplasia punctata: spectrum of arylsulfatase E gene mutations and expanded clinical variability.. Am J Med Genet A. 2003;117A:164-8",
"N Brunetti-Pierri, JV Hunter, CF Boerkoel. Gray matter heterotopias and brachytelephalangic chondrodysplasia punctata: a complication of hyperemesis gravidarum induced vitamin K deficiency?. Am J Med Genet A. 2007;143A:200-4",
"B Carach, M Woods, P Scott. Maxillonasal dysplasia (Binder syndrome): a lateral cephalometric assessment.. Aust Orthod J 2002;18:82-91",
"A Casarin, F Rusalen, M Doimo, E Trevisson, S Carraro, M Clementi, R Tenconi, E Baraldi, L Salviati. X-linked brachytelephalangic chondrodysplasia punctata: a simple trait that is not so simple.. Am J Med Genet A. 2009;149A:2464-8",
"D Chitayat, S Keating, DJ Zand, T Costa, EH Zackai, E Silverman, G Tiller, S Unger, S Miller, J Kingdom, A Toi, CJ Curry. Chondrodysplasia punctata associated with maternal autoimmune diseases: expanding the spectrum from systemic lupus erythematosus (SLE) to mixed connective tissue disease (MCTD) and scleroderma report of eight cases.. Am J Med Genet A. 2008;146A:3038-53",
"MP Cosma, S Pepe, I Annunziata, RF Newbold, M Grompe, G Parenti, A Ballabio. The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases.. Cell 2003;113:445-56",
"A Daniele, G Parenti, M d'Addio, G Andria, A Ballabio, G Meroni. Biochemical characterization of arylsulfatase E and functional analysis of mutations found in patients with X-linked chondrodysplasia punctata.. Am J Hum Genet 1998;62:562-72",
"DD Eash, DD Weaver, N Brunetti-Pierri. Cervical spine stenosis and possible vitamin K deficiency embryopathy in an unusual case of chondrodysplasia punctata and an updated classification system.. Am J Med Genet A 2003;122A:70-5",
"A Garnier, S Dauger, D Eurin, I Parisi, G Parenti, C Garel, K Delbecque, C Baumann. Brachytelephalangic chondrodysplasia punctata with severe spinal cord compression: report of four new cases.. Eur J Pediatr 2007;166:327-31",
"G He, Y Yin, J Zhao. Prenatal findings in a fetus with X-linked recessive type of chondrodysplasia punctata (CDPX1): a case report with novel mutation.. BMC Pediatr. 2019;19:250",
"GE Herman, RI Kelley, V Pureza, D Smith, K Kopacz, J Pitt, R Sutphen, LJ Sheffield, AB Metzenberg. Characterization of mutations in 22 females with X-linked dominant chondrodysplasia punctata (Happle syndrome).. Genet Med 2002;4:434-8",
"J Jaillet, E Robert-Gnansia, M Till, C Vinciguerra, P Edery. Biliary lithiasis in early pregnancy and abnormal development of facial and distal limb bones (Binder syndrome): a possible role for vitamin K deficiency.. Birth Defects Res A Clin Mol Teratol 2005;73:188-93",
"P Khau Van Kien, A Nievelon-Chevallier, G Spagnolo, S Douvier, C Maingueneau. Vitamin K deficiency embriopathy.. Am J Med Genet 1998;79:66-8",
"E Malou, J Gekas, V Troucelier-Lucas, E Mornet, L Razafimanantsoa, B Cuvelier, M Mathieu, F Thepot. X-linked recessive chondrodysplasia punctata. Cytogenetic study and role of molecular biology.. Arch Pediatr 2001;8:176-80",
"C Matos-Miranda, G Nimmo, B Williams, C Tysoe, M Owens, S Bale, N. Braverman. A prospective study of brachytelephalangic chondrodysplasia punctata: identification of arylsulfatase E mutations, functional analysis of novel missense alleles, and determination of potential phenocopies.. Genet Med. 2013;15:650-7",
"H Menger, AE Lin, HV Toriello, G Bernert, JW Spranger. Vitamin K deficiency embryopathy: a phenocopy of the warfarin embryopathy due to a disorder of embryonic vitamin K metabolism.. Am J Med Genet 1997;72:129-34",
"M Nino, C Matos-Miranda, M Maeda, L Chen, J Allanson, C Armour, C Greene, M Kamaluddeen, D Rita, L Medne, E Zackai, S Mansour, A Superti-Furga, A Lewanda, M Bober, K Rosenbaum, N Braverman. Clinical and molecular analysis of arylsulfatase E in patients with brachytelephalangic chondrodysplasia punctata.. Am J Med Genet A 2008;146A:997-1008",
"S Rost, A Fregin, V Ivaskevicius, E Conzelmann, K Hortnagel, HJ Pelz, K Lappegard, E Seifried, I Scharrer, EG Tuddenham, CR Muller, TM Strom, J Oldenburg. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2.. Nature 2004;427:537-41",
"SW Schulz, M Bober, C Johnson, N Braverman, SA Jimenez. Maternal mixed connective tissue disease and offspring with chondrodysplasia punctata.. Semin Arthritis Rheum. 2010;39:410-6",
"LJ Sheffield, AH Osborn, WM Hutchison, DO Sillence, SM Forrest, SJ White, HH Dahl. Segregation of mutations in arylsulphatase E and correlation with the clinical presentation of chondrodysplasia punctata.. J Med Genet 1998;35:1004-8",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"HV Toriello, M Erick, JL Alessandri, D Bailey, N Brunetti-Pierri, H Cox, A Fryer, D Marty, C McCurdy, JB Mulliken, H Murphy, J Omlor, RM Pauli, JD Ranells, A Sanchez-Valle, A Tobiasz, L Van Maldergem, AE Lin. Maternal vitamin K deficient embryopathy: association with hyperemesis gravidarum and Crohn disease.. Am J Med Genet A. 2013;161A:417-29",
"TW Vogel, AH Menezes. Natural history and management of cervical spine disease in chondrodysplasia punctata and coumarin embryopathy.. Childs Nerv Syst. 2012;28:609-19",
"ME Wolpoe, N Braverman, SY Lin. Severe tracheobronchial stenosis in the X-linked recessive form of chondrodysplasia punctata.. Arch Otolaryngol Head Neck Surg 2004;130:1423-6",
"Y Xie, EK Pivnick, HL Cohen, PE Adams-Graves, M Pourcyrous, B Aygun, JS Hankins. Phenocopy of warfarin syndrome in an infant born to a mother with sickle cell anemia and severe transfusional iron overload.. J Pediatr Hematol Oncol. 2013;35:e265-8"
] |
22/4/2008
|
15/10/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
cdsp
|
cdsp
|
[
"Carnitine Deficiency",
"Carnitine Transport Defect (CTD)",
"Carnitine Uptake Defect (CUD)",
"Systemic Primary Carnitine Deficiency",
"Carnitine Deficiency",
"Carnitine Transport Defect (CTD)",
"Carnitine Uptake Defect (CUD)",
"Systemic Primary Carnitine Deficiency",
"Organic cation/carnitine transporter 2",
"SLC22A5",
"Primary Carnitine Deficiency"
] |
Primary Carnitine Deficiency
|
Ayman W El-Hattab, Mohammed Almannai
|
Summary Primary carnitine deficiency (PCD) is a disorder of the carnitine cycle that results in defective fatty acid oxidation. If untreated, it encompasses a broad clinical spectrum including: (1) metabolic decompensation in infancy typically presenting between age three months and two years with episodes of hypoketotic hypoglycemia, poor feeding, irritability, lethargy, hepatomegaly, elevated liver transaminases, and hyperammonemia triggered by fasting or common illnesses such as upper respiratory tract infection or gastroenteritis; (2) childhood myopathy involving heart and skeletal muscle with onset between age two and four years; (3) pregnancy-related decreased stamina or exacerbation of cardiac arrhythmia; (4) fatigability in adulthood; and (5) absence of symptoms. The latter two categories often include mothers diagnosed with PCD after newborn screening has identified low carnitine levels in their infants. The diagnosis of PCD is established in a proband with consistent biochemical analyte findings and/or suggestive clinical and laboratory features by identification of biallelic pathogenic variants in PCD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
## Diagnosis
A diagnosis of primary carnitine deficiency (PCD) may be suspected due to an abnormal newborn screening result prior to onset of suggestive findings (see
NBS for PCD is primarily based on use of dried blood spots collected between 24 hours and 72 hours after birth to quantify free carnitine (C0) concentration by tandem mass spectrometry. (For information on NBS by state in the United States, see
Note: (1) NBS for PCD has low positive predictive value (e.g., 4.7% in California [
Positive NBS results (i.e., low blood concentrations of free carnitine) require evaluation of the newborn and mother as soon as possible and no later than three days after birth.
See
For recommendations on presumptive treatment of affected newborns while awaiting diagnosis confirmation to prevent irreversible neurocognitive impairment, consult a metabolic specialist to discuss immediate treatment for PCD with oral levocarnitine supplementation and other recommended care.
If a metabolic specialist is not available, begin treatment for PCD with oral levocarnitine supplementation (typically 100-200 mg/kg/day, divided in three doses; see
Primary Carnitine Deficiency: Testing Recommended at the Time of Diagnosis of Low Carnitine Blood Levels via NBS
Useful to rule out other causes of low carnitine levels, incl organic acidemias & defects of fatty acid oxidation (See
Note: Nonspecific dicarboxylic aciduria occurs in some persons w/PCD & is common in fatty acid oxidation disorders w/acute decompensation.
PCD = primary carnitine deficiency
See ACMG
A symptomatic individual can have either (1) typical findings associated with later-onset PCD or (2) untreated infantile-onset PCD resulting from any of the following: NBS not performed, false negative NBS result, clinical findings prior to receiving NBS result, or caregivers not adherent to recommended treatment after a positive NBS result. PCD
Episodes of hypoketotic hypoglycemia that may be associated with hepatomegaly, elevated liver transaminases, abnormal liver function tests, and hyperammonemia in infants
Skeletal myopathy and/or elevated serum concentration of creatine kinase in children
Cardiomyopathy in children
Unexplained fatigability in adults
Decreased plasma carnitine concentrations without an identified cause in individuals of any age
The biochemical diagnosis (in limited instances)
The molecular genetic diagnosis of PCD
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When NBS results and other laboratory findings suggest the diagnosis of PCD, molecular genetic testing approaches can include
In individuals with suspected PCD and negative molecular testing, a carnitine transport assay using cultured skin fibroblasts may be available to confirm the diagnosis [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Primary Carnitine Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequence analysis should include analysis of
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
• See
• For recommendations on presumptive treatment of affected newborns while awaiting diagnosis confirmation to prevent irreversible neurocognitive impairment, consult a metabolic specialist to discuss immediate treatment for PCD with oral levocarnitine supplementation and other recommended care.
• If a metabolic specialist is not available, begin treatment for PCD with oral levocarnitine supplementation (typically 100-200 mg/kg/day, divided in three doses; see
• Useful to rule out other causes of low carnitine levels, incl organic acidemias & defects of fatty acid oxidation (See
• Note: Nonspecific dicarboxylic aciduria occurs in some persons w/PCD & is common in fatty acid oxidation disorders w/acute decompensation.
• Episodes of hypoketotic hypoglycemia that may be associated with hepatomegaly, elevated liver transaminases, abnormal liver function tests, and hyperammonemia in infants
• Skeletal myopathy and/or elevated serum concentration of creatine kinase in children
• Cardiomyopathy in children
• Unexplained fatigability in adults
• Decreased plasma carnitine concentrations without an identified cause in individuals of any age
• In individuals with suspected PCD and negative molecular testing, a carnitine transport assay using cultured skin fibroblasts may be available to confirm the diagnosis [
• For an introduction to multigene panels click
## Suggestive Findings
A diagnosis of primary carnitine deficiency (PCD) may be suspected due to an abnormal newborn screening result prior to onset of suggestive findings (see
NBS for PCD is primarily based on use of dried blood spots collected between 24 hours and 72 hours after birth to quantify free carnitine (C0) concentration by tandem mass spectrometry. (For information on NBS by state in the United States, see
Note: (1) NBS for PCD has low positive predictive value (e.g., 4.7% in California [
Positive NBS results (i.e., low blood concentrations of free carnitine) require evaluation of the newborn and mother as soon as possible and no later than three days after birth.
See
For recommendations on presumptive treatment of affected newborns while awaiting diagnosis confirmation to prevent irreversible neurocognitive impairment, consult a metabolic specialist to discuss immediate treatment for PCD with oral levocarnitine supplementation and other recommended care.
If a metabolic specialist is not available, begin treatment for PCD with oral levocarnitine supplementation (typically 100-200 mg/kg/day, divided in three doses; see
Primary Carnitine Deficiency: Testing Recommended at the Time of Diagnosis of Low Carnitine Blood Levels via NBS
Useful to rule out other causes of low carnitine levels, incl organic acidemias & defects of fatty acid oxidation (See
Note: Nonspecific dicarboxylic aciduria occurs in some persons w/PCD & is common in fatty acid oxidation disorders w/acute decompensation.
PCD = primary carnitine deficiency
See ACMG
A symptomatic individual can have either (1) typical findings associated with later-onset PCD or (2) untreated infantile-onset PCD resulting from any of the following: NBS not performed, false negative NBS result, clinical findings prior to receiving NBS result, or caregivers not adherent to recommended treatment after a positive NBS result. PCD
Episodes of hypoketotic hypoglycemia that may be associated with hepatomegaly, elevated liver transaminases, abnormal liver function tests, and hyperammonemia in infants
Skeletal myopathy and/or elevated serum concentration of creatine kinase in children
Cardiomyopathy in children
Unexplained fatigability in adults
Decreased plasma carnitine concentrations without an identified cause in individuals of any age
• See
• For recommendations on presumptive treatment of affected newborns while awaiting diagnosis confirmation to prevent irreversible neurocognitive impairment, consult a metabolic specialist to discuss immediate treatment for PCD with oral levocarnitine supplementation and other recommended care.
• If a metabolic specialist is not available, begin treatment for PCD with oral levocarnitine supplementation (typically 100-200 mg/kg/day, divided in three doses; see
• Useful to rule out other causes of low carnitine levels, incl organic acidemias & defects of fatty acid oxidation (See
• Note: Nonspecific dicarboxylic aciduria occurs in some persons w/PCD & is common in fatty acid oxidation disorders w/acute decompensation.
• Episodes of hypoketotic hypoglycemia that may be associated with hepatomegaly, elevated liver transaminases, abnormal liver function tests, and hyperammonemia in infants
• Skeletal myopathy and/or elevated serum concentration of creatine kinase in children
• Cardiomyopathy in children
• Unexplained fatigability in adults
• Decreased plasma carnitine concentrations without an identified cause in individuals of any age
## Scenario 1: Abnormal Newborn Screening (NBS) Result
NBS for PCD is primarily based on use of dried blood spots collected between 24 hours and 72 hours after birth to quantify free carnitine (C0) concentration by tandem mass spectrometry. (For information on NBS by state in the United States, see
Note: (1) NBS for PCD has low positive predictive value (e.g., 4.7% in California [
Positive NBS results (i.e., low blood concentrations of free carnitine) require evaluation of the newborn and mother as soon as possible and no later than three days after birth.
See
For recommendations on presumptive treatment of affected newborns while awaiting diagnosis confirmation to prevent irreversible neurocognitive impairment, consult a metabolic specialist to discuss immediate treatment for PCD with oral levocarnitine supplementation and other recommended care.
If a metabolic specialist is not available, begin treatment for PCD with oral levocarnitine supplementation (typically 100-200 mg/kg/day, divided in three doses; see
Primary Carnitine Deficiency: Testing Recommended at the Time of Diagnosis of Low Carnitine Blood Levels via NBS
Useful to rule out other causes of low carnitine levels, incl organic acidemias & defects of fatty acid oxidation (See
Note: Nonspecific dicarboxylic aciduria occurs in some persons w/PCD & is common in fatty acid oxidation disorders w/acute decompensation.
PCD = primary carnitine deficiency
See ACMG
• See
• For recommendations on presumptive treatment of affected newborns while awaiting diagnosis confirmation to prevent irreversible neurocognitive impairment, consult a metabolic specialist to discuss immediate treatment for PCD with oral levocarnitine supplementation and other recommended care.
• If a metabolic specialist is not available, begin treatment for PCD with oral levocarnitine supplementation (typically 100-200 mg/kg/day, divided in three doses; see
• Useful to rule out other causes of low carnitine levels, incl organic acidemias & defects of fatty acid oxidation (See
• Note: Nonspecific dicarboxylic aciduria occurs in some persons w/PCD & is common in fatty acid oxidation disorders w/acute decompensation.
## Scenario 2: Symptomatic Individual
A symptomatic individual can have either (1) typical findings associated with later-onset PCD or (2) untreated infantile-onset PCD resulting from any of the following: NBS not performed, false negative NBS result, clinical findings prior to receiving NBS result, or caregivers not adherent to recommended treatment after a positive NBS result. PCD
Episodes of hypoketotic hypoglycemia that may be associated with hepatomegaly, elevated liver transaminases, abnormal liver function tests, and hyperammonemia in infants
Skeletal myopathy and/or elevated serum concentration of creatine kinase in children
Cardiomyopathy in children
Unexplained fatigability in adults
Decreased plasma carnitine concentrations without an identified cause in individuals of any age
• Episodes of hypoketotic hypoglycemia that may be associated with hepatomegaly, elevated liver transaminases, abnormal liver function tests, and hyperammonemia in infants
• Skeletal myopathy and/or elevated serum concentration of creatine kinase in children
• Cardiomyopathy in children
• Unexplained fatigability in adults
• Decreased plasma carnitine concentrations without an identified cause in individuals of any age
## Establishing the Diagnosis
The biochemical diagnosis (in limited instances)
The molecular genetic diagnosis of PCD
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When NBS results and other laboratory findings suggest the diagnosis of PCD, molecular genetic testing approaches can include
In individuals with suspected PCD and negative molecular testing, a carnitine transport assay using cultured skin fibroblasts may be available to confirm the diagnosis [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Primary Carnitine Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequence analysis should include analysis of
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
• In individuals with suspected PCD and negative molecular testing, a carnitine transport assay using cultured skin fibroblasts may be available to confirm the diagnosis [
• For an introduction to multigene panels click
## Analyte Diagnosis
The biochemical diagnosis (in limited instances)
## Molecular Genetic Diagnosis
The molecular genetic diagnosis of PCD
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When NBS results and other laboratory findings suggest the diagnosis of PCD, molecular genetic testing approaches can include
In individuals with suspected PCD and negative molecular testing, a carnitine transport assay using cultured skin fibroblasts may be available to confirm the diagnosis [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Primary Carnitine Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequence analysis should include analysis of
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
• In individuals with suspected PCD and negative molecular testing, a carnitine transport assay using cultured skin fibroblasts may be available to confirm the diagnosis [
• For an introduction to multigene panels click
##
When NBS results and other laboratory findings suggest the diagnosis of PCD, molecular genetic testing approaches can include
In individuals with suspected PCD and negative molecular testing, a carnitine transport assay using cultured skin fibroblasts may be available to confirm the diagnosis [
For an introduction to multigene panels click
• In individuals with suspected PCD and negative molecular testing, a carnitine transport assay using cultured skin fibroblasts may be available to confirm the diagnosis [
• For an introduction to multigene panels click
##
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Primary Carnitine Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequence analysis should include analysis of
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
## Clinical Characteristics
The clinical manifestations of primary carnitine deficiency (PCD) can vary widely with respect to age of onset, organ involvement, and severity. The broad clinical spectrum ranges from metabolic decompensation in infancy to cardiomyopathy in childhood, fatigability in adulthood, and absence of clinical manifestations. PCD has typically been associated with an infantile metabolic presentation that usually presents before age two years in about half of untreated affected individuals. The remaining half have a childhood myopathic presentation that typically presents between ages two and four years with dilated cardiomyopathy, hypotonia, muscle weakness, and elevated creatine kinase (CK). However, adults with PCD and mild or no manifestations are likely underdiagnosed, making it difficult to determine the relative proportion of these presentations [
Primary Carnitine Deficiency: Select Features
Based on
Hypoketotic hypoglycemia, hyperammonemia, elevated liver enzymes
Infants diagnosed with newborn screening (NBS) and treated early are usually asymptomatic, as manifestations can be prevented by maintaining normal plasma carnitine levels.
Adults can present with life-threatening symptoms after being asymptomatic [
One study from the Faroe Islands estimated an odds ratio (OR) of 54.3 for the association between sudden death and untreated PCD [
Several women have been diagnosed with PCD after NBS identified low carnitine levels in their infants. About half of those women reported fatigability, whereas the other half were asymptomatic. One woman had dilated cardiomyopathy, and another had arrhythmias [
No genotype-phenotype correlations have been identified.
Nonsense and frameshift variants in
PCD is very common in the Faroe Islands, where the reported prevalence is 1:300 [
NBS data estimated the incidence of PCD to be 1:348,333 in Australia and New Zealand, 1:121,609 in North America, 1:127,912 in Europe (excluding Denmark, Greenland, and the Faroe Islands) and 1:50,386 in Asia [
## Clinical Description
The clinical manifestations of primary carnitine deficiency (PCD) can vary widely with respect to age of onset, organ involvement, and severity. The broad clinical spectrum ranges from metabolic decompensation in infancy to cardiomyopathy in childhood, fatigability in adulthood, and absence of clinical manifestations. PCD has typically been associated with an infantile metabolic presentation that usually presents before age two years in about half of untreated affected individuals. The remaining half have a childhood myopathic presentation that typically presents between ages two and four years with dilated cardiomyopathy, hypotonia, muscle weakness, and elevated creatine kinase (CK). However, adults with PCD and mild or no manifestations are likely underdiagnosed, making it difficult to determine the relative proportion of these presentations [
Primary Carnitine Deficiency: Select Features
Based on
Hypoketotic hypoglycemia, hyperammonemia, elevated liver enzymes
Infants diagnosed with newborn screening (NBS) and treated early are usually asymptomatic, as manifestations can be prevented by maintaining normal plasma carnitine levels.
Adults can present with life-threatening symptoms after being asymptomatic [
One study from the Faroe Islands estimated an odds ratio (OR) of 54.3 for the association between sudden death and untreated PCD [
Several women have been diagnosed with PCD after NBS identified low carnitine levels in their infants. About half of those women reported fatigability, whereas the other half were asymptomatic. One woman had dilated cardiomyopathy, and another had arrhythmias [
## Infantile Early Diagnosis and Treatment
Infants diagnosed with newborn screening (NBS) and treated early are usually asymptomatic, as manifestations can be prevented by maintaining normal plasma carnitine levels.
## Infantile Metabolic (Hepatic) Presentation
## Childhood Myopathic (Cardiac) Presentation
## Adulthood Presentation
Adults can present with life-threatening symptoms after being asymptomatic [
One study from the Faroe Islands estimated an odds ratio (OR) of 54.3 for the association between sudden death and untreated PCD [
Several women have been diagnosed with PCD after NBS identified low carnitine levels in their infants. About half of those women reported fatigability, whereas the other half were asymptomatic. One woman had dilated cardiomyopathy, and another had arrhythmias [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
Nonsense and frameshift variants in
## Prevalence
PCD is very common in the Faroe Islands, where the reported prevalence is 1:300 [
NBS data estimated the incidence of PCD to be 1:348,333 in Australia and New Zealand, 1:121,609 in North America, 1:127,912 in Europe (excluding Denmark, Greenland, and the Faroe Islands) and 1:50,386 in Asia [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Primary carnitine deficiency (PCD) needs to be differentiated from secondary carnitine deficiency associated with other inherited metabolic disorders, including organic acidemias and fatty acid oxidation defects (see
Selected Autosomal Recessive Disorders Associated with Secondary Carnitine Deficiency in the Differential Diagnosis of Primary Carnitine Deficiency
AR = autosomal recessive; CoA = coenzyme A; MOI = mode of inheritance
Pharmacologic therapy (e.g., valproate, cyclosporine, pivampicillin)
Malnutrition
Hemodialysis and renal tubular dysfunction (e.g., renal Fanconi syndrome)
Prematurity. Premature neonates may have mild reduction in plasma carnitine concentrations due to a lack of carnitine placental transfer in the third trimester and decreased tissue stores. Moreover, immature renal tubular function in premature neonates could lead to increased renal carnitine elimination [
• Pharmacologic therapy (e.g., valproate, cyclosporine, pivampicillin)
• Malnutrition
• Hemodialysis and renal tubular dysfunction (e.g., renal Fanconi syndrome)
• Prematurity. Premature neonates may have mild reduction in plasma carnitine concentrations due to a lack of carnitine placental transfer in the third trimester and decreased tissue stores. Moreover, immature renal tubular function in premature neonates could lead to increased renal carnitine elimination [
## Management
No clinical practice guidelines for primary carnitine deficiency (PCD) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.
To establish the extent of disease and needs in an individual diagnosed with PCD, the evaluations summarized in
Primary Carnitine Deficiency: Recommended Evaluations Following Initial Diagnosis
CK & liver transaminases
Post-prandial blood glucose concentration
Plasma free/total carnitine concentration following initiation of treatment
CK = creatine kinase; MOI = mode of inheritance; PCD = primary carnitine deficiency
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Targeted therapy for PCD involves oral carnitine supplementation to prevent carnitine deficiency (see
Primary Carnitine Deficiency: Targeted Therapy
High doses of oral levocarnitine can cause increased gastrointestinal motility, diarrhea, and intestinal discomfort. Oral levocarnitine can be metabolized by intestinal bacteria to produce trimethylamine, which has a fishy odor. Oral metronidazole at a dose of 10 mg/kg/day for 7-10 days and/or decreasing the carnitine dose usually results in the resolution of the odor [
Oral levocarnitine supplementation in infants with PCD identified through newborn screening (NBS) results in slow normalization of the plasma carnitine concentration.
Metabolic decompensation and skeletal and cardiac muscle function improve with levocarnitine supplementation. Individuals with PCD respond well if oral levocarnitine supplementation is started before irreversible organ damage occurs.
One of the most important components of preventing carnitine deficiency is education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see
Primary Carnitine Deficiency: Routine Outpatient Treatment of Manifestations
Frequent feeds
Avoid fasting
Written protocols for outpatient routine & emergency treatment should be provided to parents, primary care providers, teachers, & school staff.
Emergency letter/card should be provided summarizing key info, principles of emergency treatment, & contact information for primary treating metabolic center.
For any planned travel or vacations, consider contacting center of expertise near destination prior to travel dates.
Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
Hospitalization to administer IV glucose is recommended for persons w/PCD who are required to fast because of medical or surgical procedures or who cannot tolerate oral intake because of illness such as gastroenteritis.
Consider placing a "flag" in affected person's medical record such that all care providers are aware of diagnosis & need to solicit opinions & guidance from designated metabolic specialists in the setting of certain procedures.
Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).
IV = intravenous; PCD = primary carnitine deficiency
Essential information including written treatment protocols should be provided
Perioperative/perianesthetic management precautions may include evaluation at specialist anesthetic clinics for affected individuals deemed to be high risk for perioperative complications. Note: Hospitalization to administer IV glucose is recommended for individuals with PCD who are required to fast because of medical or surgical procedures or who cannot tolerate oral intake because of an illness such as gastroenteritis.
Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with PCD together with pediatric metabolic experts, dietitians, psychologists, and social workers.
As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.
Fever
Vomiting/diarrhea or other manifestations of intercurrent illness
New neurologic findings
Primary Carnitine Deficiency: Emergency Outpatient Treatment
If affected person is not vomiting, carnitine & feeds may be given orally.
Carbohydrate supplementation orally or via tube feeding
Increase carnitine supplementation.
Assess serum CK concentration & liver transaminases during acute illness.
Trial of outpatient treatment at home for up to 12 hrs
Reassessment (~every 2 hrs) for clinical changes
Hospitalization to administer IV glucose is recommended for persons w/PCD who cannot tolerate oral intake because of vomiting.
Based on
CK = creatine kinase; IV = intravenous; PCD = primary carnitine deficiency
Stringent guidelines to quantify carbohydrate/caloric requirements are available to guide dietary recommendations in the outpatient setting, with some centers recommending frequent provision of carbohydrate-rich, protein-free beverages every two hours, with frequent reassessment.
Alterations in mentation/alertness, fever, and enteral feeding tolerance, with any new or evolving clinical features discussed with the designated center of expertise for inherited metabolic diseases
Some classes of antiemetics can be used safely on an occasional basis to temporarily improve enteral tolerance of food and beverages at home or during transfer to hospital.
Primary Carnitine Deficiency: Acute Inpatient Treatment
Administration of high-calorie fluids &, if needed, insulin
Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
Administration of high-energy fluids &, if needed, insulin
Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
Administration of high-energy fluids &, if needed, insulin
Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
Administration of high-energy fluids &, if needed, insulin
Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
Eval by cardiologist
EKG
Echocardiogram
CK = creatine kinase; IV = intravenous; PO =
In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in
Primary Carnitine Deficiency: Recommended Surveillance
EKG
Echocardiogram
Annually during childhood; less frequently in adulthood
Note: In those nonadherent w/carnitine supplementation, consider more frequent monitoring.
Avoid the following:
Prolonged fasting beyond age-appropriate periods
Catabolic illness (using measures to avoid intercurrent infection, such as being up to date on vaccinations with anticipation of likelihood of febrile illness post vaccination, wearing a mask in crowded environments, considering alternatives to daycare, recognizing symptoms early)
Inadequate caloric provision during other stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)
If the
If the pathogenic variants in the family are not known, measure plasma free carnitine concentrations. If the free carnitine concentrations are low, further evaluation for PCD is available using carnitine uptake studies in cultured skin fibroblasts [
See
Pregnancy is a metabolically challenging state for women with PCD because energy consumption significantly increases. In addition, plasma carnitine concentrations are physiologically lower in women with PCD during pregnancy than those of non-pregnant controls. Women with PCD can have decreased stamina or worsening of cardiac arrhythmia during pregnancy, suggesting that PCD may manifest or exacerbate during pregnancy [
Search
• CK & liver transaminases
• Post-prandial blood glucose concentration
• Plasma free/total carnitine concentration following initiation of treatment
• Frequent feeds
• Avoid fasting
• Written protocols for outpatient routine & emergency treatment should be provided to parents, primary care providers, teachers, & school staff.
• Emergency letter/card should be provided summarizing key info, principles of emergency treatment, & contact information for primary treating metabolic center.
• For any planned travel or vacations, consider contacting center of expertise near destination prior to travel dates.
• Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
• Hospitalization to administer IV glucose is recommended for persons w/PCD who are required to fast because of medical or surgical procedures or who cannot tolerate oral intake because of illness such as gastroenteritis.
• Consider placing a "flag" in affected person's medical record such that all care providers are aware of diagnosis & need to solicit opinions & guidance from designated metabolic specialists in the setting of certain procedures.
• Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).
• Fever
• Vomiting/diarrhea or other manifestations of intercurrent illness
• New neurologic findings
• If affected person is not vomiting, carnitine & feeds may be given orally.
• Carbohydrate supplementation orally or via tube feeding
• Increase carnitine supplementation.
• Assess serum CK concentration & liver transaminases during acute illness.
• Trial of outpatient treatment at home for up to 12 hrs
• Reassessment (~every 2 hrs) for clinical changes
• Hospitalization to administer IV glucose is recommended for persons w/PCD who cannot tolerate oral intake because of vomiting.
• Administration of high-calorie fluids &, if needed, insulin
• Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
• Administration of high-energy fluids &, if needed, insulin
• Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
• Administration of high-energy fluids &, if needed, insulin
• Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
• Administration of high-energy fluids &, if needed, insulin
• Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
• Eval by cardiologist
• EKG
• Echocardiogram
• EKG
• Echocardiogram
• Annually during childhood; less frequently in adulthood
• Note: In those nonadherent w/carnitine supplementation, consider more frequent monitoring.
• Prolonged fasting beyond age-appropriate periods
• Catabolic illness (using measures to avoid intercurrent infection, such as being up to date on vaccinations with anticipation of likelihood of febrile illness post vaccination, wearing a mask in crowded environments, considering alternatives to daycare, recognizing symptoms early)
• Inadequate caloric provision during other stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)
• If the
• If the pathogenic variants in the family are not known, measure plasma free carnitine concentrations. If the free carnitine concentrations are low, further evaluation for PCD is available using carnitine uptake studies in cultured skin fibroblasts [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with PCD, the evaluations summarized in
Primary Carnitine Deficiency: Recommended Evaluations Following Initial Diagnosis
CK & liver transaminases
Post-prandial blood glucose concentration
Plasma free/total carnitine concentration following initiation of treatment
CK = creatine kinase; MOI = mode of inheritance; PCD = primary carnitine deficiency
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• CK & liver transaminases
• Post-prandial blood glucose concentration
• Plasma free/total carnitine concentration following initiation of treatment
## Treatment of Manifestations
Targeted therapy for PCD involves oral carnitine supplementation to prevent carnitine deficiency (see
Primary Carnitine Deficiency: Targeted Therapy
High doses of oral levocarnitine can cause increased gastrointestinal motility, diarrhea, and intestinal discomfort. Oral levocarnitine can be metabolized by intestinal bacteria to produce trimethylamine, which has a fishy odor. Oral metronidazole at a dose of 10 mg/kg/day for 7-10 days and/or decreasing the carnitine dose usually results in the resolution of the odor [
Oral levocarnitine supplementation in infants with PCD identified through newborn screening (NBS) results in slow normalization of the plasma carnitine concentration.
Metabolic decompensation and skeletal and cardiac muscle function improve with levocarnitine supplementation. Individuals with PCD respond well if oral levocarnitine supplementation is started before irreversible organ damage occurs.
One of the most important components of preventing carnitine deficiency is education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see
Primary Carnitine Deficiency: Routine Outpatient Treatment of Manifestations
Frequent feeds
Avoid fasting
Written protocols for outpatient routine & emergency treatment should be provided to parents, primary care providers, teachers, & school staff.
Emergency letter/card should be provided summarizing key info, principles of emergency treatment, & contact information for primary treating metabolic center.
For any planned travel or vacations, consider contacting center of expertise near destination prior to travel dates.
Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
Hospitalization to administer IV glucose is recommended for persons w/PCD who are required to fast because of medical or surgical procedures or who cannot tolerate oral intake because of illness such as gastroenteritis.
Consider placing a "flag" in affected person's medical record such that all care providers are aware of diagnosis & need to solicit opinions & guidance from designated metabolic specialists in the setting of certain procedures.
Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).
IV = intravenous; PCD = primary carnitine deficiency
Essential information including written treatment protocols should be provided
Perioperative/perianesthetic management precautions may include evaluation at specialist anesthetic clinics for affected individuals deemed to be high risk for perioperative complications. Note: Hospitalization to administer IV glucose is recommended for individuals with PCD who are required to fast because of medical or surgical procedures or who cannot tolerate oral intake because of an illness such as gastroenteritis.
Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with PCD together with pediatric metabolic experts, dietitians, psychologists, and social workers.
As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.
Fever
Vomiting/diarrhea or other manifestations of intercurrent illness
New neurologic findings
Primary Carnitine Deficiency: Emergency Outpatient Treatment
If affected person is not vomiting, carnitine & feeds may be given orally.
Carbohydrate supplementation orally or via tube feeding
Increase carnitine supplementation.
Assess serum CK concentration & liver transaminases during acute illness.
Trial of outpatient treatment at home for up to 12 hrs
Reassessment (~every 2 hrs) for clinical changes
Hospitalization to administer IV glucose is recommended for persons w/PCD who cannot tolerate oral intake because of vomiting.
Based on
CK = creatine kinase; IV = intravenous; PCD = primary carnitine deficiency
Stringent guidelines to quantify carbohydrate/caloric requirements are available to guide dietary recommendations in the outpatient setting, with some centers recommending frequent provision of carbohydrate-rich, protein-free beverages every two hours, with frequent reassessment.
Alterations in mentation/alertness, fever, and enteral feeding tolerance, with any new or evolving clinical features discussed with the designated center of expertise for inherited metabolic diseases
Some classes of antiemetics can be used safely on an occasional basis to temporarily improve enteral tolerance of food and beverages at home or during transfer to hospital.
Primary Carnitine Deficiency: Acute Inpatient Treatment
Administration of high-calorie fluids &, if needed, insulin
Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
Administration of high-energy fluids &, if needed, insulin
Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
Administration of high-energy fluids &, if needed, insulin
Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
Administration of high-energy fluids &, if needed, insulin
Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
Eval by cardiologist
EKG
Echocardiogram
CK = creatine kinase; IV = intravenous; PO =
• Frequent feeds
• Avoid fasting
• Written protocols for outpatient routine & emergency treatment should be provided to parents, primary care providers, teachers, & school staff.
• Emergency letter/card should be provided summarizing key info, principles of emergency treatment, & contact information for primary treating metabolic center.
• For any planned travel or vacations, consider contacting center of expertise near destination prior to travel dates.
• Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
• Hospitalization to administer IV glucose is recommended for persons w/PCD who are required to fast because of medical or surgical procedures or who cannot tolerate oral intake because of illness such as gastroenteritis.
• Consider placing a "flag" in affected person's medical record such that all care providers are aware of diagnosis & need to solicit opinions & guidance from designated metabolic specialists in the setting of certain procedures.
• Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).
• Fever
• Vomiting/diarrhea or other manifestations of intercurrent illness
• New neurologic findings
• If affected person is not vomiting, carnitine & feeds may be given orally.
• Carbohydrate supplementation orally or via tube feeding
• Increase carnitine supplementation.
• Assess serum CK concentration & liver transaminases during acute illness.
• Trial of outpatient treatment at home for up to 12 hrs
• Reassessment (~every 2 hrs) for clinical changes
• Hospitalization to administer IV glucose is recommended for persons w/PCD who cannot tolerate oral intake because of vomiting.
• Administration of high-calorie fluids &, if needed, insulin
• Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
• Administration of high-energy fluids &, if needed, insulin
• Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
• Administration of high-energy fluids &, if needed, insulin
• Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
• Administration of high-energy fluids &, if needed, insulin
• Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
• Eval by cardiologist
• EKG
• Echocardiogram
## Targeted Therapy
Targeted therapy for PCD involves oral carnitine supplementation to prevent carnitine deficiency (see
Primary Carnitine Deficiency: Targeted Therapy
High doses of oral levocarnitine can cause increased gastrointestinal motility, diarrhea, and intestinal discomfort. Oral levocarnitine can be metabolized by intestinal bacteria to produce trimethylamine, which has a fishy odor. Oral metronidazole at a dose of 10 mg/kg/day for 7-10 days and/or decreasing the carnitine dose usually results in the resolution of the odor [
Oral levocarnitine supplementation in infants with PCD identified through newborn screening (NBS) results in slow normalization of the plasma carnitine concentration.
Metabolic decompensation and skeletal and cardiac muscle function improve with levocarnitine supplementation. Individuals with PCD respond well if oral levocarnitine supplementation is started before irreversible organ damage occurs.
## Supportive Care
One of the most important components of preventing carnitine deficiency is education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see
Primary Carnitine Deficiency: Routine Outpatient Treatment of Manifestations
Frequent feeds
Avoid fasting
Written protocols for outpatient routine & emergency treatment should be provided to parents, primary care providers, teachers, & school staff.
Emergency letter/card should be provided summarizing key info, principles of emergency treatment, & contact information for primary treating metabolic center.
For any planned travel or vacations, consider contacting center of expertise near destination prior to travel dates.
Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
Hospitalization to administer IV glucose is recommended for persons w/PCD who are required to fast because of medical or surgical procedures or who cannot tolerate oral intake because of illness such as gastroenteritis.
Consider placing a "flag" in affected person's medical record such that all care providers are aware of diagnosis & need to solicit opinions & guidance from designated metabolic specialists in the setting of certain procedures.
Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).
IV = intravenous; PCD = primary carnitine deficiency
Essential information including written treatment protocols should be provided
Perioperative/perianesthetic management precautions may include evaluation at specialist anesthetic clinics for affected individuals deemed to be high risk for perioperative complications. Note: Hospitalization to administer IV glucose is recommended for individuals with PCD who are required to fast because of medical or surgical procedures or who cannot tolerate oral intake because of an illness such as gastroenteritis.
Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with PCD together with pediatric metabolic experts, dietitians, psychologists, and social workers.
As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.
Fever
Vomiting/diarrhea or other manifestations of intercurrent illness
New neurologic findings
Primary Carnitine Deficiency: Emergency Outpatient Treatment
If affected person is not vomiting, carnitine & feeds may be given orally.
Carbohydrate supplementation orally or via tube feeding
Increase carnitine supplementation.
Assess serum CK concentration & liver transaminases during acute illness.
Trial of outpatient treatment at home for up to 12 hrs
Reassessment (~every 2 hrs) for clinical changes
Hospitalization to administer IV glucose is recommended for persons w/PCD who cannot tolerate oral intake because of vomiting.
Based on
CK = creatine kinase; IV = intravenous; PCD = primary carnitine deficiency
Stringent guidelines to quantify carbohydrate/caloric requirements are available to guide dietary recommendations in the outpatient setting, with some centers recommending frequent provision of carbohydrate-rich, protein-free beverages every two hours, with frequent reassessment.
Alterations in mentation/alertness, fever, and enteral feeding tolerance, with any new or evolving clinical features discussed with the designated center of expertise for inherited metabolic diseases
Some classes of antiemetics can be used safely on an occasional basis to temporarily improve enteral tolerance of food and beverages at home or during transfer to hospital.
Primary Carnitine Deficiency: Acute Inpatient Treatment
Administration of high-calorie fluids &, if needed, insulin
Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
Administration of high-energy fluids &, if needed, insulin
Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
Administration of high-energy fluids &, if needed, insulin
Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
Administration of high-energy fluids &, if needed, insulin
Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
Eval by cardiologist
EKG
Echocardiogram
CK = creatine kinase; IV = intravenous; PO =
• Frequent feeds
• Avoid fasting
• Written protocols for outpatient routine & emergency treatment should be provided to parents, primary care providers, teachers, & school staff.
• Emergency letter/card should be provided summarizing key info, principles of emergency treatment, & contact information for primary treating metabolic center.
• For any planned travel or vacations, consider contacting center of expertise near destination prior to travel dates.
• Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
• Hospitalization to administer IV glucose is recommended for persons w/PCD who are required to fast because of medical or surgical procedures or who cannot tolerate oral intake because of illness such as gastroenteritis.
• Consider placing a "flag" in affected person's medical record such that all care providers are aware of diagnosis & need to solicit opinions & guidance from designated metabolic specialists in the setting of certain procedures.
• Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).
• Fever
• Vomiting/diarrhea or other manifestations of intercurrent illness
• New neurologic findings
• If affected person is not vomiting, carnitine & feeds may be given orally.
• Carbohydrate supplementation orally or via tube feeding
• Increase carnitine supplementation.
• Assess serum CK concentration & liver transaminases during acute illness.
• Trial of outpatient treatment at home for up to 12 hrs
• Reassessment (~every 2 hrs) for clinical changes
• Hospitalization to administer IV glucose is recommended for persons w/PCD who cannot tolerate oral intake because of vomiting.
• Administration of high-calorie fluids &, if needed, insulin
• Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
• Administration of high-energy fluids &, if needed, insulin
• Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
• Administration of high-energy fluids &, if needed, insulin
• Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
• Administration of high-energy fluids &, if needed, insulin
• Levocarnitine supplementation (100 mg/kg divided q.i.d. PO or IV)
• Eval by cardiologist
• EKG
• Echocardiogram
## Surveillance
In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in
Primary Carnitine Deficiency: Recommended Surveillance
EKG
Echocardiogram
Annually during childhood; less frequently in adulthood
Note: In those nonadherent w/carnitine supplementation, consider more frequent monitoring.
• EKG
• Echocardiogram
• Annually during childhood; less frequently in adulthood
• Note: In those nonadherent w/carnitine supplementation, consider more frequent monitoring.
## Agents/Circumstances to Avoid
Avoid the following:
Prolonged fasting beyond age-appropriate periods
Catabolic illness (using measures to avoid intercurrent infection, such as being up to date on vaccinations with anticipation of likelihood of febrile illness post vaccination, wearing a mask in crowded environments, considering alternatives to daycare, recognizing symptoms early)
Inadequate caloric provision during other stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)
• Prolonged fasting beyond age-appropriate periods
• Catabolic illness (using measures to avoid intercurrent infection, such as being up to date on vaccinations with anticipation of likelihood of febrile illness post vaccination, wearing a mask in crowded environments, considering alternatives to daycare, recognizing symptoms early)
• Inadequate caloric provision during other stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)
## Evaluation of Relatives at Risk
If the
If the pathogenic variants in the family are not known, measure plasma free carnitine concentrations. If the free carnitine concentrations are low, further evaluation for PCD is available using carnitine uptake studies in cultured skin fibroblasts [
See
• If the
• If the pathogenic variants in the family are not known, measure plasma free carnitine concentrations. If the free carnitine concentrations are low, further evaluation for PCD is available using carnitine uptake studies in cultured skin fibroblasts [
## Pregnancy Management
Pregnancy is a metabolically challenging state for women with PCD because energy consumption significantly increases. In addition, plasma carnitine concentrations are physiologically lower in women with PCD during pregnancy than those of non-pregnant controls. Women with PCD can have decreased stamina or worsening of cardiac arrhythmia during pregnancy, suggesting that PCD may manifest or exacerbate during pregnancy [
## Therapies Under Investigation
Search
## Genetic Counseling
Primary carnitine deficiency (PCD) is inherited in an autosomal recessive manner.
The parents of an affected individual are presumed to be heterozygous for an
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to determine the genetic status of the parents and allow reliable recurrence risk assessment.
Occasionally an asymptomatic parent is found to have biallelic
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with PCD, particularly if both partners are of the same ancestry. A founder variant has been identified in the Faroe Islander population (see
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are presumed to be heterozygous for an
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to determine the genetic status of the parents and allow reliable recurrence risk assessment.
• Occasionally an asymptomatic parent is found to have biallelic
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with PCD, particularly if both partners are of the same ancestry. A founder variant has been identified in the Faroe Islander population (see
## Mode of Inheritance
Primary carnitine deficiency (PCD) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are presumed to be heterozygous for an
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to determine the genetic status of the parents and allow reliable recurrence risk assessment.
Occasionally an asymptomatic parent is found to have biallelic
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected individual are presumed to be heterozygous for an
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to determine the genetic status of the parents and allow reliable recurrence risk assessment.
• Occasionally an asymptomatic parent is found to have biallelic
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with PCD, particularly if both partners are of the same ancestry. A founder variant has been identified in the Faroe Islander population (see
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with PCD, particularly if both partners are of the same ancestry. A founder variant has been identified in the Faroe Islander population (see
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
Health Resources & Services Administration
•
•
•
•
•
• United Kingdom
•
•
• Health Resources & Services Administration
•
## Molecular Genetics
Primary Carnitine Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Primary Carnitine Deficiency (
Carnitine, required for the intracellular transfer of long-chain fatty acids from the cytoplasm to the mitochondrial matrix for beta-oxidation, is transported into cells by OCTN2 (encoded by
UTR = untranslated region
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Carnitine, required for the intracellular transfer of long-chain fatty acids from the cytoplasm to the mitochondrial matrix for beta-oxidation, is transported into cells by OCTN2 (encoded by
UTR = untranslated region
Variants listed in the table have been provided by the authors.
## Chapter Notes
5 December 2024 (gf) Comprehensive update posted live
3 November 2016 (sw) Comprehensive update posted live
26 June 2014 (me) Comprehensive update posted live
15 March 2012 (me) Review posted live
5 December 2011 (aeh) Original submission
• 5 December 2024 (gf) Comprehensive update posted live
• 3 November 2016 (sw) Comprehensive update posted live
• 26 June 2014 (me) Comprehensive update posted live
• 15 March 2012 (me) Review posted live
• 5 December 2011 (aeh) Original submission
## Revision History
5 December 2024 (gf) Comprehensive update posted live
3 November 2016 (sw) Comprehensive update posted live
26 June 2014 (me) Comprehensive update posted live
15 March 2012 (me) Review posted live
5 December 2011 (aeh) Original submission
• 5 December 2024 (gf) Comprehensive update posted live
• 3 November 2016 (sw) Comprehensive update posted live
• 26 June 2014 (me) Comprehensive update posted live
• 15 March 2012 (me) Review posted live
• 5 December 2011 (aeh) Original submission
## Key Sections in This
## References
## Literature Cited
|
[] |
15/3/2012
|
5/12/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
ce-dysp
|
ce-dysp
|
[
"Sensenbrenner Syndrome",
"Sensenbrenner Syndrome",
"Intraflagellar transport protein 122 homolog",
"Intraflagellar transport protein 140 homolog",
"Intraflagellar transport protein 43 homolog",
"Intraflagellar transport protein 52 homolog",
"WD repeat-containing protein 19",
"WD repeat-containing protein 35",
"IFT122",
"IFT140",
"IFT43",
"IFT52",
"WDR19",
"WDR35",
"Cranioectodermal Dysplasia"
] |
Cranioectodermal Dysplasia
|
Weizhen Tan, Angela Lin, Kim Keppler-Noreuil
|
Summary Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly), ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth deficiency, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage kidney disease in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur. The diagnosis of CED is established in a proband with characteristic clinical and radiographic features (including two frequent features and two other abnormalities, with at least one ectodermal defect – i.e., involvement of the teeth, hair, or nails) and/or by identification of biallelic pathogenic variants in one of the six genes currently known to be associated with CED: CED is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CED-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible once the CED-causing pathogenic variants have been identified in an affected family member. Second-trimester ultrasound examination may detect renal cysts, shortening of the limbs, and/or polydactyly.
|
## Diagnosis
Cranioectodermal dysplasia (CED)
Characteristic facial features (e.g., frontal bossing, low-set/simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip)
Brachydactyly
Dolichocephaly and sagittal craniosynostosis
Shortening (and bowing) of proximal bones (mostly humeri)
Short stature
Narrow thorax (with dysplastic ribs and pectus excavatum)
Dental abnormalities (malformed, widely spaced teeth, and/or hypodontia)
Sparse and/or thin hair
Nephronophthisis (a phenotype of progressive kidney disease that may include features such as renal cysts, scarring, echogenic kidneys on ultrasound, chronic tubulointerstitial nephritis, and reduced renal function / renal concentrating ability)
Developmental delay (most often affecting motor development)
Joint laxity
Liver disease (hepatic fibrosis, cirrhosis, and/or hepatomegaly)
Syndactyly
Polydactyly
Abnormal nails
Skin laxity
Recurrent lung infections
Bilateral inguinal hernias
Retinal dystrophy
Hip dysplasia
Cystic hygroma
Congenital heart defect
Intellectual disability
Note: Some suggestive findings (e.g., developmental delay, dental abnormalities, abnormalities of the retina, kidney, and liver) may not be present in a neonate at the time of evaluation.
Although formal evidence-based diagnostic criteria have not been delineated, the clinical diagnosis of CED can be
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by ectodermal dysplasia and/or skeletal anomalies,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cranioectodermal Dysplasia
CED = cranioectodermal dysplasia; NA = not applicable
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis has not identified any deletions/duplications.
No deletions or duplications involving
• Characteristic facial features (e.g., frontal bossing, low-set/simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip)
• Brachydactyly
• Dolichocephaly and sagittal craniosynostosis
• Shortening (and bowing) of proximal bones (mostly humeri)
• Short stature
• Narrow thorax (with dysplastic ribs and pectus excavatum)
• Dental abnormalities (malformed, widely spaced teeth, and/or hypodontia)
• Sparse and/or thin hair
• Nephronophthisis (a phenotype of progressive kidney disease that may include features such as renal cysts, scarring, echogenic kidneys on ultrasound, chronic tubulointerstitial nephritis, and reduced renal function / renal concentrating ability)
• Developmental delay (most often affecting motor development)
• Joint laxity
• Liver disease (hepatic fibrosis, cirrhosis, and/or hepatomegaly)
• Syndactyly
• Polydactyly
• Abnormal nails
• Skin laxity
• Recurrent lung infections
• Bilateral inguinal hernias
• Retinal dystrophy
• Hip dysplasia
• Cystic hygroma
• Congenital heart defect
• Intellectual disability
## Suggestive Findings
Cranioectodermal dysplasia (CED)
Characteristic facial features (e.g., frontal bossing, low-set/simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip)
Brachydactyly
Dolichocephaly and sagittal craniosynostosis
Shortening (and bowing) of proximal bones (mostly humeri)
Short stature
Narrow thorax (with dysplastic ribs and pectus excavatum)
Dental abnormalities (malformed, widely spaced teeth, and/or hypodontia)
Sparse and/or thin hair
Nephronophthisis (a phenotype of progressive kidney disease that may include features such as renal cysts, scarring, echogenic kidneys on ultrasound, chronic tubulointerstitial nephritis, and reduced renal function / renal concentrating ability)
Developmental delay (most often affecting motor development)
Joint laxity
Liver disease (hepatic fibrosis, cirrhosis, and/or hepatomegaly)
Syndactyly
Polydactyly
Abnormal nails
Skin laxity
Recurrent lung infections
Bilateral inguinal hernias
Retinal dystrophy
Hip dysplasia
Cystic hygroma
Congenital heart defect
Intellectual disability
Note: Some suggestive findings (e.g., developmental delay, dental abnormalities, abnormalities of the retina, kidney, and liver) may not be present in a neonate at the time of evaluation.
• Characteristic facial features (e.g., frontal bossing, low-set/simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip)
• Brachydactyly
• Dolichocephaly and sagittal craniosynostosis
• Shortening (and bowing) of proximal bones (mostly humeri)
• Short stature
• Narrow thorax (with dysplastic ribs and pectus excavatum)
• Dental abnormalities (malformed, widely spaced teeth, and/or hypodontia)
• Sparse and/or thin hair
• Nephronophthisis (a phenotype of progressive kidney disease that may include features such as renal cysts, scarring, echogenic kidneys on ultrasound, chronic tubulointerstitial nephritis, and reduced renal function / renal concentrating ability)
• Developmental delay (most often affecting motor development)
• Joint laxity
• Liver disease (hepatic fibrosis, cirrhosis, and/or hepatomegaly)
• Syndactyly
• Polydactyly
• Abnormal nails
• Skin laxity
• Recurrent lung infections
• Bilateral inguinal hernias
• Retinal dystrophy
• Hip dysplasia
• Cystic hygroma
• Congenital heart defect
• Intellectual disability
## Establishing the Diagnosis
Although formal evidence-based diagnostic criteria have not been delineated, the clinical diagnosis of CED can be
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by ectodermal dysplasia and/or skeletal anomalies,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cranioectodermal Dysplasia
CED = cranioectodermal dysplasia; NA = not applicable
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis has not identified any deletions/duplications.
No deletions or duplications involving
## Option 1
For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by ectodermal dysplasia and/or skeletal anomalies,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cranioectodermal Dysplasia
CED = cranioectodermal dysplasia; NA = not applicable
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis has not identified any deletions/duplications.
No deletions or duplications involving
## Clinical Characteristics
Cranioectodermal dysplasia (CED) is a ciliopathy with significant involvement of the skeleton, ectoderm (teeth, hair, and nails), retina, kidneys, liver, lungs, and occasionally the brain. The current understanding of the CED phenotype is limited by the small number of well-described affected individuals reported and the even smaller number with a molecularly confirmed diagnosis.
To date, 44 individuals with biallelic pathogenic variants in one of the genes listed in
Select Features of Cranioectodermal Dysplasia
Teeth. Tooth eruption is often delayed. Deciduous teeth are generally small and widely spaced. Hypodontia, enamel defects, taurodontia, and fused and cone-shaped teeth have also been reported. Similar characteristics are seen in permanent teeth. Hypo- or oligodontia may affect upper as well as lower permanent teeth [
Renal ultrasound examination in infancy and early childhood usually shows normal-sized or small kidneys with increased echogenicity and poor corticomedullary differentiation [
Other ophthalmologic findings include hyperopia, myopia, esotropia, myopic/hypermetropic astigmatism, and euryblepharon (excess horizontal eyelid length) [
Brain imaging has revealed cortical atrophy, ventriculomegaly, large cisterna magna, hypoplasia of the corpus callosum, focal microdysgenesis, enlarged extracerebral fluid spaces, large posterior fossa cyst, and Dandy-Walker malformation [
Phenotypes resulting from biallelic pathogenic variants in any one of the six known genes (i.e.,
No genotype-phenotype correlations have been confirmed.
CED was first described as Sensenbrenner syndrome in a sib pair with dolichocephaly, rhizomelic shortening of the bones, brachydactyly, and ectodermal defects [
CED is rare; its exact frequency is unknown. Fewer than 100 affected individuals have been reported.
• Teeth. Tooth eruption is often delayed. Deciduous teeth are generally small and widely spaced. Hypodontia, enamel defects, taurodontia, and fused and cone-shaped teeth have also been reported. Similar characteristics are seen in permanent teeth. Hypo- or oligodontia may affect upper as well as lower permanent teeth [
## Clinical Description
Cranioectodermal dysplasia (CED) is a ciliopathy with significant involvement of the skeleton, ectoderm (teeth, hair, and nails), retina, kidneys, liver, lungs, and occasionally the brain. The current understanding of the CED phenotype is limited by the small number of well-described affected individuals reported and the even smaller number with a molecularly confirmed diagnosis.
To date, 44 individuals with biallelic pathogenic variants in one of the genes listed in
Select Features of Cranioectodermal Dysplasia
Teeth. Tooth eruption is often delayed. Deciduous teeth are generally small and widely spaced. Hypodontia, enamel defects, taurodontia, and fused and cone-shaped teeth have also been reported. Similar characteristics are seen in permanent teeth. Hypo- or oligodontia may affect upper as well as lower permanent teeth [
Renal ultrasound examination in infancy and early childhood usually shows normal-sized or small kidneys with increased echogenicity and poor corticomedullary differentiation [
Other ophthalmologic findings include hyperopia, myopia, esotropia, myopic/hypermetropic astigmatism, and euryblepharon (excess horizontal eyelid length) [
Brain imaging has revealed cortical atrophy, ventriculomegaly, large cisterna magna, hypoplasia of the corpus callosum, focal microdysgenesis, enlarged extracerebral fluid spaces, large posterior fossa cyst, and Dandy-Walker malformation [
• Teeth. Tooth eruption is often delayed. Deciduous teeth are generally small and widely spaced. Hypodontia, enamel defects, taurodontia, and fused and cone-shaped teeth have also been reported. Similar characteristics are seen in permanent teeth. Hypo- or oligodontia may affect upper as well as lower permanent teeth [
## Phenotype Correlations by Gene
Phenotypes resulting from biallelic pathogenic variants in any one of the six known genes (i.e.,
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been confirmed.
## Nomenclature
CED was first described as Sensenbrenner syndrome in a sib pair with dolichocephaly, rhizomelic shortening of the bones, brachydactyly, and ectodermal defects [
## Prevalence
CED is rare; its exact frequency is unknown. Fewer than 100 affected individuals have been reported.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Heterozygous pathogenic variants in
Biallelic pathogenic variants in
Allelic Disorders to Consider in the Differential Diagnosis of Cranioectodermal Dysplasia
SRPS = short-rib polydactyly syndrome
## Differential Diagnosis
Cranioectodermal dysplasia (CED) is part of a spectrum of disorders caused by disruption of the cilium, an organelle of the cell that appears and functions as an antenna (see
Within the ciliopathies, Jeune asphyxiating thoracic dystrophy, Mainzer-Saldino syndrome,
Skeletal Ciliopathies of Interest in the Differential Diagnosis of Cranioectodermal Dysplasia
CED = cranioectodermal dysplasia
In addition to the genes listed, SRPS and EVC can be caused by pathogenic variants in
Other ciliopathies that clinically overlap with CED include isolated
## Management
To establish the extent of disease and needs of a newborn or infant diagnosed with cranioectodermal dysplasia (CED), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Cranioectodermal Dysplasia
Urinalysis (first AM void) (& optional 24-hour urine collection) to identify polyuria
Osmolarity testing on morning urine
Blood pressure
Serum creatinine & blood urea concentration
Renal ultrasound exam
Liver ultrasound exam
Measurement of transaminases & synthetic liver function
Community or online
Social work involvement for parental support
Home nursing referral
CED = cranioectodermal dysplasia; EKG = electrocardiogram; ERG = electroretinography; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment of Manifestations in Individuals with Cranioectodermal Dysplasia
Chest radiograph & sputum analysis if pneumonia suspected
Antibiotics as indicated
Speech therapy & PT
Early intervention &/or IEP as needed
IEP = individualized educational plan; PT = physical therapy
Recommended Surveillance for Individuals with Cranioectodermal Dysplasia
Osmolarity testing in AM urine
Urine collection assays to test for polyuria
Blood pressure
Serum creatinine & blood urea concentration
Renal ultrasound exam to determine renal size & presence of cysts
W/each visit during infancy & childhood
Formal eval w/neuropsychologist if delays are present
EKG = electrocardiogram; ERG = electroretinography
If kidney disease is present, a nephrologist may recommend reduction of potassium and phosphorus from the diet.
Nephrotoxic medications, including the NSAID class of drugs, may also be a relative contraindication in individuals with kidney involvement. Individuals should be under the care of a nephrologist, if indicated, to discuss what nephrotoxic agents to avoid.
If the CED-causing pathogenic variants have been identified in an affected family member, it is appropriate to clarify the genetic status of at-risk infants to allow early diagnosis and appropriate management and surveillance, particularly for respiratory complications, renal and liver disease, and visual impairment.
If the pathogenic variants are not known in a family, the following is recommended for at-risk children:
Parents should be alerted to the signs of CED and advised to contact their child's health care provider if suspicious symptoms, such as polydipsia and/or jaundice, appear.
See
Search
• Urinalysis (first AM void) (& optional 24-hour urine collection) to identify polyuria
• Osmolarity testing on morning urine
• Blood pressure
• Serum creatinine & blood urea concentration
• Renal ultrasound exam
• Liver ultrasound exam
• Measurement of transaminases & synthetic liver function
• Community or online
• Social work involvement for parental support
• Home nursing referral
• Chest radiograph & sputum analysis if pneumonia suspected
• Antibiotics as indicated
• Speech therapy & PT
• Early intervention &/or IEP as needed
• Osmolarity testing in AM urine
• Urine collection assays to test for polyuria
• Blood pressure
• Serum creatinine & blood urea concentration
• Renal ultrasound exam to determine renal size & presence of cysts
• W/each visit during infancy & childhood
• Formal eval w/neuropsychologist if delays are present
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of a newborn or infant diagnosed with cranioectodermal dysplasia (CED), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Cranioectodermal Dysplasia
Urinalysis (first AM void) (& optional 24-hour urine collection) to identify polyuria
Osmolarity testing on morning urine
Blood pressure
Serum creatinine & blood urea concentration
Renal ultrasound exam
Liver ultrasound exam
Measurement of transaminases & synthetic liver function
Community or online
Social work involvement for parental support
Home nursing referral
CED = cranioectodermal dysplasia; EKG = electrocardiogram; ERG = electroretinography; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Urinalysis (first AM void) (& optional 24-hour urine collection) to identify polyuria
• Osmolarity testing on morning urine
• Blood pressure
• Serum creatinine & blood urea concentration
• Renal ultrasound exam
• Liver ultrasound exam
• Measurement of transaminases & synthetic liver function
• Community or online
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Cranioectodermal Dysplasia
Chest radiograph & sputum analysis if pneumonia suspected
Antibiotics as indicated
Speech therapy & PT
Early intervention &/or IEP as needed
IEP = individualized educational plan; PT = physical therapy
• Chest radiograph & sputum analysis if pneumonia suspected
• Antibiotics as indicated
• Speech therapy & PT
• Early intervention &/or IEP as needed
## Surveillance
Recommended Surveillance for Individuals with Cranioectodermal Dysplasia
Osmolarity testing in AM urine
Urine collection assays to test for polyuria
Blood pressure
Serum creatinine & blood urea concentration
Renal ultrasound exam to determine renal size & presence of cysts
W/each visit during infancy & childhood
Formal eval w/neuropsychologist if delays are present
EKG = electrocardiogram; ERG = electroretinography
• Osmolarity testing in AM urine
• Urine collection assays to test for polyuria
• Blood pressure
• Serum creatinine & blood urea concentration
• Renal ultrasound exam to determine renal size & presence of cysts
• W/each visit during infancy & childhood
• Formal eval w/neuropsychologist if delays are present
## Agents/Circumstances to Avoid
If kidney disease is present, a nephrologist may recommend reduction of potassium and phosphorus from the diet.
Nephrotoxic medications, including the NSAID class of drugs, may also be a relative contraindication in individuals with kidney involvement. Individuals should be under the care of a nephrologist, if indicated, to discuss what nephrotoxic agents to avoid.
## Evaluation of Relatives at Risk
If the CED-causing pathogenic variants have been identified in an affected family member, it is appropriate to clarify the genetic status of at-risk infants to allow early diagnosis and appropriate management and surveillance, particularly for respiratory complications, renal and liver disease, and visual impairment.
If the pathogenic variants are not known in a family, the following is recommended for at-risk children:
Parents should be alerted to the signs of CED and advised to contact their child's health care provider if suspicious symptoms, such as polydipsia and/or jaundice, appear.
See
## Therapies Under Investigation
Search
## Genetic Counseling
Cranioectodermal dysplasia (CED) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one CED-causing pathogenic variant based on family history).
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CED-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a CED-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Clinical manifestations of CED are highly variable and may differ among affected sibs.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the CED-causing pathogenic variants in the family.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one CED-causing pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CED-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a CED-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Clinical manifestations of CED are highly variable and may differ among affected sibs.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Cranioectodermal dysplasia (CED) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one CED-causing pathogenic variant based on family history).
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CED-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a CED-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Clinical manifestations of CED are highly variable and may differ among affected sibs.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one CED-causing pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CED-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a CED-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Clinical manifestations of CED are highly variable and may differ among affected sibs.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the CED-causing pathogenic variants in the family.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
## Molecular Genetics
Cranioectodermal Dysplasia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Cranioectodermal Dysplasia (
Cranioectodermal dysplasia (CED) belongs to a spectrum of disorders known as ciliopathies [
A process that is required for ciliogenesis and regulation of signaling pathways is ciliary transport (also known as intraflagellar transport [IFT]) [
Most pathogenic variants in individuals with CED identified to date occur in genes that encode members of the IFT-A hexamere protein complex:
When the IFT-A protein complex is disrupted in CED, cilia in fibroblasts have bulging tips, which contain accumulations of IFT-B complex proteins that normally regulate base-to-tip (anterograde) ciliary transport [
Pathogenic variants in
Although shortening of cilia in fibroblasts from persons with CED has also been reported [
## Molecular Pathogenesis
Cranioectodermal dysplasia (CED) belongs to a spectrum of disorders known as ciliopathies [
A process that is required for ciliogenesis and regulation of signaling pathways is ciliary transport (also known as intraflagellar transport [IFT]) [
Most pathogenic variants in individuals with CED identified to date occur in genes that encode members of the IFT-A hexamere protein complex:
When the IFT-A protein complex is disrupted in CED, cilia in fibroblasts have bulging tips, which contain accumulations of IFT-B complex proteins that normally regulate base-to-tip (anterograde) ciliary transport [
Pathogenic variants in
Although shortening of cilia in fibroblasts from persons with CED has also been reported [
## Chapter Notes
This work was funded by the grants from the Dutch Kidney Foundation (CP11.18 "KOUNCIL" to N Knoers and H Arts) and the Netherlands Organization for Health Research and Development (ZonMw 91613008 to H Arts); both projects aim to unravel the genetics and mechanisms of disease of renal ciliopathies including Sensenbrenner syndrome.
We are thankful for the participation of the Sensenbrenner syndrome families in our study and for their consent for publication of clinical images. We also thank Dr E Lapi and Dr E Andreucci for their clinical contribution, Dr C Marcelis, Dr N van de Kar, Dr L Koster-Kamphuis, and Dr K Noordam for useful discussions, and Prof Dr HG Brunner for communication.
Heleen Arts, PhD; McMaster University (2013-2021)Kim Keppler-Noreuil, MD (2021-present)Nine Knoers, MD, PhD; University Medical Center Groningen (2013-2021)Angela Lin, MD (2021-present)Weizhen Tan, MD (2021-present)
15 December 2022 (aa) Revision: added
11 March 2021 (sw) Comprehensive update posted live
12 April 2018 (ha) Revision:
12 September 2013 (me) Review posted live
26 April 2012 (ha) Original submission
• 15 December 2022 (aa) Revision: added
• 11 March 2021 (sw) Comprehensive update posted live
• 12 April 2018 (ha) Revision:
• 12 September 2013 (me) Review posted live
• 26 April 2012 (ha) Original submission
## Author Notes
This work was funded by the grants from the Dutch Kidney Foundation (CP11.18 "KOUNCIL" to N Knoers and H Arts) and the Netherlands Organization for Health Research and Development (ZonMw 91613008 to H Arts); both projects aim to unravel the genetics and mechanisms of disease of renal ciliopathies including Sensenbrenner syndrome.
## Acknowledgments
We are thankful for the participation of the Sensenbrenner syndrome families in our study and for their consent for publication of clinical images. We also thank Dr E Lapi and Dr E Andreucci for their clinical contribution, Dr C Marcelis, Dr N van de Kar, Dr L Koster-Kamphuis, and Dr K Noordam for useful discussions, and Prof Dr HG Brunner for communication.
## Author History
Heleen Arts, PhD; McMaster University (2013-2021)Kim Keppler-Noreuil, MD (2021-present)Nine Knoers, MD, PhD; University Medical Center Groningen (2013-2021)Angela Lin, MD (2021-present)Weizhen Tan, MD (2021-present)
## Revision History
15 December 2022 (aa) Revision: added
11 March 2021 (sw) Comprehensive update posted live
12 April 2018 (ha) Revision:
12 September 2013 (me) Review posted live
26 April 2012 (ha) Original submission
• 15 December 2022 (aa) Revision: added
• 11 March 2021 (sw) Comprehensive update posted live
• 12 April 2018 (ha) Revision:
• 12 September 2013 (me) Review posted live
• 26 April 2012 (ha) Original submission
## References
## Literature Cited
Clinical and radiographic features of cranioectodermal dysplasia (CED)
Patient 1 (A-E):
A. Newborn with cranioectodermal dysplasia (CED) with rhizomelic shortening of the arms, narrow thorax, and characteristic facies with prominent forehead, ocular hypertelorism, and low-set ears
B. Short, broad hands with interphalangeal swelling at age 16 years
C. CED facial features in a young adult
D. Radiograph showing rhizomelia in the newborn period
E. Radiograph showing short phalanges at age nine years
Patient 2 (F-H):
F. Female with typical facial characteristics, including a prominent forehead, and bilateral epicanthal folds
G. Radiograph showing dolichocephaly in the newborn period
H. Radiograph showing narrow thorax
Images are shown with informed consent of the families/affected individuals.
Schematic architecture of a cilium and ciliary transport
The cilium is a tail-like protrusion from the apical plasma membrane of the cell. It is composed of two compartments: the basal body from which the cilium is initially assembled, and the ciliary axoneme that protrudes from the plasma membrane. Cilia assembly and signaling depend on ciliary transport known as intraflagellar transport (IFT). This transport process occurs bidirectionally along the axonemal microtubules from the ciliary base to its tip (anterograde transport) and back (retrograde transport). While anterograde transport is driven by the kinesin-2 motor and the IFT-B complex, the dynein-2 motor and the IFT-A complex regulate transport in the opposite direction. The IFT-A complex consists of six different proteins; biallelic pathogenic variants have been identified in four of the six genes that encode these IFT-A complex proteins in individuals with cranioectodermal dysplasia. The IFT-B complex consists of at least 12 proteins.
|
[] |
12/9/2013
|
11/3/2021
|
15/12/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cebpa-aml
|
cebpa-aml
|
[
"CEBPA-Dependent Familial Acute Myeloid Leukemia",
"CEBPA-Dependent Familial Acute Myeloid Leukemia",
"CCAAT/enhancer-binding protein alpha",
"CEBPA",
"CEBPA-Associated Familial Acute Myeloid Leukemia (AML)"
] |
Kiran Tawana, Jude Fitzgibbon
|
Summary The diagnosis of Predisposition to
|
## Diagnosis
Individuals with AML who also have a family history of AML
Individuals who have developed AML at an early age (<50 years)
Typically, individuals with AML presenting before age 50 years with pathogenic variants in both copies of
In the majority of individuals, a normal karyotype detected in leukemic cells
A preponderance of French-American-British Cooperative Group AML Classification subtypes M1 or M2 as established by morphologic analysis of peripheral blood or bone marrow blasts
Auer rods seen in blasts (i.e., abnormal, needle-shaped, or round, light blue- or pink-staining inclusions found in the cytoplasm of leukemic cells)
Aberrant CD7 expression on blasts as demonstrated by flow cytometry
For this
The diagnosis of
Note: In the literature, the terms
Molecular testing approaches include
Note: (1) Testing for a germline pathogenic variant should not be performed on blood or bone marrow during active AML. Testing an uninvolved specimen, such as cells obtained by buccal swab/saliva, skin biopsy, or cultured dendritic cells, is imperative. (2) It should be noted that
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequencing of the coding region does not detect putative partial or complete gene deletions or variants in promoter regions. To date, however, no such germline
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Individuals with AML who also have a family history of AML
• Individuals who have developed AML at an early age (<50 years)
• Typically, individuals with AML presenting before age 50 years with pathogenic variants in both copies of
• In the majority of individuals, a normal karyotype detected in leukemic cells
• A preponderance of French-American-British Cooperative Group AML Classification subtypes M1 or M2 as established by morphologic analysis of peripheral blood or bone marrow blasts
• Auer rods seen in blasts (i.e., abnormal, needle-shaped, or round, light blue- or pink-staining inclusions found in the cytoplasm of leukemic cells)
• Aberrant CD7 expression on blasts as demonstrated by flow cytometry
• Note: (1) Testing for a germline pathogenic variant should not be performed on blood or bone marrow during active AML. Testing an uninvolved specimen, such as cells obtained by buccal swab/saliva, skin biopsy, or cultured dendritic cells, is imperative. (2) It should be noted that
• For an introduction to multigene panels click
## Suggestive Findings
Individuals with AML who also have a family history of AML
Individuals who have developed AML at an early age (<50 years)
Typically, individuals with AML presenting before age 50 years with pathogenic variants in both copies of
In the majority of individuals, a normal karyotype detected in leukemic cells
A preponderance of French-American-British Cooperative Group AML Classification subtypes M1 or M2 as established by morphologic analysis of peripheral blood or bone marrow blasts
Auer rods seen in blasts (i.e., abnormal, needle-shaped, or round, light blue- or pink-staining inclusions found in the cytoplasm of leukemic cells)
Aberrant CD7 expression on blasts as demonstrated by flow cytometry
For this
• Individuals with AML who also have a family history of AML
• Individuals who have developed AML at an early age (<50 years)
• Typically, individuals with AML presenting before age 50 years with pathogenic variants in both copies of
• In the majority of individuals, a normal karyotype detected in leukemic cells
• A preponderance of French-American-British Cooperative Group AML Classification subtypes M1 or M2 as established by morphologic analysis of peripheral blood or bone marrow blasts
• Auer rods seen in blasts (i.e., abnormal, needle-shaped, or round, light blue- or pink-staining inclusions found in the cytoplasm of leukemic cells)
• Aberrant CD7 expression on blasts as demonstrated by flow cytometry
## Establishing the Diagnosis
The diagnosis of
Note: In the literature, the terms
Molecular testing approaches include
Note: (1) Testing for a germline pathogenic variant should not be performed on blood or bone marrow during active AML. Testing an uninvolved specimen, such as cells obtained by buccal swab/saliva, skin biopsy, or cultured dendritic cells, is imperative. (2) It should be noted that
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequencing of the coding region does not detect putative partial or complete gene deletions or variants in promoter regions. To date, however, no such germline
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Note: (1) Testing for a germline pathogenic variant should not be performed on blood or bone marrow during active AML. Testing an uninvolved specimen, such as cells obtained by buccal swab/saliva, skin biopsy, or cultured dendritic cells, is imperative. (2) It should be noted that
• For an introduction to multigene panels click
## Clinical Characteristics
To date, fourteen families with
The age of onset of
Individuals commonly present with AML (of French-American-British subtypes M1, M2 or M4) following the acquisition of a somatic
From an analysis of ten pedigrees with
Individuals with
To date, the majority of germline
Analysis of pedigrees reported to date suggests that germline
International recognition of inherited hematologic malignancies has grown significantly following the WHO classification in 2016, which incorporated myeloid neoplasms associated with germline
## Clinical Description
To date, fourteen families with
The age of onset of
Individuals commonly present with AML (of French-American-British subtypes M1, M2 or M4) following the acquisition of a somatic
From an analysis of ten pedigrees with
Individuals with
## Genotype-Phenotype Correlations
To date, the majority of germline
## Penetrance
Analysis of pedigrees reported to date suggests that germline
## Nomenclature
International recognition of inherited hematologic malignancies has grown significantly following the WHO classification in 2016, which incorporated myeloid neoplasms associated with germline
## Prevalence
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Note: Sporadic
## Differential Diagnosis
The differential diagnosis for
Hereditary disorders associated with an increased risk of myeloid malignancy (e.g.,
Sporadic AML with somatic
AML secondary to environmental exposures (e.g., benzene, radiation, chemotherapy)
Note: AML is a relatively rare disorder (~13,300 cases/year in the US); therefore, the more affected individuals in a family (and the closer the relationships), the greater the likelihood of a common cause (i.e., a heritable predisposition or a common exposure) [
• Hereditary disorders associated with an increased risk of myeloid malignancy (e.g.,
• Sporadic AML with somatic
• AML secondary to environmental exposures (e.g., benzene, radiation, chemotherapy)
## Management
To establish the extent of disease and needs of an individual newly diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Buccal, salivary, or skin DNA
Peripheral blood DNA in persons w/no history of preceding hematologic disease & normal CBC
Provide info re oocyte & sperm cryopreservation to persons of childbearing potential
Women: negative pregnancy test prior to commencing therapy
By genetics professionals
Obtain a detailed family history & identify relatives who are obligate heterozygotes or potential heterozygotes for a
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
AYA = adolescent and young adult; AML = acute myeloid leukemia; CBC = complete blood count; CNS = central nervous system; HLA = human leukocyte antigen; HSCT = hematopoietic stem cell transplantation; LP = lumbar puncture; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Management of
Treatment usually includes cytarabine/anthracycline-based induction and cytarabine-based consolidation chemotherapy with or without hematopoietic stem cell transplantation (HSCT) according to clinical, cytogenetic, and molecular risk. Specific treatment strategies are based on characteristics of the individual, response to chemotherapy, treatment setting, and protocol (if the individual is enrolled in a clinical trial). Note: Whenever possible, persons with AML should be treated as part of a clinical trial protocol.
Germline variants should be investigated and excluded in donors prior to consideration of HSCT using sib/related donors.
Supportive care includes blood products such as red blood cell and platelet transfusions as needed and treatment of infections with antibiotics.
Prophylactic antibiotics and antifungal agents are administered during periods of severe neutropenia including the consolidation and post-transplantation periods (
Relapses are treated with cytarabine-based salvage chemotherapy followed by allogeneic HSCT (if a suitable donor is available and if cure is the intent of treatment).
Individuals are monitored and evaluated in accordance with administered treatment, clinical course, symptoms, and protocol, if enrolled in clinical trials. When complete remission is achieved and intensification therapy is complete, individuals are monitored with:
CBC and platelet counts every one to three months for two years with the frequency decreasing to every three to six months for up to five years;
Bone marrow aspiration when cytopenia and/or an abnormal peripheral blood smear are present.
Note: The use of flow cytometry for MRD monitoring is controversial.
Individuals with a germline
CBC every six to 12 months
Bone marrow examination for those with CBC abnormalities
Use of sib or related donors for HSCT without prior assessment of the germline
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from clinical monitoring. Clinical monitoring may enable earlier diagnosis (and treatment) of AML, hence minimizing the risks associated with delayed presentation (e.g., severe anemia, neutropenic sepsis, and severe hemorrhage).
Note:
There are currently no preemptive treatments available for asymptomatic individuals who have a germline
To date, all individuals with germline
See
Search
• Buccal, salivary, or skin DNA
• Peripheral blood DNA in persons w/no history of preceding hematologic disease & normal CBC
• Provide info re oocyte & sperm cryopreservation to persons of childbearing potential
• Women: negative pregnancy test prior to commencing therapy
• By genetics professionals
• Obtain a detailed family history & identify relatives who are obligate heterozygotes or potential heterozygotes for a
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
• CBC and platelet counts every one to three months for two years with the frequency decreasing to every three to six months for up to five years;
• Bone marrow aspiration when cytopenia and/or an abnormal peripheral blood smear are present.
• CBC every six to 12 months
• Bone marrow examination for those with CBC abnormalities
• There are currently no preemptive treatments available for asymptomatic individuals who have a germline
• To date, all individuals with germline
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual newly diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Buccal, salivary, or skin DNA
Peripheral blood DNA in persons w/no history of preceding hematologic disease & normal CBC
Provide info re oocyte & sperm cryopreservation to persons of childbearing potential
Women: negative pregnancy test prior to commencing therapy
By genetics professionals
Obtain a detailed family history & identify relatives who are obligate heterozygotes or potential heterozygotes for a
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
AYA = adolescent and young adult; AML = acute myeloid leukemia; CBC = complete blood count; CNS = central nervous system; HLA = human leukocyte antigen; HSCT = hematopoietic stem cell transplantation; LP = lumbar puncture; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Buccal, salivary, or skin DNA
• Peripheral blood DNA in persons w/no history of preceding hematologic disease & normal CBC
• Provide info re oocyte & sperm cryopreservation to persons of childbearing potential
• Women: negative pregnancy test prior to commencing therapy
• By genetics professionals
• Obtain a detailed family history & identify relatives who are obligate heterozygotes or potential heterozygotes for a
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
## Treatment of Manifestations
Management of
Treatment usually includes cytarabine/anthracycline-based induction and cytarabine-based consolidation chemotherapy with or without hematopoietic stem cell transplantation (HSCT) according to clinical, cytogenetic, and molecular risk. Specific treatment strategies are based on characteristics of the individual, response to chemotherapy, treatment setting, and protocol (if the individual is enrolled in a clinical trial). Note: Whenever possible, persons with AML should be treated as part of a clinical trial protocol.
Germline variants should be investigated and excluded in donors prior to consideration of HSCT using sib/related donors.
Supportive care includes blood products such as red blood cell and platelet transfusions as needed and treatment of infections with antibiotics.
Prophylactic antibiotics and antifungal agents are administered during periods of severe neutropenia including the consolidation and post-transplantation periods (
Relapses are treated with cytarabine-based salvage chemotherapy followed by allogeneic HSCT (if a suitable donor is available and if cure is the intent of treatment).
## Surveillance
Individuals are monitored and evaluated in accordance with administered treatment, clinical course, symptoms, and protocol, if enrolled in clinical trials. When complete remission is achieved and intensification therapy is complete, individuals are monitored with:
CBC and platelet counts every one to three months for two years with the frequency decreasing to every three to six months for up to five years;
Bone marrow aspiration when cytopenia and/or an abnormal peripheral blood smear are present.
Note: The use of flow cytometry for MRD monitoring is controversial.
Individuals with a germline
CBC every six to 12 months
Bone marrow examination for those with CBC abnormalities
• CBC and platelet counts every one to three months for two years with the frequency decreasing to every three to six months for up to five years;
• Bone marrow aspiration when cytopenia and/or an abnormal peripheral blood smear are present.
• CBC every six to 12 months
• Bone marrow examination for those with CBC abnormalities
## Agents/Circumstances to Avoid
Use of sib or related donors for HSCT without prior assessment of the germline
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from clinical monitoring. Clinical monitoring may enable earlier diagnosis (and treatment) of AML, hence minimizing the risks associated with delayed presentation (e.g., severe anemia, neutropenic sepsis, and severe hemorrhage).
Note:
There are currently no preemptive treatments available for asymptomatic individuals who have a germline
To date, all individuals with germline
See
• There are currently no preemptive treatments available for asymptomatic individuals who have a germline
• To date, all individuals with germline
## Therapies Under Investigation
Search
## Genetic Counseling
Predisposition to
Most individuals diagnosed with
In rare cases, a proband may have a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
The family history of some individuals diagnosed with
If a parent of the proband has the
The likelihood that a sib who inherits a familial
If the germline
If the parents have not been tested for the
See Management,
The optimal time for determination of genetic risk in offspring of persons with known
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have a molecular diagnosis of
Once a germline
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While use of prenatal testing is a personal decision, discussion of these issues may be helpful.
• Most individuals diagnosed with
• In rare cases, a proband may have a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The family history of some individuals diagnosed with
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• If a parent of the proband has the
• The likelihood that a sib who inherits a familial
• If the germline
• If the parents have not been tested for the
• The optimal time for determination of genetic risk in offspring of persons with known
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have a molecular diagnosis of
## Mode of Inheritance
Predisposition to
## Risk to Family Members
Most individuals diagnosed with
In rare cases, a proband may have a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
The family history of some individuals diagnosed with
If a parent of the proband has the
The likelihood that a sib who inherits a familial
If the germline
If the parents have not been tested for the
• Most individuals diagnosed with
• In rare cases, a proband may have a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The family history of some individuals diagnosed with
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• If a parent of the proband has the
• The likelihood that a sib who inherits a familial
• If the germline
• If the parents have not been tested for the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk in offspring of persons with known
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have a molecular diagnosis of
• The optimal time for determination of genetic risk in offspring of persons with known
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have a molecular diagnosis of
## Prenatal Testing and Preimplantation Genetic Testing
Once a germline
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While use of prenatal testing is a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
CEBPA-Associated Familial Acute Myeloid Leukemia (AML): Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CEBPA-Associated Familial Acute Myeloid Leukemia (AML) (
Initiation of translation at two in-frame AUG start codons (nucleotides 151-153 and 508-510) results in two C/EBPα protein isoforms with different lengths (see
All reported germline pathogenic variants are small deletions, duplications, or insertions before codon 120. These result in a frameshift causing premature truncation at the N-terminal region of the full-length C/EBPα protein, with preservation of the 30-kd isoform. The 30-kd isoform is believed to inhibit the action of the 42-kd isoform in a dominant-negative manner.
Notable Familial Acute Myeloid Leukemia-Associated
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Initiation of translation at two in-frame AUG start codons (nucleotides 151-153 and 508-510) results in two C/EBPα protein isoforms with different lengths (see
All reported germline pathogenic variants are small deletions, duplications, or insertions before codon 120. These result in a frameshift causing premature truncation at the N-terminal region of the full-length C/EBPα protein, with preservation of the 30-kd isoform. The 30-kd isoform is believed to inhibit the action of the 42-kd isoform in a dominant-negative manner.
Notable Familial Acute Myeloid Leukemia-Associated
Variants listed in the table have been provided by the authors.
## Cancer and Benign Tumors
## Chapter Notes
Jude Fitzgibbon, PhD (2016-present)Roger D Klein, MD, JD; Cleveland Clinic (2010-2016)Guido Marcucci, MD; Ohio State University (2010-2016)Kiran Tawana, MBChB, FRCPath, PhD (2016-present)
18 February 2021 (sw) Comprehensive update posted live
28 April 2016 (sw) Comprehensive update posted live
21 October 2010 (me) Review posted live
30 December 2009 (rdk) Original submission
• 18 February 2021 (sw) Comprehensive update posted live
• 28 April 2016 (sw) Comprehensive update posted live
• 21 October 2010 (me) Review posted live
• 30 December 2009 (rdk) Original submission
## Author History
Jude Fitzgibbon, PhD (2016-present)Roger D Klein, MD, JD; Cleveland Clinic (2010-2016)Guido Marcucci, MD; Ohio State University (2010-2016)Kiran Tawana, MBChB, FRCPath, PhD (2016-present)
## Revision History
18 February 2021 (sw) Comprehensive update posted live
28 April 2016 (sw) Comprehensive update posted live
21 October 2010 (me) Review posted live
30 December 2009 (rdk) Original submission
• 18 February 2021 (sw) Comprehensive update posted live
• 28 April 2016 (sw) Comprehensive update posted live
• 21 October 2010 (me) Review posted live
• 30 December 2009 (rdk) Original submission
## References
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"O Bereshchenko, E Mancini, S Moore, D Bilbao, R Månsson, S Luc, A Grover, SE Jacobsen, D Bryder, C Nerlov. Hematopoietic stem cell expansion precedes the generation of committed myeloid leukemia-initiating cells in C/EBPalpha mutant AML.. Cancer Cell. 2009;16:390-400",
"M Debeljak, L Kitanovski, T Pajič, J Jazbec. Concordant acute myeloblastic leukemia in monozygotic twins with germline and shared somatic mutations in the gene for CCAAT-enhancer-binding protein α with 13 years difference at onset.. Haematologica. 2013;98:e73-4",
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"A Dufour, F Schneider, KH Metzeler, E Hoster, S Schneider, E Zellmeier, T Benthaus, MC Sauerland, WE Berdel, T Büchner, B Wörmann, J Braess, W Hiddemann, SK Bohlander, K Spiekermann. Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome.. J Clin Oncol. 2010;28:570-7",
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"CL Green, KK Koo, RK Hills, AK Burnett, DC Linch, RE Gale. Prognostic Significance of CEBPA Mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations.. J Clin Oncol. 2010;28:2739-47",
"IH Hollink, MM van den Heuvel-Eibrink, ST Arentsen-Peters, M Zimmermann, JK Peeters, PJ Valk, BV Balgobind, E Sonneveld, GJ Kaspers, ES de Bont, J Trka, A Baruchel, U Creutzig, R Pieters, D Reinhardt, CM Zwaan. Characterization of CEBPA mutations and promoter hypermethylation in pediatric acute myeloid leukemia.. Haematologica. 2011;96:384-92",
"P Kirstetter, MB Schuster, O Bereshchenko, S Moore, H Dvinge, E Kurz, K Theilgaard-Mönch, R Månsson, TA Pedersen, T Pabst, E Schrock, BT Porse, SE Jacobsen, P Bertone, DG Tenen, C Nerlov. Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells.. Cancer Cell. 2008;13:299-310",
"S Koschmieder, H Balazs, E Levantini, DG Tenen. Dysregulation of the C/EBPα differentiation pathway in human cancer.. J Clin Oncol. 2009;27:619-28",
"AR Lourenço, PJ Coffer. A tumor suppressor role for C/EBPα in solid tumors: more than fat and blood.. Oncogene. 2017;36:5221-30",
"H Mendoza, PH Chen, AB Pine, AJ Siddon, AE Bale, L Gowda, A Killie, J Richards, C Varin-Tremblay, R Kloss, NA Podoltsev. A case of acute myeloid leukemia with unusual germline.. Leuk Lymphoma. 2021;62:1251-4",
"T Nanri, N Uike, T Kawakita, E Iwanaga, K Hoshino, H Mitsuya, N Asou. A family harboring a germ-line N-terminal C/EBPα mutation and development of acute myeloblastic leukemia with an additional somatic C-terminal C/EBPα mutation.. Genes Chromosomes Cancer 2010;49:237-41",
"EM Nickels, J Soodalter, JE Churpek, LA Godley. Recognizing familial myeloid leukemia in adults.. Ther Adv Hematol. 2013;4:254-69",
"C Owen, M Barnett, J Fitzgibbon. Familial myelodysplasia and acute myeloid leukemia--a review.. Br J Haematol. 2008;140:123-32",
"T Pabst, M Eyholzer, J Fos, BU Mueller. Heterogeneity within AML with CEBPA mutations; only CEBPA double mutations, but not single CEBPA mutations are associated with favourable prognosis.. Br J Cancer 2009;100:1343-46",
"T Pabst, M Eyholzer, S Haefliger, J Schardt, BU Mueller. Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia.. J Clin Oncol 2008;26:5088-93",
"T Pabst, BU Mueller. Transcriptional dysreguln during myeloid transformation in AML.. Oncogene 2007;26:6829-37",
"T Pabst, BU Mueller. Complexity of CEBPA dysregulation in human acute myeloid leukemia.. Clin Cancer Res 2009;15:5303-7",
"A Pathak, K Seipel, A Pemov, R Dewan, C Brown, S Ravichandran, BT Luke, M Malasky, S Suman, M Yeager, RA Gatti, NE Caporaso, JJ Mulvihill, LR Goldin, T Pabst, ML McMaster, DR Stewart. Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family.. Haematologica. 2016;101:846-52",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"A Renneville, V Mialou, N Philippe, S Kagialis-Girard, V Biggio, MT Zabot, X Thomas, Y Bertrand, C Preudhomme. Another pedigree with familial acute myeloid leukemia and germline CEBPA mutation.. Leukemia. 2009;23:804-6",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"GS Sellick, HE Spendlove, D Catovsky, K Pritchard-Jones, RS Houlston. Further evidence that germline CEBPA mutations cause dominant inheritance of acute myeloid leukemia.. Leukemia 2005;19:1276-8",
"LY Shih, DC Liang, CF Huang, JH Wu, TL Lin, PN Wang, P Dunn, MC Kuo, TC Tang. AML patients with CEBPalpha mutations mostly retain identical mutant patterns but frequently change in allelic distribution at relapse: a comparative analysis on paired diagnosis and relapse samples.. Leukemia. 2006;20:604-9",
"ML Smith, JD Cavenagh, TA Lister, J Fitzgibbon. Mutation of CEBPA in familial acute myeloid leukemia.. N Engl J Med 2004;351:2403-7",
"M Stelljes, A Corbacioglu, RF Schlenk, K Döhner, MC Frühwald, C Rossig, K Ehlert, G Silling, C Müller-Tidow, H Juergens, H Döhner, WE Berdel, J Kienast, S Koschmieder. Allogeneic stem cell transplant to eliminate germline mutations in the gene for CCAAT-enhancer-binding protein α from hematopoietic cells in a family with AML.. Leukemia. 2011;25:1209-10",
"E Taskesen, L Bullinger, A Corbacioglu, MA Sanders, CA Erpelinck, BJ Wouters, SC van der Poel-van de Luytgaarde, F Damm, J Krauter, A Ganser, RF Schlenk, B Löwenberg, R Delwel, H Döhner, PJ Valk, K Döhner. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity.. Blood. 2011;117:2469-75",
"K Tawana, A Rio-Machin, C Preudhomme, J. Fitzgibbon. Familial CEBPA-mutated acute myeloid leukemia.. Semin Hematol. 2017;54:87-93",
"K Tawana, J Wang, A Renneville, C Bödör, R Hills, C Loveday, A Savic, FW Van Delft, J Treleaven, P Georgiades, E Uglow, N Asou, N Uike, M Debeljak, J Jazbec, P Ancliff, R Gale, X Thomas, V Mialou, K Döhner, L Bullinger, B Mueller, T Pabst, M Stelljes, B Schlegelberger, E Wozniak, S Iqbal, J Okosun, S Araf, AK Frank, FB Lauridsen, B Porse, C Nerlov, C Owen, I Dokal, J Gribben, M Smith, C Preudhomme, C Chelala, J Cavenagh, J Fitzgibbon. Disease evolution and outcomes in familial AML with germline CEBPA mutations.. Blood. 2015;126:1214-23",
"J Tiesmeier, A Czwalinna, C Müller-Tidow, J Krauter, H Serve, G Heil, A Ganser, W Verbeek. Evidence for allelic evolution of C/EBPalpha mutations in acute myeloid leukaemia.. Br J Haematol. 2003;123:413-9",
"H Xiao, J Shi, Y Luo, Y Tan, J He, W Xie, L Zhang, Y Wang, L Liu, K Wu, X Yu, Z Cai, M Lin, X Ye, H. Huang. First report of multiple CEBPA mutations contributing to donor origin of leukemia relapse after allogeneic hematopoietic stem cell transplantation.. Blood. 2011;117:5257-60",
"B Yan, C Ng, G Moshi, K Ban, PL Lee, E Seah, L Chiu, ES Koay, TC Liu, CH Ng, WJ Chng, LP Koh. Myelodysplastic features in a patient with germline CEBPA-mutant acute myeloid leukaemia.. J Clin Pathol. 2016;69:652-4",
"M Ye, H Zhang, G Amabile, H Yang, PB Staber, P Zhang, E Levantini, M Alberich-Jordà, J Zhang, A Kawasaki, DG Tenen. C/EBPa controls acquisition and maintenance of adult haematopoietic stem cell quiescence.. Nat Cell Biol. 2013;15:385-94"
] |
21/10/2010
|
18/2/2021
|
GeneReviews®
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https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
ced
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ced
|
[
"Progressive Diaphyseal Dysplasia, TGFB1-Related Diaphyseal Dysplasia Camurati-Engelmann",
"Progressive Diaphyseal Dysplasia",
"TGFB1-Related Diaphyseal Dysplasia Camurati-Engelmann",
"Ribbing Disease",
"Transforming growth factor beta-1 proprotein",
"TGFB1",
"Camurati-Engelmann Disease"
] |
Camurati-Engelmann Disease
|
Stephanie E Wallace, William R Wilcox
|
Summary Camurati-Engelmann disease (CED) is characterized by hyperostosis of the long bones and the skull, proximal muscle weakness, limb pain, a wide-based, waddling gait, and joint contractures. Facial features such as macrocephaly, frontal bossing, enlargement of the mandible, proptosis, and cranial nerve impingement resulting in facial palsy are seen in severely affected individuals later in life. The diagnosis of CED is established in a proband with the characteristic radiographic findings or (if radiographic findings are inconclusive) a heterozygous pathogenic variant in CED is inherited in an autosomal dominant manner. Many individuals diagnosed with CED have an affected parent; some individuals diagnosed with CED may have the disorder as the result of a
|
The scope of this
## Diagnosis
No consensus clinical diagnostic criteria for Camurati-Engelmann disease have been published.
Camurati-Engelmann disease (CED)
Proximal muscle weakness
Easy fatigability
Bone pain primarily affecting the lower extremities
Waddling gait
The clinical diagnosis of CED can be
The clinical diagnosis is based on the following radiographic findings:
Periosteal involvement results in uneven cortical thickening and increased bone diameter.
Endosteal bony sclerosis can lead to a narrowed medullary canal.
Hyperostosis is usually symmetric in the appendicular skeleton but in some instances is asymmetric.
The molecular diagnosis can be established in a proband with
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Note: CED is postulated to occur through a gain-of-function mechanism. Large intragenic deletions or duplications have not been reported in individuals with CED; testing for intragenic deletions or duplication is not indicated.
For an introduction to multigene panels click
When the diagnosis of CED has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Camurati-Engelmann Disease
NA = not applicable
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
The majority are missense variants in exon 4 leading to single amino acid substitutions in the encoded protein [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Large intragenic deletions or duplications have not been reported in individuals with CED.
The affected members of one family with clinical and radiographic features of CED did not share marker haplotypes at the
• Proximal muscle weakness
• Easy fatigability
• Bone pain primarily affecting the lower extremities
• Waddling gait
• Periosteal involvement results in uneven cortical thickening and increased bone diameter.
• Endosteal bony sclerosis can lead to a narrowed medullary canal.
• Hyperostosis is usually symmetric in the appendicular skeleton but in some instances is asymmetric.
• Periosteal involvement results in uneven cortical thickening and increased bone diameter.
• Endosteal bony sclerosis can lead to a narrowed medullary canal.
• Hyperostosis is usually symmetric in the appendicular skeleton but in some instances is asymmetric.
• Periosteal involvement results in uneven cortical thickening and increased bone diameter.
• Endosteal bony sclerosis can lead to a narrowed medullary canal.
• Hyperostosis is usually symmetric in the appendicular skeleton but in some instances is asymmetric.
## Suggestive Findings
Camurati-Engelmann disease (CED)
Proximal muscle weakness
Easy fatigability
Bone pain primarily affecting the lower extremities
Waddling gait
• Proximal muscle weakness
• Easy fatigability
• Bone pain primarily affecting the lower extremities
• Waddling gait
## Establishing the Diagnosis
The clinical diagnosis of CED can be
The clinical diagnosis is based on the following radiographic findings:
Periosteal involvement results in uneven cortical thickening and increased bone diameter.
Endosteal bony sclerosis can lead to a narrowed medullary canal.
Hyperostosis is usually symmetric in the appendicular skeleton but in some instances is asymmetric.
The molecular diagnosis can be established in a proband with
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Note: CED is postulated to occur through a gain-of-function mechanism. Large intragenic deletions or duplications have not been reported in individuals with CED; testing for intragenic deletions or duplication is not indicated.
For an introduction to multigene panels click
When the diagnosis of CED has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Camurati-Engelmann Disease
NA = not applicable
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
The majority are missense variants in exon 4 leading to single amino acid substitutions in the encoded protein [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Large intragenic deletions or duplications have not been reported in individuals with CED.
The affected members of one family with clinical and radiographic features of CED did not share marker haplotypes at the
• Periosteal involvement results in uneven cortical thickening and increased bone diameter.
• Endosteal bony sclerosis can lead to a narrowed medullary canal.
• Hyperostosis is usually symmetric in the appendicular skeleton but in some instances is asymmetric.
• Periosteal involvement results in uneven cortical thickening and increased bone diameter.
• Endosteal bony sclerosis can lead to a narrowed medullary canal.
• Hyperostosis is usually symmetric in the appendicular skeleton but in some instances is asymmetric.
• Periosteal involvement results in uneven cortical thickening and increased bone diameter.
• Endosteal bony sclerosis can lead to a narrowed medullary canal.
• Hyperostosis is usually symmetric in the appendicular skeleton but in some instances is asymmetric.
## Clinical Diagnosis
The clinical diagnosis is based on the following radiographic findings:
Periosteal involvement results in uneven cortical thickening and increased bone diameter.
Endosteal bony sclerosis can lead to a narrowed medullary canal.
Hyperostosis is usually symmetric in the appendicular skeleton but in some instances is asymmetric.
• Periosteal involvement results in uneven cortical thickening and increased bone diameter.
• Endosteal bony sclerosis can lead to a narrowed medullary canal.
• Hyperostosis is usually symmetric in the appendicular skeleton but in some instances is asymmetric.
• Periosteal involvement results in uneven cortical thickening and increased bone diameter.
• Endosteal bony sclerosis can lead to a narrowed medullary canal.
• Hyperostosis is usually symmetric in the appendicular skeleton but in some instances is asymmetric.
• Periosteal involvement results in uneven cortical thickening and increased bone diameter.
• Endosteal bony sclerosis can lead to a narrowed medullary canal.
• Hyperostosis is usually symmetric in the appendicular skeleton but in some instances is asymmetric.
## Molecular Diagnosis
The molecular diagnosis can be established in a proband with
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Note: CED is postulated to occur through a gain-of-function mechanism. Large intragenic deletions or duplications have not been reported in individuals with CED; testing for intragenic deletions or duplication is not indicated.
For an introduction to multigene panels click
When the diagnosis of CED has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Camurati-Engelmann Disease
NA = not applicable
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
The majority are missense variants in exon 4 leading to single amino acid substitutions in the encoded protein [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Large intragenic deletions or duplications have not been reported in individuals with CED.
The affected members of one family with clinical and radiographic features of CED did not share marker haplotypes at the
## Clinical Characteristics
Individuals with Camurati-Engelmann disease (CED) present with proximal muscle weakness, poor muscular development, a wide-based, waddling gait, easy fatigability, bone pain, and headaches. The average age of onset of symptoms in the 306 reported individuals is 13.4 years [
Camurati-Engelmann Disease: Frequency of Select Features
Bone pain is reported in the majority of affected individuals [
Although bone mineral density measured at the hip and femoral neck are increased in individuals with CED, bone strength measured by bone impact microindentation in three sibs with CED was below normal. Because of the small sample size, the difference in bone strength was not statistically significant [
Approximately 19%-54% of individuals with CED have conductive and/or sensorineural hearing loss [
Vestibulopathy including tinnitus and vertigo have also been reported in several individuals [
Involvement of the orbit has led to blurred vision, proptosis, papilledema, epiphora, glaucoma, subluxation of the globe, and retinal detachment [
Facial paralysis has been successfully treated by surgical decompression of the facial nerve in one affected individual [
Calvarial hyperostosis can lead to increased intracranial pressure, chronic headaches that can be severe, and frontal bossing. Chronic intracranial hypertension led to a bone defect and meningoencephalocele in one individual at age 57 years [
Rarely, clonus [
Corticosteroids may delay bone hyperostosis and prevent or delay the onset of skull involvement. Although histologic studies following steroid therapy showed increased bone resorption and secondary remodeling with increased osteoblast activity and decreased lamellar bone deposition, several authors reported no regression of sclerosis on radiographic evaluation [
Less common manifestations in individuals with CED include anemia (hypothesized to be caused by a narrowed medullary cavity), hepatosplenomegaly, atrophic skin, hyperhidrosis of the hands and feet, delayed dental eruption, and extensive dental caries.
The authors are aware of one teenager with CED who died following dissection of a dilated ascending aorta [Authors, personal communication]. To date, it is unknown if dilatation of the aorta is a rare manifestation of CED. The authors are unaware of any additional individuals with aortic disease. Because the mechanism of CED involves increased TGFB1 signaling, also found in
No known correlation exists between the nature of the
Some obligate heterozygotes with an identified
Engelmann described the second reported occurrence of CED in 1929 as "osteopathic hyperostotica (sclerotisans) multiplex infantilis."
The terms "Engelmann disease" and "diaphyseal dysplasia" were commonly used until
CED is referred to as "
The prevalence is unknown. More than 300 affected individuals have been reported.
## Clinical Description
Individuals with Camurati-Engelmann disease (CED) present with proximal muscle weakness, poor muscular development, a wide-based, waddling gait, easy fatigability, bone pain, and headaches. The average age of onset of symptoms in the 306 reported individuals is 13.4 years [
Camurati-Engelmann Disease: Frequency of Select Features
Bone pain is reported in the majority of affected individuals [
Although bone mineral density measured at the hip and femoral neck are increased in individuals with CED, bone strength measured by bone impact microindentation in three sibs with CED was below normal. Because of the small sample size, the difference in bone strength was not statistically significant [
Approximately 19%-54% of individuals with CED have conductive and/or sensorineural hearing loss [
Vestibulopathy including tinnitus and vertigo have also been reported in several individuals [
Involvement of the orbit has led to blurred vision, proptosis, papilledema, epiphora, glaucoma, subluxation of the globe, and retinal detachment [
Facial paralysis has been successfully treated by surgical decompression of the facial nerve in one affected individual [
Calvarial hyperostosis can lead to increased intracranial pressure, chronic headaches that can be severe, and frontal bossing. Chronic intracranial hypertension led to a bone defect and meningoencephalocele in one individual at age 57 years [
Rarely, clonus [
Corticosteroids may delay bone hyperostosis and prevent or delay the onset of skull involvement. Although histologic studies following steroid therapy showed increased bone resorption and secondary remodeling with increased osteoblast activity and decreased lamellar bone deposition, several authors reported no regression of sclerosis on radiographic evaluation [
Less common manifestations in individuals with CED include anemia (hypothesized to be caused by a narrowed medullary cavity), hepatosplenomegaly, atrophic skin, hyperhidrosis of the hands and feet, delayed dental eruption, and extensive dental caries.
The authors are aware of one teenager with CED who died following dissection of a dilated ascending aorta [Authors, personal communication]. To date, it is unknown if dilatation of the aorta is a rare manifestation of CED. The authors are unaware of any additional individuals with aortic disease. Because the mechanism of CED involves increased TGFB1 signaling, also found in
## Genotype-Phenotype Correlations
No known correlation exists between the nature of the
## Penetrance
Some obligate heterozygotes with an identified
## Nomenclature
Engelmann described the second reported occurrence of CED in 1929 as "osteopathic hyperostotica (sclerotisans) multiplex infantilis."
The terms "Engelmann disease" and "diaphyseal dysplasia" were commonly used until
CED is referred to as "
## Prevalence
The prevalence is unknown. More than 300 affected individuals have been reported.
## Genetically Related (Allelic) Disorders
Biallelic loss-of-function variants in
## Differential Diagnosis
Few disorders share the clinical and radiographic findings of Camurati-Engelmann disease (CED). The correct diagnosis is made by physical examination and skeletal survey.
Genes of Interest in the Differential Diagnosis of Camurati-Engelmann Disease
AD = autosomal dominant; AR = autosomal recessive; CED = Camurati-Engelmann disease; MOI = mode of inheritance
## Management
No clinical practice guidelines for Camurati-Engelmann disease (CED) have been published.
To establish the extent of disease and needs in an individual diagnosed with CED, the evaluations summarized in
Camurati-Engelmann Disease: Recommended Evaluations Following Initial Diagnosis
Gross motor skills
Mobility, ADL, & need for adaptive devices
Need for PT
Serum ESR
Bone scan (scintigraphy) exam
ADL = activities of daily living; BAER = brain stem auditory evoked response; CBC = complete blood count; CED = Camurati-Engelmann disease; ESR = erythrocyte sedimentation rate; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for CED.
Individuals with severe symptoms can be treated with a bolus of prednisolone 1.0-2.0 mg/kg/day followed by rapid tapering to the lowest alternate-day dose tolerated. Less symptomatic individuals can be started on 0.5-1.0 mg/kg every other day. Some individuals may be able to discontinue steroid therapy during quiescent periods. Higher-dose steroids may help with acute pain crises.
After initiating corticosteroids, affected individuals should be followed monthly, with efforts to taper the steroids to the lowest tolerated dose to reduce the risk of osteoporosis and compression fractures of the spine. Blood pressure should be monitored at each visit, as hypertension can develop following the initiation of corticosteroid therapy.
Combination corticosteroid therapy and losartan led to decreased bone pain and initiation of pubertal development in a female age 18 years [
Long-term follow-up studies are needed to further evaluate the benefits and risk of corticosteroid therapy, losartan, and combination therapy.
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Camurati-Engelmann Disease: Treatment of Manifestations
Corticosteroids
Losartan
Analgesic medications
Non-pharmacologic pain control methods
Surgical treatment (intramedullary reaming)
See
Successful surgical treatment of persistent bone pain has been described.
Pain relief from intranasal calcitonin was reported in 1 person.
Infliximab treatment alleviated pain in 1 person who did not respond to corticosteroids.
Mgmt per otolaryngologist
Eval should incl BAER & CT w/fine cuts through inner ear.
Bilateral myringotomy can improve conductive hearing loss resulting from serous otitis in persons w/CED.
Cochlear implantation improved hearing in 1 person w/conductive hearing loss & patent internal auditory canals.
See also
Reports of successful treatment of hearing loss are rare. Surgical decompression of internal auditory canals can improve hearing. However, reported results are mixed.
General contraindications for cochlear implants incl narrowed internal auditory canal & absence of functioning 8th cranial nerve, both of which can occur in CED.
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Craniectomy
See
Adjust corticosteroid dose as needed.
Standard treatments for hypertension as needed.
Adjust losartan dose as needed.
Assess mobility, need for adaptive devices, & fall precautions.
BAER = brain stem auditory evoked response; CED = Camurati-Engelmann disease; ICP = intracranial pressure; OT = occupational therapy; PT = physical therapy
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Camurati-Engelmann Disease: Recommended Surveillance
Serum ESR
Bone scan (bone scintigraphy) exam
Annually in those treated w/corticosteroids
CED does not appear to cause ↑ in spine density; therefore, steroid therapy could lead to osteoporosis of spine [Authors, personal observation].
Neurologic exam to assess for cranial nerve deficits & headaches
Monitor for signs & symptoms of ↑ ICP.
BAER = brain stem auditory evoked response; CBC = complete blood count; CED = Camurati-Engelmann disease; ESR = erythrocyte sedimentation rate; ICP = intracranial pressure
It is appropriate to evaluate relatives at risk in order to identify the diagnosis as early as possible, avoid potential misdiagnosis, and provide appropriate treatment for extremity pain. Evaluations can include:
Molecular genetic testing if the pathogenic variant in the family is known;
Radiographic evaluation for hyperostosis if the pathogenic variant in the family is not known.
See
Search
• Gross motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT
• Serum ESR
• Bone scan (scintigraphy) exam
• Corticosteroids
• Losartan
• Analgesic medications
• Non-pharmacologic pain control methods
• Surgical treatment (intramedullary reaming)
• See
• Successful surgical treatment of persistent bone pain has been described.
• Pain relief from intranasal calcitonin was reported in 1 person.
• Infliximab treatment alleviated pain in 1 person who did not respond to corticosteroids.
• Mgmt per otolaryngologist
• Eval should incl BAER & CT w/fine cuts through inner ear.
• Bilateral myringotomy can improve conductive hearing loss resulting from serous otitis in persons w/CED.
• Cochlear implantation improved hearing in 1 person w/conductive hearing loss & patent internal auditory canals.
• See also
• Reports of successful treatment of hearing loss are rare. Surgical decompression of internal auditory canals can improve hearing. However, reported results are mixed.
• General contraindications for cochlear implants incl narrowed internal auditory canal & absence of functioning 8th cranial nerve, both of which can occur in CED.
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Craniectomy
• See
• Adjust corticosteroid dose as needed.
• Standard treatments for hypertension as needed.
• Adjust losartan dose as needed.
• Assess mobility, need for adaptive devices, & fall precautions.
• Serum ESR
• Bone scan (bone scintigraphy) exam
• Annually in those treated w/corticosteroids
• CED does not appear to cause ↑ in spine density; therefore, steroid therapy could lead to osteoporosis of spine [Authors, personal observation].
• Neurologic exam to assess for cranial nerve deficits & headaches
• Monitor for signs & symptoms of ↑ ICP.
• Molecular genetic testing if the pathogenic variant in the family is known;
• Radiographic evaluation for hyperostosis if the pathogenic variant in the family is not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CED, the evaluations summarized in
Camurati-Engelmann Disease: Recommended Evaluations Following Initial Diagnosis
Gross motor skills
Mobility, ADL, & need for adaptive devices
Need for PT
Serum ESR
Bone scan (scintigraphy) exam
ADL = activities of daily living; BAER = brain stem auditory evoked response; CBC = complete blood count; CED = Camurati-Engelmann disease; ESR = erythrocyte sedimentation rate; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Gross motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT
• Serum ESR
• Bone scan (scintigraphy) exam
## Treatment of Manifestations
There is no cure for CED.
Individuals with severe symptoms can be treated with a bolus of prednisolone 1.0-2.0 mg/kg/day followed by rapid tapering to the lowest alternate-day dose tolerated. Less symptomatic individuals can be started on 0.5-1.0 mg/kg every other day. Some individuals may be able to discontinue steroid therapy during quiescent periods. Higher-dose steroids may help with acute pain crises.
After initiating corticosteroids, affected individuals should be followed monthly, with efforts to taper the steroids to the lowest tolerated dose to reduce the risk of osteoporosis and compression fractures of the spine. Blood pressure should be monitored at each visit, as hypertension can develop following the initiation of corticosteroid therapy.
Combination corticosteroid therapy and losartan led to decreased bone pain and initiation of pubertal development in a female age 18 years [
Long-term follow-up studies are needed to further evaluate the benefits and risk of corticosteroid therapy, losartan, and combination therapy.
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Camurati-Engelmann Disease: Treatment of Manifestations
Corticosteroids
Losartan
Analgesic medications
Non-pharmacologic pain control methods
Surgical treatment (intramedullary reaming)
See
Successful surgical treatment of persistent bone pain has been described.
Pain relief from intranasal calcitonin was reported in 1 person.
Infliximab treatment alleviated pain in 1 person who did not respond to corticosteroids.
Mgmt per otolaryngologist
Eval should incl BAER & CT w/fine cuts through inner ear.
Bilateral myringotomy can improve conductive hearing loss resulting from serous otitis in persons w/CED.
Cochlear implantation improved hearing in 1 person w/conductive hearing loss & patent internal auditory canals.
See also
Reports of successful treatment of hearing loss are rare. Surgical decompression of internal auditory canals can improve hearing. However, reported results are mixed.
General contraindications for cochlear implants incl narrowed internal auditory canal & absence of functioning 8th cranial nerve, both of which can occur in CED.
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Craniectomy
See
Adjust corticosteroid dose as needed.
Standard treatments for hypertension as needed.
Adjust losartan dose as needed.
Assess mobility, need for adaptive devices, & fall precautions.
BAER = brain stem auditory evoked response; CED = Camurati-Engelmann disease; ICP = intracranial pressure; OT = occupational therapy; PT = physical therapy
• Corticosteroids
• Losartan
• Analgesic medications
• Non-pharmacologic pain control methods
• Surgical treatment (intramedullary reaming)
• See
• Successful surgical treatment of persistent bone pain has been described.
• Pain relief from intranasal calcitonin was reported in 1 person.
• Infliximab treatment alleviated pain in 1 person who did not respond to corticosteroids.
• Mgmt per otolaryngologist
• Eval should incl BAER & CT w/fine cuts through inner ear.
• Bilateral myringotomy can improve conductive hearing loss resulting from serous otitis in persons w/CED.
• Cochlear implantation improved hearing in 1 person w/conductive hearing loss & patent internal auditory canals.
• See also
• Reports of successful treatment of hearing loss are rare. Surgical decompression of internal auditory canals can improve hearing. However, reported results are mixed.
• General contraindications for cochlear implants incl narrowed internal auditory canal & absence of functioning 8th cranial nerve, both of which can occur in CED.
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Craniectomy
• See
• Adjust corticosteroid dose as needed.
• Standard treatments for hypertension as needed.
• Adjust losartan dose as needed.
• Assess mobility, need for adaptive devices, & fall precautions.
## Targeted Therapy
Individuals with severe symptoms can be treated with a bolus of prednisolone 1.0-2.0 mg/kg/day followed by rapid tapering to the lowest alternate-day dose tolerated. Less symptomatic individuals can be started on 0.5-1.0 mg/kg every other day. Some individuals may be able to discontinue steroid therapy during quiescent periods. Higher-dose steroids may help with acute pain crises.
After initiating corticosteroids, affected individuals should be followed monthly, with efforts to taper the steroids to the lowest tolerated dose to reduce the risk of osteoporosis and compression fractures of the spine. Blood pressure should be monitored at each visit, as hypertension can develop following the initiation of corticosteroid therapy.
Combination corticosteroid therapy and losartan led to decreased bone pain and initiation of pubertal development in a female age 18 years [
Long-term follow-up studies are needed to further evaluate the benefits and risk of corticosteroid therapy, losartan, and combination therapy.
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Camurati-Engelmann Disease: Treatment of Manifestations
Corticosteroids
Losartan
Analgesic medications
Non-pharmacologic pain control methods
Surgical treatment (intramedullary reaming)
See
Successful surgical treatment of persistent bone pain has been described.
Pain relief from intranasal calcitonin was reported in 1 person.
Infliximab treatment alleviated pain in 1 person who did not respond to corticosteroids.
Mgmt per otolaryngologist
Eval should incl BAER & CT w/fine cuts through inner ear.
Bilateral myringotomy can improve conductive hearing loss resulting from serous otitis in persons w/CED.
Cochlear implantation improved hearing in 1 person w/conductive hearing loss & patent internal auditory canals.
See also
Reports of successful treatment of hearing loss are rare. Surgical decompression of internal auditory canals can improve hearing. However, reported results are mixed.
General contraindications for cochlear implants incl narrowed internal auditory canal & absence of functioning 8th cranial nerve, both of which can occur in CED.
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Craniectomy
See
Adjust corticosteroid dose as needed.
Standard treatments for hypertension as needed.
Adjust losartan dose as needed.
Assess mobility, need for adaptive devices, & fall precautions.
BAER = brain stem auditory evoked response; CED = Camurati-Engelmann disease; ICP = intracranial pressure; OT = occupational therapy; PT = physical therapy
• Corticosteroids
• Losartan
• Analgesic medications
• Non-pharmacologic pain control methods
• Surgical treatment (intramedullary reaming)
• See
• Successful surgical treatment of persistent bone pain has been described.
• Pain relief from intranasal calcitonin was reported in 1 person.
• Infliximab treatment alleviated pain in 1 person who did not respond to corticosteroids.
• Mgmt per otolaryngologist
• Eval should incl BAER & CT w/fine cuts through inner ear.
• Bilateral myringotomy can improve conductive hearing loss resulting from serous otitis in persons w/CED.
• Cochlear implantation improved hearing in 1 person w/conductive hearing loss & patent internal auditory canals.
• See also
• Reports of successful treatment of hearing loss are rare. Surgical decompression of internal auditory canals can improve hearing. However, reported results are mixed.
• General contraindications for cochlear implants incl narrowed internal auditory canal & absence of functioning 8th cranial nerve, both of which can occur in CED.
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Craniectomy
• See
• Adjust corticosteroid dose as needed.
• Standard treatments for hypertension as needed.
• Adjust losartan dose as needed.
• Assess mobility, need for adaptive devices, & fall precautions.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Camurati-Engelmann Disease: Recommended Surveillance
Serum ESR
Bone scan (bone scintigraphy) exam
Annually in those treated w/corticosteroids
CED does not appear to cause ↑ in spine density; therefore, steroid therapy could lead to osteoporosis of spine [Authors, personal observation].
Neurologic exam to assess for cranial nerve deficits & headaches
Monitor for signs & symptoms of ↑ ICP.
BAER = brain stem auditory evoked response; CBC = complete blood count; CED = Camurati-Engelmann disease; ESR = erythrocyte sedimentation rate; ICP = intracranial pressure
• Serum ESR
• Bone scan (bone scintigraphy) exam
• Annually in those treated w/corticosteroids
• CED does not appear to cause ↑ in spine density; therefore, steroid therapy could lead to osteoporosis of spine [Authors, personal observation].
• Neurologic exam to assess for cranial nerve deficits & headaches
• Monitor for signs & symptoms of ↑ ICP.
## Agents/Circumstances to Avoid
## Evaluation of Relatives at Risk
It is appropriate to evaluate relatives at risk in order to identify the diagnosis as early as possible, avoid potential misdiagnosis, and provide appropriate treatment for extremity pain. Evaluations can include:
Molecular genetic testing if the pathogenic variant in the family is known;
Radiographic evaluation for hyperostosis if the pathogenic variant in the family is not known.
See
• Molecular genetic testing if the pathogenic variant in the family is known;
• Radiographic evaluation for hyperostosis if the pathogenic variant in the family is not known.
## Therapies Under Investigation
Search
## Genetic Counseling
Camurati-Engelmann disease (CED) is inherited in an autosomal dominant manner.
Many individuals diagnosed with CED have an affected parent.
Some individuals diagnosed with CED may have the disorder as the result of a
If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with CED may appear to be negative because of failure to recognize the disorder in family members, early death of a parent before the onset of symptoms, or reduced penetrance in a parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation (radiographs) of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of reduced penetrance, some individuals who inherit a
CED is associated with significant intrafamilial phenotypic variability; the severity of disease manifestations in affected sibs is impossible to predict [
If the proband has a known
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Many individuals diagnosed with CED have an affected parent.
• Some individuals diagnosed with CED may have the disorder as the result of a
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with CED may appear to be negative because of failure to recognize the disorder in family members, early death of a parent before the onset of symptoms, or reduced penetrance in a parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation (radiographs) of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of reduced penetrance, some individuals who inherit a
• CED is associated with significant intrafamilial phenotypic variability; the severity of disease manifestations in affected sibs is impossible to predict [
• If the proband has a known
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Camurati-Engelmann disease (CED) is inherited in an autosomal dominant manner.
## Risk to Family Members
Many individuals diagnosed with CED have an affected parent.
Some individuals diagnosed with CED may have the disorder as the result of a
If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with CED may appear to be negative because of failure to recognize the disorder in family members, early death of a parent before the onset of symptoms, or reduced penetrance in a parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation (radiographs) of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of reduced penetrance, some individuals who inherit a
CED is associated with significant intrafamilial phenotypic variability; the severity of disease manifestations in affected sibs is impossible to predict [
If the proband has a known
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.
• Many individuals diagnosed with CED have an affected parent.
• Some individuals diagnosed with CED may have the disorder as the result of a
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with CED may appear to be negative because of failure to recognize the disorder in family members, early death of a parent before the onset of symptoms, or reduced penetrance in a parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation (radiographs) of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of reduced penetrance, some individuals who inherit a
• CED is associated with significant intrafamilial phenotypic variability; the severity of disease manifestations in affected sibs is impossible to predict [
• If the proband has a known
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
• United Kingdom
•
•
•
•
•
## Molecular Genetics
Camurati-Engelmann Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Camurati-Engelmann Disease (
The majority of pathogenic variants in individuals with Camurati-Engelmann disease (CED) result in single amino acid substitutions in the carboxy terminus of LAP. The substitutions are near the site of interchain disulfide bonds between the LAP homodimers. These pathogenic variants disrupt dimerization of LAP and binding to active TGFB1 [
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
The majority of pathogenic variants in individuals with Camurati-Engelmann disease (CED) result in single amino acid substitutions in the carboxy terminus of LAP. The substitutions are near the site of interchain disulfide bonds between the LAP homodimers. These pathogenic variants disrupt dimerization of LAP and binding to active TGFB1 [
Variants listed in the table have been provided by the authors.
## Chapter Notes
The authors would like to thank all of the individuals with Camurati-Engelmann disease and their families for contributing to the understanding of this disorder.
31 August 2023 (sw) Comprehensive updated posted live
12 October 2017 (ha) Comprehensive update posted live
5 March 2015 (me) Comprehensive update posted live
6 December 2012 (me) Comprehensive update posted live
1 June 2010 (me) Comprehensive update posted live
16 August 2006 (me) Comprehensive update posted live
25 June 2004 (me) Review posted live
18 March 2004 (sw) Original submission
• 31 August 2023 (sw) Comprehensive updated posted live
• 12 October 2017 (ha) Comprehensive update posted live
• 5 March 2015 (me) Comprehensive update posted live
• 6 December 2012 (me) Comprehensive update posted live
• 1 June 2010 (me) Comprehensive update posted live
• 16 August 2006 (me) Comprehensive update posted live
• 25 June 2004 (me) Review posted live
• 18 March 2004 (sw) Original submission
## Acknowledgments
The authors would like to thank all of the individuals with Camurati-Engelmann disease and their families for contributing to the understanding of this disorder.
## Revision History
31 August 2023 (sw) Comprehensive updated posted live
12 October 2017 (ha) Comprehensive update posted live
5 March 2015 (me) Comprehensive update posted live
6 December 2012 (me) Comprehensive update posted live
1 June 2010 (me) Comprehensive update posted live
16 August 2006 (me) Comprehensive update posted live
25 June 2004 (me) Review posted live
18 March 2004 (sw) Original submission
• 31 August 2023 (sw) Comprehensive updated posted live
• 12 October 2017 (ha) Comprehensive update posted live
• 5 March 2015 (me) Comprehensive update posted live
• 6 December 2012 (me) Comprehensive update posted live
• 1 June 2010 (me) Comprehensive update posted live
• 16 August 2006 (me) Comprehensive update posted live
• 25 June 2004 (me) Review posted live
• 18 March 2004 (sw) Original submission
## Key Sections in this
## References
## Literature Cited
|
[] |
25/6/2004
|
31/8/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
celiac
|
celiac
|
[
"Celiac Sprue",
"Cœliac Disease",
"Gluten-Sensitive Enteropathy",
"Nontropical Sprue",
"Coeliac Disease",
"Celiac Sprue",
"Nontropical Sprue",
"Gluten-Sensitive Enteropathy",
"HLA class II histocompatibility antigen, DQ alpha 1 chain",
"HLA class II histocompatibility antigen, DQ(W1.1) beta chain",
"HLA-DQA1",
"HLA-DQB1",
"Celiac Disease"
] |
Celiac Disease
|
Annette K Taylor, Benjamin Lebwohl, Cara L Snyder, Peter HR Green
|
Summary Celiac disease is a systemic autoimmune disease that can be associated with gastrointestinal findings (diarrhea, malabsorption, abdominal pain and distension, bloating, vomiting, and weight loss) and/or highly variable non-gastrointestinal findings (dermatitis herpetiformis, chronic fatigue, joint pain/inflammation, iron deficiency anemia, migraines, depression, attention-deficit disorder, epilepsy, osteoporosis/osteopenia, infertility and/or recurrent fetal loss, vitamin deficiencies, short stature, failure to thrive, delayed puberty, dental enamel defects, and autoimmune disorders). Classic celiac disease, characterized by mild to severe gastrointestinal symptoms, is less common than non-classic celiac disease, characterized by absence of gastrointestinal symptoms. The diagnosis of celiac disease is established in an individual with: Positive celiac serologic testing while on a gluten-containing diet (tissue transglutaminase IgA, anti-deamidated gliadin-related peptide IgA and IgG, endomysial antibody IgA), Characteristic histologic findings on small-bowel biopsy, and Human leukocyte antigen (HLA) haplotype DQ2 or DQ8 identified by molecular genetic testing of Celiac disease is a multifactorial disorder resulting from the interaction of
|
## Diagnosis
Celiac disease
Gastrointestinal signs/symptoms (e.g., diarrhea, malabsorption, abdominal pain, distention, bloating, vomiting, weight loss)
Dermatitis herpetiformis
Chronic fatigue
Joint pain/inflammation
Neurologic symptoms (e.g., peripheral neuropathy, ataxia, seizures, migraines, attention-deficit disorder, poor school performance)
Osteoporosis/osteopenia
Infertility and/or recurrent fetal loss
Short stature and/or failure to thrive
Delayed puberty
Dental enamel defects
Autoimmune disorders
Individuals with disorders associated with celiac disease (e.g., Down syndrome, Turner syndrome, Williams syndrome, selective IgA deficiency, insulin-dependent diabetes mellitus, Sjögren syndrome, thyroiditis)
Absence of history of self-limited enteritis and/or tropical sprue
Iron deficiency anemia
Vitamin and/or mineral deficiencies (e.g., calcium, vitamin D, vitamin B
In individuals on a gluten-containing diet:
Elevated serum
Elevated serum
Elevated serum
The diagnosis of celiac disease
HLA Haplotypes Associated with an Increased Risk for Celiac Disease
Haplotype-defining variants of
DQ2-positive haplotype is also present in 20%-30% of the general population; the DQ8-positive haplotype is also present in 10% of the general population [
• Gastrointestinal signs/symptoms (e.g., diarrhea, malabsorption, abdominal pain, distention, bloating, vomiting, weight loss)
• Dermatitis herpetiformis
• Chronic fatigue
• Joint pain/inflammation
• Neurologic symptoms (e.g., peripheral neuropathy, ataxia, seizures, migraines, attention-deficit disorder, poor school performance)
• Osteoporosis/osteopenia
• Infertility and/or recurrent fetal loss
• Short stature and/or failure to thrive
• Delayed puberty
• Dental enamel defects
• Autoimmune disorders
• Individuals with disorders associated with celiac disease (e.g., Down syndrome, Turner syndrome, Williams syndrome, selective IgA deficiency, insulin-dependent diabetes mellitus, Sjögren syndrome, thyroiditis)
• Absence of history of self-limited enteritis and/or tropical sprue
• Iron deficiency anemia
• Vitamin and/or mineral deficiencies (e.g., calcium, vitamin D, vitamin B
• In individuals on a gluten-containing diet:
• Elevated serum
• Elevated serum
• Elevated serum
• Elevated serum
• Elevated serum
• Elevated serum
• Elevated serum
• Elevated serum
• Elevated serum
•
## Suggestive Findings
Celiac disease
Gastrointestinal signs/symptoms (e.g., diarrhea, malabsorption, abdominal pain, distention, bloating, vomiting, weight loss)
Dermatitis herpetiformis
Chronic fatigue
Joint pain/inflammation
Neurologic symptoms (e.g., peripheral neuropathy, ataxia, seizures, migraines, attention-deficit disorder, poor school performance)
Osteoporosis/osteopenia
Infertility and/or recurrent fetal loss
Short stature and/or failure to thrive
Delayed puberty
Dental enamel defects
Autoimmune disorders
Individuals with disorders associated with celiac disease (e.g., Down syndrome, Turner syndrome, Williams syndrome, selective IgA deficiency, insulin-dependent diabetes mellitus, Sjögren syndrome, thyroiditis)
Absence of history of self-limited enteritis and/or tropical sprue
Iron deficiency anemia
Vitamin and/or mineral deficiencies (e.g., calcium, vitamin D, vitamin B
In individuals on a gluten-containing diet:
Elevated serum
Elevated serum
Elevated serum
• Gastrointestinal signs/symptoms (e.g., diarrhea, malabsorption, abdominal pain, distention, bloating, vomiting, weight loss)
• Dermatitis herpetiformis
• Chronic fatigue
• Joint pain/inflammation
• Neurologic symptoms (e.g., peripheral neuropathy, ataxia, seizures, migraines, attention-deficit disorder, poor school performance)
• Osteoporosis/osteopenia
• Infertility and/or recurrent fetal loss
• Short stature and/or failure to thrive
• Delayed puberty
• Dental enamel defects
• Autoimmune disorders
• Individuals with disorders associated with celiac disease (e.g., Down syndrome, Turner syndrome, Williams syndrome, selective IgA deficiency, insulin-dependent diabetes mellitus, Sjögren syndrome, thyroiditis)
• Absence of history of self-limited enteritis and/or tropical sprue
• Iron deficiency anemia
• Vitamin and/or mineral deficiencies (e.g., calcium, vitamin D, vitamin B
• In individuals on a gluten-containing diet:
• Elevated serum
• Elevated serum
• Elevated serum
• Elevated serum
• Elevated serum
• Elevated serum
• Elevated serum
• Elevated serum
• Elevated serum
## Establishing the Diagnosis
The diagnosis of celiac disease
HLA Haplotypes Associated with an Increased Risk for Celiac Disease
Haplotype-defining variants of
DQ2-positive haplotype is also present in 20%-30% of the general population; the DQ8-positive haplotype is also present in 10% of the general population [
•
## Clinical Characteristics
Celiac disease is a systemic autoimmune disease with gastrointestinal symptoms and multiple, highly variable non-gastrointestinal symptoms (see
Recently a consensus paper redefined the types of celiac disease [
Iron deficiency anemia is a common presentation of non-classic celiac disease and may be the only finding.
Dermatitis herpetiformis, an intensely pruritic rash found most commonly on the extensor surfaces of the extremities, is a common non-gastrointestinal manifestation.
Other extraintestinal presentations include osteoporosis/osteopenia, dental enamel hypoplasia, infertility and/or recurrent fetal loss, vitamin deficiencies, abnormal liver function tests (typically elevated transaminases), fatigue, psychiatric syndromes, and various neurologic conditions including peripheral neuropathy, ataxia, seizures, migraines, attention-deficit hyperactivity disorder, and poor school performance.
Non-classic celiac disease usually presents in later childhood or adulthood. Children with non-classic celiac disease can present with unexplained short stature, neurologic symptoms, and delayed puberty.
Non-classic celiac disease is more common than classic celiac disease [
Reversal of (a) growth failure and (b) reduced bone mineralization in children with celiac disease;
Decreased frequency of (a) spontaneous abortions and (b) low-birth-weight infants in women with celiac disease;
Reduced risk for certain types of cancers including small-intestine adenocarcinoma, esophageal cancer, and non-Hodgkin's lymphoma;
Reduced risk of mortality in symptomatic individuals.
An alternate classification for RCD involves the characterization of the intraepithelial lymphocytes (IELs) in persons with RCD:
In active, uncomplicated celiac disease the IELs have surface expression of CD3 and CD8, a normal occurrence. In addition, these lymphocytes are not clonally restricted (i.e., polyclonal).
In RCD1, the IELs are normal.
In RCD2, the IELs are abnormal in the following ways:
They have lost surface expression of CD3, CD8, and the T-cell receptor.
CD3 is detectable within the cell.
They have generally become clonal.
RCD1 is considered to be relatively common. Individuals usually respond to corticosteroids (e.g., budesonide, prednisone).
RCD2 is rare. An international series demonstrated a 30% five-year mortality rate and prognostic factors that determined survival [
Among affected individuals, no difference in clinical severity of celiac disease is observed between those who are homozygous for the DQ2 haplotype and those who are homozygous for the DQ8 haplotype.
The penetrance of celiac disease is low. The risk of developing celiac disease is affected by HLA diplotype (see
Risk of Developing Celiac Disease Based on HLA Diplotype
From
A half-DQ2 allele
From
Celiac disease affects approximately 1% of individuals in the US. Celiac disease is considered to be common in Europe, the US, Australia, Mexico, and some South American countries. The highest reported prevalence of celiac disease is 5.6%, found in a refugee population in North Africa.
The prevalence of celiac disease is increased in individuals with the following disorders [
Down syndrome (prevalence of celiac disease: 5%-12%)
Turner syndrome (~3%)
Selective IgA deficiency (~2%-10%)
Insulin-dependent diabetes mellitus (~6%)
Sjögren syndrome (~5%)
Autoimmune thyroid disease (~2%-4%)
• Reversal of (a) growth failure and (b) reduced bone mineralization in children with celiac disease;
• Decreased frequency of (a) spontaneous abortions and (b) low-birth-weight infants in women with celiac disease;
• Reduced risk for certain types of cancers including small-intestine adenocarcinoma, esophageal cancer, and non-Hodgkin's lymphoma;
• Reduced risk of mortality in symptomatic individuals.
• In active, uncomplicated celiac disease the IELs have surface expression of CD3 and CD8, a normal occurrence. In addition, these lymphocytes are not clonally restricted (i.e., polyclonal).
• In RCD1, the IELs are normal.
• In RCD2, the IELs are abnormal in the following ways:
• They have lost surface expression of CD3, CD8, and the T-cell receptor.
• CD3 is detectable within the cell.
• They have generally become clonal.
• They have lost surface expression of CD3, CD8, and the T-cell receptor.
• CD3 is detectable within the cell.
• They have generally become clonal.
• They have lost surface expression of CD3, CD8, and the T-cell receptor.
• CD3 is detectable within the cell.
• They have generally become clonal.
• Down syndrome (prevalence of celiac disease: 5%-12%)
• Turner syndrome (~3%)
• Selective IgA deficiency (~2%-10%)
• Insulin-dependent diabetes mellitus (~6%)
• Sjögren syndrome (~5%)
• Autoimmune thyroid disease (~2%-4%)
## Clinical Description
Celiac disease is a systemic autoimmune disease with gastrointestinal symptoms and multiple, highly variable non-gastrointestinal symptoms (see
Recently a consensus paper redefined the types of celiac disease [
Iron deficiency anemia is a common presentation of non-classic celiac disease and may be the only finding.
Dermatitis herpetiformis, an intensely pruritic rash found most commonly on the extensor surfaces of the extremities, is a common non-gastrointestinal manifestation.
Other extraintestinal presentations include osteoporosis/osteopenia, dental enamel hypoplasia, infertility and/or recurrent fetal loss, vitamin deficiencies, abnormal liver function tests (typically elevated transaminases), fatigue, psychiatric syndromes, and various neurologic conditions including peripheral neuropathy, ataxia, seizures, migraines, attention-deficit hyperactivity disorder, and poor school performance.
Non-classic celiac disease usually presents in later childhood or adulthood. Children with non-classic celiac disease can present with unexplained short stature, neurologic symptoms, and delayed puberty.
Non-classic celiac disease is more common than classic celiac disease [
Reversal of (a) growth failure and (b) reduced bone mineralization in children with celiac disease;
Decreased frequency of (a) spontaneous abortions and (b) low-birth-weight infants in women with celiac disease;
Reduced risk for certain types of cancers including small-intestine adenocarcinoma, esophageal cancer, and non-Hodgkin's lymphoma;
Reduced risk of mortality in symptomatic individuals.
An alternate classification for RCD involves the characterization of the intraepithelial lymphocytes (IELs) in persons with RCD:
In active, uncomplicated celiac disease the IELs have surface expression of CD3 and CD8, a normal occurrence. In addition, these lymphocytes are not clonally restricted (i.e., polyclonal).
In RCD1, the IELs are normal.
In RCD2, the IELs are abnormal in the following ways:
They have lost surface expression of CD3, CD8, and the T-cell receptor.
CD3 is detectable within the cell.
They have generally become clonal.
RCD1 is considered to be relatively common. Individuals usually respond to corticosteroids (e.g., budesonide, prednisone).
RCD2 is rare. An international series demonstrated a 30% five-year mortality rate and prognostic factors that determined survival [
• Reversal of (a) growth failure and (b) reduced bone mineralization in children with celiac disease;
• Decreased frequency of (a) spontaneous abortions and (b) low-birth-weight infants in women with celiac disease;
• Reduced risk for certain types of cancers including small-intestine adenocarcinoma, esophageal cancer, and non-Hodgkin's lymphoma;
• Reduced risk of mortality in symptomatic individuals.
• In active, uncomplicated celiac disease the IELs have surface expression of CD3 and CD8, a normal occurrence. In addition, these lymphocytes are not clonally restricted (i.e., polyclonal).
• In RCD1, the IELs are normal.
• In RCD2, the IELs are abnormal in the following ways:
• They have lost surface expression of CD3, CD8, and the T-cell receptor.
• CD3 is detectable within the cell.
• They have generally become clonal.
• They have lost surface expression of CD3, CD8, and the T-cell receptor.
• CD3 is detectable within the cell.
• They have generally become clonal.
• They have lost surface expression of CD3, CD8, and the T-cell receptor.
• CD3 is detectable within the cell.
• They have generally become clonal.
## Types of Celiac Disease
Recently a consensus paper redefined the types of celiac disease [
Iron deficiency anemia is a common presentation of non-classic celiac disease and may be the only finding.
Dermatitis herpetiformis, an intensely pruritic rash found most commonly on the extensor surfaces of the extremities, is a common non-gastrointestinal manifestation.
Other extraintestinal presentations include osteoporosis/osteopenia, dental enamel hypoplasia, infertility and/or recurrent fetal loss, vitamin deficiencies, abnormal liver function tests (typically elevated transaminases), fatigue, psychiatric syndromes, and various neurologic conditions including peripheral neuropathy, ataxia, seizures, migraines, attention-deficit hyperactivity disorder, and poor school performance.
Non-classic celiac disease usually presents in later childhood or adulthood. Children with non-classic celiac disease can present with unexplained short stature, neurologic symptoms, and delayed puberty.
Non-classic celiac disease is more common than classic celiac disease [
Reversal of (a) growth failure and (b) reduced bone mineralization in children with celiac disease;
Decreased frequency of (a) spontaneous abortions and (b) low-birth-weight infants in women with celiac disease;
Reduced risk for certain types of cancers including small-intestine adenocarcinoma, esophageal cancer, and non-Hodgkin's lymphoma;
Reduced risk of mortality in symptomatic individuals.
An alternate classification for RCD involves the characterization of the intraepithelial lymphocytes (IELs) in persons with RCD:
In active, uncomplicated celiac disease the IELs have surface expression of CD3 and CD8, a normal occurrence. In addition, these lymphocytes are not clonally restricted (i.e., polyclonal).
In RCD1, the IELs are normal.
In RCD2, the IELs are abnormal in the following ways:
They have lost surface expression of CD3, CD8, and the T-cell receptor.
CD3 is detectable within the cell.
They have generally become clonal.
RCD1 is considered to be relatively common. Individuals usually respond to corticosteroids (e.g., budesonide, prednisone).
RCD2 is rare. An international series demonstrated a 30% five-year mortality rate and prognostic factors that determined survival [
• Reversal of (a) growth failure and (b) reduced bone mineralization in children with celiac disease;
• Decreased frequency of (a) spontaneous abortions and (b) low-birth-weight infants in women with celiac disease;
• Reduced risk for certain types of cancers including small-intestine adenocarcinoma, esophageal cancer, and non-Hodgkin's lymphoma;
• Reduced risk of mortality in symptomatic individuals.
• In active, uncomplicated celiac disease the IELs have surface expression of CD3 and CD8, a normal occurrence. In addition, these lymphocytes are not clonally restricted (i.e., polyclonal).
• In RCD1, the IELs are normal.
• In RCD2, the IELs are abnormal in the following ways:
• They have lost surface expression of CD3, CD8, and the T-cell receptor.
• CD3 is detectable within the cell.
• They have generally become clonal.
• They have lost surface expression of CD3, CD8, and the T-cell receptor.
• CD3 is detectable within the cell.
• They have generally become clonal.
• They have lost surface expression of CD3, CD8, and the T-cell receptor.
• CD3 is detectable within the cell.
• They have generally become clonal.
## Genotype-Phenotype Correlations
Among affected individuals, no difference in clinical severity of celiac disease is observed between those who are homozygous for the DQ2 haplotype and those who are homozygous for the DQ8 haplotype.
## Penetrance
The penetrance of celiac disease is low. The risk of developing celiac disease is affected by HLA diplotype (see
Risk of Developing Celiac Disease Based on HLA Diplotype
From
A half-DQ2 allele
From
## Prevalence
Celiac disease affects approximately 1% of individuals in the US. Celiac disease is considered to be common in Europe, the US, Australia, Mexico, and some South American countries. The highest reported prevalence of celiac disease is 5.6%, found in a refugee population in North Africa.
The prevalence of celiac disease is increased in individuals with the following disorders [
Down syndrome (prevalence of celiac disease: 5%-12%)
Turner syndrome (~3%)
Selective IgA deficiency (~2%-10%)
Insulin-dependent diabetes mellitus (~6%)
Sjögren syndrome (~5%)
Autoimmune thyroid disease (~2%-4%)
• Down syndrome (prevalence of celiac disease: 5%-12%)
• Turner syndrome (~3%)
• Selective IgA deficiency (~2%-10%)
• Insulin-dependent diabetes mellitus (~6%)
• Sjögren syndrome (~5%)
• Autoimmune thyroid disease (~2%-4%)
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The clinical manifestations of celiac disease overlap with several other conditions, including:
Helicobacter pylori gastritis
Irritable bowel syndrome
Inflammatory bowel disease
Tropical sprue
Various neurologic syndromes, including myasthesia gravis and peripheral neuropathy
Drug-induced small-bowel disease (e.g., nonsteroidal anti-inflammatory drugs, olmesartan)
Small-bowel bacterial overgrowth
• Helicobacter pylori gastritis
• Irritable bowel syndrome
• Inflammatory bowel disease
• Tropical sprue
• Various neurologic syndromes, including myasthesia gravis and peripheral neuropathy
• Drug-induced small-bowel disease (e.g., nonsteroidal anti-inflammatory drugs, olmesartan)
• Small-bowel bacterial overgrowth
## Other (non-Celiac) Causes of Gluten Sensitivity
## Management
To establish the extent of disease in an individual diagnosed with celiac disease, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Baseline bone-density test in adults to evaluate for osteoporosis/osteopenia. In those with osteoporosis, vitamin D and parathyroid hormone concentrations should be evaluated.
Screening tests for anemia, abnormal liver function, and nutrient deficiencies (iron, calcium, vitamin D, vitamin B
Evaluation for a coexisting autoimmune disease. Because of the frequent association of celiac disease with autoimmune thyroid disease, thyroid function assessment is often performed [
Failure to regain weight or gastrointestinal bleeding should prompt evaluation for an intestinal malignancy with radiologic and endoscopic studies.
The only treatment for individuals with celiac disease is strict adherence to a gluten-free diet that requires lifelong avoidance of wheat, rye, and barley:
Treatment with a gluten-free diet should be started only after the diagnosis has been established by intestinal biopsy.
A dietitian experienced in treating celiac disease should be involved.
Symptoms may improve rapidly while serologic tests may take up to 12 months to normalize on the gluten-free diet.
For some individuals, even a small amount of gluten (i.e., 100 mg) can damage the small intestine. Note that a slice of bread contains approximately 2.5 grams of gluten.
It can be difficult to adhere to the gluten-free diet, as gluten is found in many foods and other ingested products. Some hidden sources of gluten:
Non-starchy foods such as soy sauce and beer
Non-food items such as some medications and cosmetics (e.g., lipstick)
Nutritional deficiencies and metabolic bone disease should be treated in the usual manner.
The most common reason for unresponsive celiac disease is the presence of small amounts of gluten in the diet. This gluten ingestion may be intentional, such as "cheating" at social events or using communion wafers, or unintentional, including ingestion of gluten in medications and gluten-containing foods in restaurants. Advice from a nutritionist experienced in management of the gluten-free diet is recommended to achieve the best results.
Assessment for lactose or fructose intolerance is important, as these conditions can be responsible for lack of response to the gluten-free diet [
Assessment for alternative or additional diagnoses such as microscopic colitis, pancreatic exocrine insufficiency, IBS, small intestinal bacterial overgrowth, and eating disorders is necessary in those in whom gluten contamination is not the explanation.
Abnormal celiac disease serologies should be followed to normalization, which usually occurs within six to 12 months of starting a strict gluten-free diet.
Periodic physical examination and assessment of growth, nutritional status, and non-gastrointestinal disease manifestations
Follow-up biopsy can be considered to confirm healing of intestinal villi. Because some individuals on a strict gluten-free diet can heal gradually, this should typically be done at least two years after the initial diagnosis.
The most frequently used classification is the Marsh-Oberhuber classification (
Classification of Intestinal Lesions in Celiac Disease
Partial villous atrophy (termed 3a)
Subtotal villous atrophy (3b)
Total villous atrophy (3c)
Small-bowel biopsy can fail to detect histologic changes in the following circumstances: gluten-free diet, early stages of the disease, patchy mucosal lesions, masking of celiac effect by peptic changes, insufficient number of samples taken, latent celiac disease.
Comparisons with other classifications are detailed in
Avoid dietary gluten.
Molecular genetic testing of first-degree relatives of a proband for the celiac disease-associated
Early diagnosis of celiac disease and treatment with a gluten-free diet can prevent secondary complications.
Individuals who do not have the celiac disease-associated
Individuals who have celiac disease-associated HLA alleles (
Small-bowel biopsy is recommended when celiac disease-associated antibody testing is positive.
A definitive diagnosis of celiac disease is made in a person with a positive small-bowel biopsy and clinical and/or histologic improvement on a gluten-free diet.
See
Several novel therapeutic approaches that potentially could be used as alternatives for or additives to a gluten-free diet are being investigated (reviewed in
Larazotide, a tight junction regulatory peptide that is considered to prevent the passage of gliadin peptides into the mucosa. This drug is in clinical trials.
Peptides that block the binding groove of DQ2 and DQ8 to prevent activation of gluten-sensitive T cells. The viability of this approach is currently uncertain.
Transglutaminase (tTG) inhibitors
Cytokine blockers, particularly for refractory celiac disease. Of particular interest is an anti-IL15 antibody.
Drugs that selectively inhibit leukocyte adhesion and migration of lymphocytes into inflamed tissues
Detoxifying gluten, using oral proteases. Latiglutenase, a glutenase, is currently in clinical trials.
Gluten-sequestering polymers. An oral polymeric resin, P(HEMA-co-SS), binds to gluten and is under study.
Gluten tolerization. A peptide-based vaccine could desensitize or induce tolerance in individuals with celiac disease. A prototype vaccine, Nexvax2, involving a set of gluten peptides recognized by HLA-DQ2, is in clinical trials.
Rho/Rho kinase inhibition to theoretically reverse gluten-dependent increase in intestinal permeability [
Antibodies to proteins involved in autoimmune pathologies, including anti-IFN-γ, anti-CD3, anti-CD20 therapy, and anti-IL-15. [
Another approach: interfering with the homing of gluten-specific T cells to the gut mucosa by using CCR9 antagonists. A Phase II clinical trial is listed in
Search
• Baseline bone-density test in adults to evaluate for osteoporosis/osteopenia. In those with osteoporosis, vitamin D and parathyroid hormone concentrations should be evaluated.
• Screening tests for anemia, abnormal liver function, and nutrient deficiencies (iron, calcium, vitamin D, vitamin B
• Evaluation for a coexisting autoimmune disease. Because of the frequent association of celiac disease with autoimmune thyroid disease, thyroid function assessment is often performed [
• Failure to regain weight or gastrointestinal bleeding should prompt evaluation for an intestinal malignancy with radiologic and endoscopic studies.
• Treatment with a gluten-free diet should be started only after the diagnosis has been established by intestinal biopsy.
• A dietitian experienced in treating celiac disease should be involved.
• Symptoms may improve rapidly while serologic tests may take up to 12 months to normalize on the gluten-free diet.
• For some individuals, even a small amount of gluten (i.e., 100 mg) can damage the small intestine. Note that a slice of bread contains approximately 2.5 grams of gluten.
• It can be difficult to adhere to the gluten-free diet, as gluten is found in many foods and other ingested products. Some hidden sources of gluten:
• Non-starchy foods such as soy sauce and beer
• Non-food items such as some medications and cosmetics (e.g., lipstick)
• Non-starchy foods such as soy sauce and beer
• Non-food items such as some medications and cosmetics (e.g., lipstick)
• Nutritional deficiencies and metabolic bone disease should be treated in the usual manner.
• Non-starchy foods such as soy sauce and beer
• Non-food items such as some medications and cosmetics (e.g., lipstick)
• The most common reason for unresponsive celiac disease is the presence of small amounts of gluten in the diet. This gluten ingestion may be intentional, such as "cheating" at social events or using communion wafers, or unintentional, including ingestion of gluten in medications and gluten-containing foods in restaurants. Advice from a nutritionist experienced in management of the gluten-free diet is recommended to achieve the best results.
• Assessment for lactose or fructose intolerance is important, as these conditions can be responsible for lack of response to the gluten-free diet [
• Assessment for alternative or additional diagnoses such as microscopic colitis, pancreatic exocrine insufficiency, IBS, small intestinal bacterial overgrowth, and eating disorders is necessary in those in whom gluten contamination is not the explanation.
• Abnormal celiac disease serologies should be followed to normalization, which usually occurs within six to 12 months of starting a strict gluten-free diet.
• Periodic physical examination and assessment of growth, nutritional status, and non-gastrointestinal disease manifestations
• Follow-up biopsy can be considered to confirm healing of intestinal villi. Because some individuals on a strict gluten-free diet can heal gradually, this should typically be done at least two years after the initial diagnosis.
• Partial villous atrophy (termed 3a)
• Subtotal villous atrophy (3b)
• Total villous atrophy (3c)
• Individuals who do not have the celiac disease-associated
• Individuals who have celiac disease-associated HLA alleles (
• Small-bowel biopsy is recommended when celiac disease-associated antibody testing is positive.
• A definitive diagnosis of celiac disease is made in a person with a positive small-bowel biopsy and clinical and/or histologic improvement on a gluten-free diet.
• Larazotide, a tight junction regulatory peptide that is considered to prevent the passage of gliadin peptides into the mucosa. This drug is in clinical trials.
• Peptides that block the binding groove of DQ2 and DQ8 to prevent activation of gluten-sensitive T cells. The viability of this approach is currently uncertain.
• Transglutaminase (tTG) inhibitors
• Cytokine blockers, particularly for refractory celiac disease. Of particular interest is an anti-IL15 antibody.
• Drugs that selectively inhibit leukocyte adhesion and migration of lymphocytes into inflamed tissues
• Detoxifying gluten, using oral proteases. Latiglutenase, a glutenase, is currently in clinical trials.
• Gluten-sequestering polymers. An oral polymeric resin, P(HEMA-co-SS), binds to gluten and is under study.
• Gluten tolerization. A peptide-based vaccine could desensitize or induce tolerance in individuals with celiac disease. A prototype vaccine, Nexvax2, involving a set of gluten peptides recognized by HLA-DQ2, is in clinical trials.
• Rho/Rho kinase inhibition to theoretically reverse gluten-dependent increase in intestinal permeability [
• Antibodies to proteins involved in autoimmune pathologies, including anti-IFN-γ, anti-CD3, anti-CD20 therapy, and anti-IL-15. [
• Another approach: interfering with the homing of gluten-specific T cells to the gut mucosa by using CCR9 antagonists. A Phase II clinical trial is listed in
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with celiac disease, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Baseline bone-density test in adults to evaluate for osteoporosis/osteopenia. In those with osteoporosis, vitamin D and parathyroid hormone concentrations should be evaluated.
Screening tests for anemia, abnormal liver function, and nutrient deficiencies (iron, calcium, vitamin D, vitamin B
Evaluation for a coexisting autoimmune disease. Because of the frequent association of celiac disease with autoimmune thyroid disease, thyroid function assessment is often performed [
Failure to regain weight or gastrointestinal bleeding should prompt evaluation for an intestinal malignancy with radiologic and endoscopic studies.
• Baseline bone-density test in adults to evaluate for osteoporosis/osteopenia. In those with osteoporosis, vitamin D and parathyroid hormone concentrations should be evaluated.
• Screening tests for anemia, abnormal liver function, and nutrient deficiencies (iron, calcium, vitamin D, vitamin B
• Evaluation for a coexisting autoimmune disease. Because of the frequent association of celiac disease with autoimmune thyroid disease, thyroid function assessment is often performed [
• Failure to regain weight or gastrointestinal bleeding should prompt evaluation for an intestinal malignancy with radiologic and endoscopic studies.
## Treatment of Manifestations
The only treatment for individuals with celiac disease is strict adherence to a gluten-free diet that requires lifelong avoidance of wheat, rye, and barley:
Treatment with a gluten-free diet should be started only after the diagnosis has been established by intestinal biopsy.
A dietitian experienced in treating celiac disease should be involved.
Symptoms may improve rapidly while serologic tests may take up to 12 months to normalize on the gluten-free diet.
For some individuals, even a small amount of gluten (i.e., 100 mg) can damage the small intestine. Note that a slice of bread contains approximately 2.5 grams of gluten.
It can be difficult to adhere to the gluten-free diet, as gluten is found in many foods and other ingested products. Some hidden sources of gluten:
Non-starchy foods such as soy sauce and beer
Non-food items such as some medications and cosmetics (e.g., lipstick)
Nutritional deficiencies and metabolic bone disease should be treated in the usual manner.
The most common reason for unresponsive celiac disease is the presence of small amounts of gluten in the diet. This gluten ingestion may be intentional, such as "cheating" at social events or using communion wafers, or unintentional, including ingestion of gluten in medications and gluten-containing foods in restaurants. Advice from a nutritionist experienced in management of the gluten-free diet is recommended to achieve the best results.
Assessment for lactose or fructose intolerance is important, as these conditions can be responsible for lack of response to the gluten-free diet [
Assessment for alternative or additional diagnoses such as microscopic colitis, pancreatic exocrine insufficiency, IBS, small intestinal bacterial overgrowth, and eating disorders is necessary in those in whom gluten contamination is not the explanation.
• Treatment with a gluten-free diet should be started only after the diagnosis has been established by intestinal biopsy.
• A dietitian experienced in treating celiac disease should be involved.
• Symptoms may improve rapidly while serologic tests may take up to 12 months to normalize on the gluten-free diet.
• For some individuals, even a small amount of gluten (i.e., 100 mg) can damage the small intestine. Note that a slice of bread contains approximately 2.5 grams of gluten.
• It can be difficult to adhere to the gluten-free diet, as gluten is found in many foods and other ingested products. Some hidden sources of gluten:
• Non-starchy foods such as soy sauce and beer
• Non-food items such as some medications and cosmetics (e.g., lipstick)
• Non-starchy foods such as soy sauce and beer
• Non-food items such as some medications and cosmetics (e.g., lipstick)
• Nutritional deficiencies and metabolic bone disease should be treated in the usual manner.
• Non-starchy foods such as soy sauce and beer
• Non-food items such as some medications and cosmetics (e.g., lipstick)
• The most common reason for unresponsive celiac disease is the presence of small amounts of gluten in the diet. This gluten ingestion may be intentional, such as "cheating" at social events or using communion wafers, or unintentional, including ingestion of gluten in medications and gluten-containing foods in restaurants. Advice from a nutritionist experienced in management of the gluten-free diet is recommended to achieve the best results.
• Assessment for lactose or fructose intolerance is important, as these conditions can be responsible for lack of response to the gluten-free diet [
• Assessment for alternative or additional diagnoses such as microscopic colitis, pancreatic exocrine insufficiency, IBS, small intestinal bacterial overgrowth, and eating disorders is necessary in those in whom gluten contamination is not the explanation.
## Surveillance
Abnormal celiac disease serologies should be followed to normalization, which usually occurs within six to 12 months of starting a strict gluten-free diet.
Periodic physical examination and assessment of growth, nutritional status, and non-gastrointestinal disease manifestations
Follow-up biopsy can be considered to confirm healing of intestinal villi. Because some individuals on a strict gluten-free diet can heal gradually, this should typically be done at least two years after the initial diagnosis.
The most frequently used classification is the Marsh-Oberhuber classification (
Classification of Intestinal Lesions in Celiac Disease
Partial villous atrophy (termed 3a)
Subtotal villous atrophy (3b)
Total villous atrophy (3c)
Small-bowel biopsy can fail to detect histologic changes in the following circumstances: gluten-free diet, early stages of the disease, patchy mucosal lesions, masking of celiac effect by peptic changes, insufficient number of samples taken, latent celiac disease.
Comparisons with other classifications are detailed in
• Abnormal celiac disease serologies should be followed to normalization, which usually occurs within six to 12 months of starting a strict gluten-free diet.
• Periodic physical examination and assessment of growth, nutritional status, and non-gastrointestinal disease manifestations
• Follow-up biopsy can be considered to confirm healing of intestinal villi. Because some individuals on a strict gluten-free diet can heal gradually, this should typically be done at least two years after the initial diagnosis.
• Partial villous atrophy (termed 3a)
• Subtotal villous atrophy (3b)
• Total villous atrophy (3c)
## Agents/Circumstances to Avoid
Avoid dietary gluten.
## Evaluation of Relatives at Risk
Molecular genetic testing of first-degree relatives of a proband for the celiac disease-associated
Early diagnosis of celiac disease and treatment with a gluten-free diet can prevent secondary complications.
Individuals who do not have the celiac disease-associated
Individuals who have celiac disease-associated HLA alleles (
Small-bowel biopsy is recommended when celiac disease-associated antibody testing is positive.
A definitive diagnosis of celiac disease is made in a person with a positive small-bowel biopsy and clinical and/or histologic improvement on a gluten-free diet.
See
• Individuals who do not have the celiac disease-associated
• Individuals who have celiac disease-associated HLA alleles (
• Small-bowel biopsy is recommended when celiac disease-associated antibody testing is positive.
• A definitive diagnosis of celiac disease is made in a person with a positive small-bowel biopsy and clinical and/or histologic improvement on a gluten-free diet.
## Therapies Under Investigation
Several novel therapeutic approaches that potentially could be used as alternatives for or additives to a gluten-free diet are being investigated (reviewed in
Larazotide, a tight junction regulatory peptide that is considered to prevent the passage of gliadin peptides into the mucosa. This drug is in clinical trials.
Peptides that block the binding groove of DQ2 and DQ8 to prevent activation of gluten-sensitive T cells. The viability of this approach is currently uncertain.
Transglutaminase (tTG) inhibitors
Cytokine blockers, particularly for refractory celiac disease. Of particular interest is an anti-IL15 antibody.
Drugs that selectively inhibit leukocyte adhesion and migration of lymphocytes into inflamed tissues
Detoxifying gluten, using oral proteases. Latiglutenase, a glutenase, is currently in clinical trials.
Gluten-sequestering polymers. An oral polymeric resin, P(HEMA-co-SS), binds to gluten and is under study.
Gluten tolerization. A peptide-based vaccine could desensitize or induce tolerance in individuals with celiac disease. A prototype vaccine, Nexvax2, involving a set of gluten peptides recognized by HLA-DQ2, is in clinical trials.
Rho/Rho kinase inhibition to theoretically reverse gluten-dependent increase in intestinal permeability [
Antibodies to proteins involved in autoimmune pathologies, including anti-IFN-γ, anti-CD3, anti-CD20 therapy, and anti-IL-15. [
Another approach: interfering with the homing of gluten-specific T cells to the gut mucosa by using CCR9 antagonists. A Phase II clinical trial is listed in
Search
• Larazotide, a tight junction regulatory peptide that is considered to prevent the passage of gliadin peptides into the mucosa. This drug is in clinical trials.
• Peptides that block the binding groove of DQ2 and DQ8 to prevent activation of gluten-sensitive T cells. The viability of this approach is currently uncertain.
• Transglutaminase (tTG) inhibitors
• Cytokine blockers, particularly for refractory celiac disease. Of particular interest is an anti-IL15 antibody.
• Drugs that selectively inhibit leukocyte adhesion and migration of lymphocytes into inflamed tissues
• Detoxifying gluten, using oral proteases. Latiglutenase, a glutenase, is currently in clinical trials.
• Gluten-sequestering polymers. An oral polymeric resin, P(HEMA-co-SS), binds to gluten and is under study.
• Gluten tolerization. A peptide-based vaccine could desensitize or induce tolerance in individuals with celiac disease. A prototype vaccine, Nexvax2, involving a set of gluten peptides recognized by HLA-DQ2, is in clinical trials.
• Rho/Rho kinase inhibition to theoretically reverse gluten-dependent increase in intestinal permeability [
• Antibodies to proteins involved in autoimmune pathologies, including anti-IFN-γ, anti-CD3, anti-CD20 therapy, and anti-IL-15. [
• Another approach: interfering with the homing of gluten-specific T cells to the gut mucosa by using CCR9 antagonists. A Phase II clinical trial is listed in
## Genetic Counseling
In infant feeding studies in children at risk for celiac disease due to the existence of an affected family member, the major risk for the development of celiac disease was the dosage of the genetic risk (see
Children who were homozygous for HLA-DQ2 were regarded as high risk; 25.8% who had a double dose of DQ2 developed celiac disease [
Other at-risk HLA-DQ2 or -DQ8 combinations were regarded as low risk / average risk with 15.8% developing celiac disease while those without either HLA-DQ2 or -DQ8 were regarded as having no risk [
Note: Risks in
Risk of Developing Celiac Disease to Family Members
DQ2-positive =
DQ8-positive =
Children who inherit the same HLA haplotype as the parent are at lower risk than sibs of a proband with the same HLA haplotype (i.e., <40%) [
The celiac disease-susceptibility HLA status of the proband's reproductive partner is also important as the DQ2 or DQ8 heterodimer is found in 30%-40% of the general population.
See Management,
While technically possible, prenatal testing of celiac disease-susceptibility HLA variants is not relevant in this complex disorder because:
The genetic change is common in the general population;
The genetic change is predisposing to but not predictive of celiac disease;
A highly effective treatment is available.
• Children who were homozygous for HLA-DQ2 were regarded as high risk; 25.8% who had a double dose of DQ2 developed celiac disease [
• Other at-risk HLA-DQ2 or -DQ8 combinations were regarded as low risk / average risk with 15.8% developing celiac disease while those without either HLA-DQ2 or -DQ8 were regarded as having no risk [
• The genetic change is common in the general population;
• The genetic change is predisposing to but not predictive of celiac disease;
• A highly effective treatment is available.
## Risk to Family Members
In infant feeding studies in children at risk for celiac disease due to the existence of an affected family member, the major risk for the development of celiac disease was the dosage of the genetic risk (see
Children who were homozygous for HLA-DQ2 were regarded as high risk; 25.8% who had a double dose of DQ2 developed celiac disease [
Other at-risk HLA-DQ2 or -DQ8 combinations were regarded as low risk / average risk with 15.8% developing celiac disease while those without either HLA-DQ2 or -DQ8 were regarded as having no risk [
Note: Risks in
Risk of Developing Celiac Disease to Family Members
DQ2-positive =
DQ8-positive =
Children who inherit the same HLA haplotype as the parent are at lower risk than sibs of a proband with the same HLA haplotype (i.e., <40%) [
The celiac disease-susceptibility HLA status of the proband's reproductive partner is also important as the DQ2 or DQ8 heterodimer is found in 30%-40% of the general population.
• Children who were homozygous for HLA-DQ2 were regarded as high risk; 25.8% who had a double dose of DQ2 developed celiac disease [
• Other at-risk HLA-DQ2 or -DQ8 combinations were regarded as low risk / average risk with 15.8% developing celiac disease while those without either HLA-DQ2 or -DQ8 were regarded as having no risk [
## Related Genetic Counseling Issues
See Management,
## Prenatal Testing
While technically possible, prenatal testing of celiac disease-susceptibility HLA variants is not relevant in this complex disorder because:
The genetic change is common in the general population;
The genetic change is predisposing to but not predictive of celiac disease;
A highly effective treatment is available.
• The genetic change is common in the general population;
• The genetic change is predisposing to but not predictive of celiac disease;
• A highly effective treatment is available.
## Resources
•
•
•
•
## Molecular Genetics
Celiac Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Celiac Disease (
Celiac disease is a multifactorial disorder caused by an immune-mediated response to gliadin (a subcomponent of gluten) in genetically susceptible individuals leading to inflammation of the small bowel, villous damage, and resultant malabsorption. Haplotypes across adjacent
When working properly, inflammatory mechanisms and immunologic responses in the digestive system provide protection from bacteria, toxins, and other foreign elements in the food and water supply. IgA, made in abundance by the intestinal immune system, is important in local (mucosal) immunity. In celiac disease, inappropriate immune responses lead to chronic inflammation and damage. The two main categories of immune response involved in celiac disease are: the adaptive immune response (HLA-specific) and the innate immune response (independent of HLA type).
The great majority (>90%) of individuals with celiac disease express at least one copy of DQ2, referred to as being DQ2-positive, and most of the remainder express at least one copy of DQ8, referred to as DQ8-positive (see
The DQ2 at-risk haplotypes include several allelic variants of
Have the DR17-DQ2 celiac disease-susceptibility haplotype [
OR
Are heterozygous for the celiac disease-susceptibility haplotypes DR11 or DR12-DQ7 [
Individuals with celiac disease who have DQ8 have the DR4-DQ8 celiac disease-susceptibility haplotype (
Tissue transglutaminase (tTG), an enzyme found in every tissue of the body, protects the body through wound healing and bone growth. In the intestine, tTG deamidates gliadin, introducing negative charges to the gluten peptides. Both DQ2 and DQ8 preferentially bind these negatively charged deamidated gluten peptides (see
In addition to the adaptive immune response (see
• Have the DR17-DQ2 celiac disease-susceptibility haplotype [
• OR
• Are heterozygous for the celiac disease-susceptibility haplotypes DR11 or DR12-DQ7 [
## Molecular Pathogenesis
Celiac disease is a multifactorial disorder caused by an immune-mediated response to gliadin (a subcomponent of gluten) in genetically susceptible individuals leading to inflammation of the small bowel, villous damage, and resultant malabsorption. Haplotypes across adjacent
When working properly, inflammatory mechanisms and immunologic responses in the digestive system provide protection from bacteria, toxins, and other foreign elements in the food and water supply. IgA, made in abundance by the intestinal immune system, is important in local (mucosal) immunity. In celiac disease, inappropriate immune responses lead to chronic inflammation and damage. The two main categories of immune response involved in celiac disease are: the adaptive immune response (HLA-specific) and the innate immune response (independent of HLA type).
The great majority (>90%) of individuals with celiac disease express at least one copy of DQ2, referred to as being DQ2-positive, and most of the remainder express at least one copy of DQ8, referred to as DQ8-positive (see
The DQ2 at-risk haplotypes include several allelic variants of
Have the DR17-DQ2 celiac disease-susceptibility haplotype [
OR
Are heterozygous for the celiac disease-susceptibility haplotypes DR11 or DR12-DQ7 [
Individuals with celiac disease who have DQ8 have the DR4-DQ8 celiac disease-susceptibility haplotype (
Tissue transglutaminase (tTG), an enzyme found in every tissue of the body, protects the body through wound healing and bone growth. In the intestine, tTG deamidates gliadin, introducing negative charges to the gluten peptides. Both DQ2 and DQ8 preferentially bind these negatively charged deamidated gluten peptides (see
In addition to the adaptive immune response (see
• Have the DR17-DQ2 celiac disease-susceptibility haplotype [
• OR
• Are heterozygous for the celiac disease-susceptibility haplotypes DR11 or DR12-DQ7 [
## The Immunologic Mechanisms of Celiac Disease
When working properly, inflammatory mechanisms and immunologic responses in the digestive system provide protection from bacteria, toxins, and other foreign elements in the food and water supply. IgA, made in abundance by the intestinal immune system, is important in local (mucosal) immunity. In celiac disease, inappropriate immune responses lead to chronic inflammation and damage. The two main categories of immune response involved in celiac disease are: the adaptive immune response (HLA-specific) and the innate immune response (independent of HLA type).
The great majority (>90%) of individuals with celiac disease express at least one copy of DQ2, referred to as being DQ2-positive, and most of the remainder express at least one copy of DQ8, referred to as DQ8-positive (see
The DQ2 at-risk haplotypes include several allelic variants of
Have the DR17-DQ2 celiac disease-susceptibility haplotype [
OR
Are heterozygous for the celiac disease-susceptibility haplotypes DR11 or DR12-DQ7 [
Individuals with celiac disease who have DQ8 have the DR4-DQ8 celiac disease-susceptibility haplotype (
Tissue transglutaminase (tTG), an enzyme found in every tissue of the body, protects the body through wound healing and bone growth. In the intestine, tTG deamidates gliadin, introducing negative charges to the gluten peptides. Both DQ2 and DQ8 preferentially bind these negatively charged deamidated gluten peptides (see
• Have the DR17-DQ2 celiac disease-susceptibility haplotype [
• OR
• Are heterozygous for the celiac disease-susceptibility haplotypes DR11 or DR12-DQ7 [
## Innate Immune Response
In addition to the adaptive immune response (see
## References
## Literature Cited
## Chapter Notes
We would like to acknowledge genetic counselor Katie Storm, MS for her contribution to revisions.
We would also like to thank Dr Ludvig Sollid for sharing his knowledge and insight.
Peter HR Green, MD (2008-present)Benjamin Lebwohl, MD, MS (2015-present)Cara L Snyder, MS, CGC (2008-present)Annette K Taylor, MS, PhD, CGC (2008-present)Danielle O Young, MS, CGC; Kimball Genetics, Inc (2008-2015)
31 January 2018 (sw) Comprehensive update posted live
17 September 2015 (me) Comprehensive update posted live
3 July 2008 (me) Review posted live
28 September 2006 (cs) Original submission
• 31 January 2018 (sw) Comprehensive update posted live
• 17 September 2015 (me) Comprehensive update posted live
• 3 July 2008 (me) Review posted live
• 28 September 2006 (cs) Original submission
## Acknowledgments
We would like to acknowledge genetic counselor Katie Storm, MS for her contribution to revisions.
We would also like to thank Dr Ludvig Sollid for sharing his knowledge and insight.
## Author History
Peter HR Green, MD (2008-present)Benjamin Lebwohl, MD, MS (2015-present)Cara L Snyder, MS, CGC (2008-present)Annette K Taylor, MS, PhD, CGC (2008-present)Danielle O Young, MS, CGC; Kimball Genetics, Inc (2008-2015)
## Revision History
31 January 2018 (sw) Comprehensive update posted live
17 September 2015 (me) Comprehensive update posted live
3 July 2008 (me) Review posted live
28 September 2006 (cs) Original submission
• 31 January 2018 (sw) Comprehensive update posted live
• 17 September 2015 (me) Comprehensive update posted live
• 3 July 2008 (me) Review posted live
• 28 September 2006 (cs) Original submission
Formation of DQ2 and DQ8
A. The DQ2 molecule, consisting of the α-chain protein encoded by the
B. The DQ2 molecule, consisting of the α-chain protein encoded from the
C. The DQ8 molecule, consisting of the β-chain protein encoded by the
Note: The DR alleles are the result of linkage disequilibrium and are included for illustration only.
Modified and expanded from
Presenting signs/symptoms in celiac disease. The presenting signs/symptoms are the main indications that led to a diagnosis of celiac disease. "Bone disease" refers to evaluation for low bone density. "Incidental" refers to discovery of villous atrophy during endoscopy performed for signs/symptoms not usually associated with celiac disease [
With permission from PHR Green, MD
The celiac iceberg represents all people who are genetically susceptible to celiac disease and have a positive celiac-associated antibody test result. The majority of these individuals have latent celiac disease. The "tip of the iceberg" represents the minority who have clinical manifestations of celiac disease [
An approach to the management of newly diagnosed celiac disease [
With permission from MM Pietzak, MD
Gluten-reactive CD4+ T-helper cells (with cell-surface CD4 markers) become activated upon recognition by a T-cell receptor of gluten peptides presented by HLA-DQ2 or HLA-DQ8 protein molecules on the surface of antigen-presenting cells (APCs) in the lamina propria.
Modified and expanded from
The celiac small intestinal lesion showing both adaptive and innate immune mechanisms
A. Gluten peptides are transported across the epithelial barrier and are deamidated by tissue transglutaminase (tTG). CD4+ T cells in the lamina propria recognize the gluten peptides presented by HLA-DQ2 or HLA-DQ8 molecules on the cell surface of the antigen presenting cells. In the epithelium-infiltrated CD8+ T cells express NK cell receptors, such as NKG2D. B cells specific for gluten and tTG are in the lamina propria.
B. Intraepithelial T cells, upregulated by NKG2D, can kill enterocytes expressing MIC molecules directly or by reducing the T-cell receptor (TCR) activation threshold. Gluten can induce NKG2D and MIC expression by stimulating the expression of IL-15.
C. HLA-DQ2 and -DQ8 molecules bind with increased affinity gluten peptides deamidated by tTG.
D. Gluten-specific T cells control the formation of antibodies to tTG by intramolecular help.
From
|
[] |
3/7/2008
|
31/1/2019
|
14/6/2012
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cep
|
cep
|
[
"Günther Disease",
"Günther disease",
"Erythroid transcription factor",
"Uroporphyrinogen-III synthase",
"GATA1",
"UROS",
"Congenital Erythropoietic Porphyria"
] |
Congenital Erythropoietic Porphyria
|
Angelika Erwin, Manisha Balwani, Robert J Desnick
|
Summary Congenital erythropoietic porphyria (CEP) is characterized in most individuals by severe cutaneous photosensitivity with blistering and increased friability of the skin over light-exposed areas. Onset in most affected individuals occurs at birth or early infancy. The first manifestation is often pink-to-dark red discoloration of the urine. Hemolytic anemia is common and can range from mild to severe, with some affected individuals requiring chronic blood transfusions. Porphyrin deposition may lead to corneal ulcers and scarring, reddish-brown discoloration of the teeth (erythrodontia), and bone loss and/or expansion of the bone marrow. The phenotypic spectrum, however, is broad and ranges from nonimmune hydrops fetalis in utero to late-onset disease with only mild cutaneous manifestations in adulthood. The diagnosis of CEP in a proband with suggestive clinical and biochemical findings is most commonly established by identification of biallelic pathogenic variants in CEP caused by biallelic
|
## Diagnosis
No consensus clinical diagnostic criteria for congenital erythropoietic porphyria (CEP) have been published.
Congenital erythropoietic porphyria (CEP)
Nonimmune hydrops fetalis
Signs of congenital erythropoietic porphyria
Pink-to-dark red discoloration of the urine (pink or dark red urine-stained diapers are often the first sign in infants)
Hemolytic anemia
Severe cutaneous photosensitivity with onset usually in infancy or early childhood
Blisters and vesicles in light-exposed areas, which are prone to rupture and infection
Scarring and deformities (photomutilation) of digits and facial features, caused by recurrent blistering, infections, and bone resorption
In light-exposed areas: friable skin, skin thickening, hypo- and hyperpigmentation
Reddish-brown discoloration of teeth (fluoresce on exposure to long-wave ultraviolet light), also called erythrodontia
Corneal ulcers and scarring
Hypertrichosis of the face and extremities
Biochemical Characteristics of Congenital Erythropoietic Porphyria
↑ = markedly elevated
The deficient activity of uroporphyrinogen III synthase EC 4.2.1.75, encoded by
The assay for the enzyme uroporphyrinogen III synthase is available on a clinical basis and can be used to establish the diagnosis of congenital erythropoietic porphyria.
Amniotic fluid appears red to dark brown. Prenatal diagnosis is also possible by demonstrating markedly deficient URO-synthase activity in cultured amniotic cells or chorionic villi cells [
The diagnosis of CEP
Note:
In the absence of biochemical or enzymatic testing results, identification of biallelic
If the diagnosis cannot be established by molecular genetic testing, the findings of reduced URO-synthase activity in erythrocytes and markedly elevated urinary or erythrocyte uroporphyrin and coproporphyrin I isomers (
Identification of a hemizygous
Molecular genetic testing approaches can include
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Congenital Erythropoietic Porphyria
CEP = congenital erythropoietic porphyria
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Two gross deletions, two gross duplications, and one complex rearrangement have been reported [
A
• Nonimmune hydrops fetalis
• Signs of congenital erythropoietic porphyria
• Pink-to-dark red discoloration of the urine (pink or dark red urine-stained diapers are often the first sign in infants)
• Hemolytic anemia
• Severe cutaneous photosensitivity with onset usually in infancy or early childhood
• Blisters and vesicles in light-exposed areas, which are prone to rupture and infection
• Scarring and deformities (photomutilation) of digits and facial features, caused by recurrent blistering, infections, and bone resorption
• In light-exposed areas: friable skin, skin thickening, hypo- and hyperpigmentation
• Reddish-brown discoloration of teeth (fluoresce on exposure to long-wave ultraviolet light), also called erythrodontia
• Corneal ulcers and scarring
• Hypertrichosis of the face and extremities
• Pink-to-dark red discoloration of the urine (pink or dark red urine-stained diapers are often the first sign in infants)
• Hemolytic anemia
• Severe cutaneous photosensitivity with onset usually in infancy or early childhood
• Blisters and vesicles in light-exposed areas, which are prone to rupture and infection
• Scarring and deformities (photomutilation) of digits and facial features, caused by recurrent blistering, infections, and bone resorption
• In light-exposed areas: friable skin, skin thickening, hypo- and hyperpigmentation
• Reddish-brown discoloration of teeth (fluoresce on exposure to long-wave ultraviolet light), also called erythrodontia
• Corneal ulcers and scarring
• Hypertrichosis of the face and extremities
• Pink-to-dark red discoloration of the urine (pink or dark red urine-stained diapers are often the first sign in infants)
• Hemolytic anemia
• Severe cutaneous photosensitivity with onset usually in infancy or early childhood
• Blisters and vesicles in light-exposed areas, which are prone to rupture and infection
• Scarring and deformities (photomutilation) of digits and facial features, caused by recurrent blistering, infections, and bone resorption
• In light-exposed areas: friable skin, skin thickening, hypo- and hyperpigmentation
• Reddish-brown discoloration of teeth (fluoresce on exposure to long-wave ultraviolet light), also called erythrodontia
• Corneal ulcers and scarring
• Hypertrichosis of the face and extremities
• In the absence of biochemical or enzymatic testing results, identification of biallelic
• If the diagnosis cannot be established by molecular genetic testing, the findings of reduced URO-synthase activity in erythrocytes and markedly elevated urinary or erythrocyte uroporphyrin and coproporphyrin I isomers (
• Identification of a hemizygous
## Suggestive Findings
Congenital erythropoietic porphyria (CEP)
Nonimmune hydrops fetalis
Signs of congenital erythropoietic porphyria
Pink-to-dark red discoloration of the urine (pink or dark red urine-stained diapers are often the first sign in infants)
Hemolytic anemia
Severe cutaneous photosensitivity with onset usually in infancy or early childhood
Blisters and vesicles in light-exposed areas, which are prone to rupture and infection
Scarring and deformities (photomutilation) of digits and facial features, caused by recurrent blistering, infections, and bone resorption
In light-exposed areas: friable skin, skin thickening, hypo- and hyperpigmentation
Reddish-brown discoloration of teeth (fluoresce on exposure to long-wave ultraviolet light), also called erythrodontia
Corneal ulcers and scarring
Hypertrichosis of the face and extremities
Biochemical Characteristics of Congenital Erythropoietic Porphyria
↑ = markedly elevated
The deficient activity of uroporphyrinogen III synthase EC 4.2.1.75, encoded by
The assay for the enzyme uroporphyrinogen III synthase is available on a clinical basis and can be used to establish the diagnosis of congenital erythropoietic porphyria.
Amniotic fluid appears red to dark brown. Prenatal diagnosis is also possible by demonstrating markedly deficient URO-synthase activity in cultured amniotic cells or chorionic villi cells [
• Nonimmune hydrops fetalis
• Signs of congenital erythropoietic porphyria
• Pink-to-dark red discoloration of the urine (pink or dark red urine-stained diapers are often the first sign in infants)
• Hemolytic anemia
• Severe cutaneous photosensitivity with onset usually in infancy or early childhood
• Blisters and vesicles in light-exposed areas, which are prone to rupture and infection
• Scarring and deformities (photomutilation) of digits and facial features, caused by recurrent blistering, infections, and bone resorption
• In light-exposed areas: friable skin, skin thickening, hypo- and hyperpigmentation
• Reddish-brown discoloration of teeth (fluoresce on exposure to long-wave ultraviolet light), also called erythrodontia
• Corneal ulcers and scarring
• Hypertrichosis of the face and extremities
• Pink-to-dark red discoloration of the urine (pink or dark red urine-stained diapers are often the first sign in infants)
• Hemolytic anemia
• Severe cutaneous photosensitivity with onset usually in infancy or early childhood
• Blisters and vesicles in light-exposed areas, which are prone to rupture and infection
• Scarring and deformities (photomutilation) of digits and facial features, caused by recurrent blistering, infections, and bone resorption
• In light-exposed areas: friable skin, skin thickening, hypo- and hyperpigmentation
• Reddish-brown discoloration of teeth (fluoresce on exposure to long-wave ultraviolet light), also called erythrodontia
• Corneal ulcers and scarring
• Hypertrichosis of the face and extremities
• Pink-to-dark red discoloration of the urine (pink or dark red urine-stained diapers are often the first sign in infants)
• Hemolytic anemia
• Severe cutaneous photosensitivity with onset usually in infancy or early childhood
• Blisters and vesicles in light-exposed areas, which are prone to rupture and infection
• Scarring and deformities (photomutilation) of digits and facial features, caused by recurrent blistering, infections, and bone resorption
• In light-exposed areas: friable skin, skin thickening, hypo- and hyperpigmentation
• Reddish-brown discoloration of teeth (fluoresce on exposure to long-wave ultraviolet light), also called erythrodontia
• Corneal ulcers and scarring
• Hypertrichosis of the face and extremities
## Establishing the Diagnosis
The diagnosis of CEP
Note:
In the absence of biochemical or enzymatic testing results, identification of biallelic
If the diagnosis cannot be established by molecular genetic testing, the findings of reduced URO-synthase activity in erythrocytes and markedly elevated urinary or erythrocyte uroporphyrin and coproporphyrin I isomers (
Identification of a hemizygous
Molecular genetic testing approaches can include
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Congenital Erythropoietic Porphyria
CEP = congenital erythropoietic porphyria
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Two gross deletions, two gross duplications, and one complex rearrangement have been reported [
A
• In the absence of biochemical or enzymatic testing results, identification of biallelic
• If the diagnosis cannot be established by molecular genetic testing, the findings of reduced URO-synthase activity in erythrocytes and markedly elevated urinary or erythrocyte uroporphyrin and coproporphyrin I isomers (
• Identification of a hemizygous
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Congenital Erythropoietic Porphyria
CEP = congenital erythropoietic porphyria
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Two gross deletions, two gross duplications, and one complex rearrangement have been reported [
A
## Clinical Characteristics
Most individuals with congenital erythropoietic porphyria (CEP) experience severe cutaneous photosensitivity in early infancy; the first manifestation is often pink-to-dark red discoloration of the urine. Hemolytic anemia is common and can be mild to severe, requiring chronic erythrocyte transfusions in some. The phenotypic spectrum ranges from severe (nonimmune hydrops fetalis) to milder disease (adult-onset with isolated cutaneous manifestations) [
Photosensitivity symptoms are provoked mainly by visible light (400-410 nm Soret wavelength) and to a lesser degree by wavelengths in the long-wave UV region. Affected individuals are also sensitive to sunlight that passes through window glass that does not filter long-wave UVA or visible light as well as to light from artificial light sources.
Unlike the cutaneous manifestations in
Those with severe hemolytic anemia often require chronic erythrocyte transfusions, which decrease porphyrin production by suppressing erythropoiesis, but can lead to iron overload and other complications [
Secondary splenomegaly may develop as a consequence of hemolytic anemia. In addition to worsening the anemia, it can also result in leukopenia and thrombocytopenia, which may be associated with significant bleeding [
The genotype-phenotype correlations that have been established in CEP are largely determined by the amount of residual enzyme activity encoded by the specific pathogenic variants (
Homozygosity for the c.217T>C (p.Cys73Arg) variant results in less than 1% of normal URO-synthase activity and a severe phenotype that may manifest as nonimmune hydrops fetalis [
Compound heterozygosity for the c.217T>C (p.Cys73Arg) variant and a pathogenic variant that expresses a very low level of residual activity results in a severe or moderately severe phenotype.
In contrast, individuals with pathogenic variants expressing higher residual activities such as
Determination of genotype-phenotype correlations for erythroid-specific promoter pathogenic variants showed the following:
Compound heterozygotes with the
The
The two other known erythrocyte-specific promoter pathogenic variants,
Obsolete terms for CEP are erythropoietic porphyria, congenital porphyria, congenital hematoporphyria, and erythropoietic uroporphyria.
CEP is an ultra-rare disorder. To date, about 220 affected individuals have been reported.
• Homozygosity for the c.217T>C (p.Cys73Arg) variant results in less than 1% of normal URO-synthase activity and a severe phenotype that may manifest as nonimmune hydrops fetalis [
• Compound heterozygosity for the c.217T>C (p.Cys73Arg) variant and a pathogenic variant that expresses a very low level of residual activity results in a severe or moderately severe phenotype.
• Compound heterozygotes with the
• The
• The two other known erythrocyte-specific promoter pathogenic variants,
## Clinical Description
Most individuals with congenital erythropoietic porphyria (CEP) experience severe cutaneous photosensitivity in early infancy; the first manifestation is often pink-to-dark red discoloration of the urine. Hemolytic anemia is common and can be mild to severe, requiring chronic erythrocyte transfusions in some. The phenotypic spectrum ranges from severe (nonimmune hydrops fetalis) to milder disease (adult-onset with isolated cutaneous manifestations) [
Photosensitivity symptoms are provoked mainly by visible light (400-410 nm Soret wavelength) and to a lesser degree by wavelengths in the long-wave UV region. Affected individuals are also sensitive to sunlight that passes through window glass that does not filter long-wave UVA or visible light as well as to light from artificial light sources.
Unlike the cutaneous manifestations in
Those with severe hemolytic anemia often require chronic erythrocyte transfusions, which decrease porphyrin production by suppressing erythropoiesis, but can lead to iron overload and other complications [
Secondary splenomegaly may develop as a consequence of hemolytic anemia. In addition to worsening the anemia, it can also result in leukopenia and thrombocytopenia, which may be associated with significant bleeding [
## Genotype-Phenotype Correlations
The genotype-phenotype correlations that have been established in CEP are largely determined by the amount of residual enzyme activity encoded by the specific pathogenic variants (
Homozygosity for the c.217T>C (p.Cys73Arg) variant results in less than 1% of normal URO-synthase activity and a severe phenotype that may manifest as nonimmune hydrops fetalis [
Compound heterozygosity for the c.217T>C (p.Cys73Arg) variant and a pathogenic variant that expresses a very low level of residual activity results in a severe or moderately severe phenotype.
In contrast, individuals with pathogenic variants expressing higher residual activities such as
Determination of genotype-phenotype correlations for erythroid-specific promoter pathogenic variants showed the following:
Compound heterozygotes with the
The
The two other known erythrocyte-specific promoter pathogenic variants,
• Homozygosity for the c.217T>C (p.Cys73Arg) variant results in less than 1% of normal URO-synthase activity and a severe phenotype that may manifest as nonimmune hydrops fetalis [
• Compound heterozygosity for the c.217T>C (p.Cys73Arg) variant and a pathogenic variant that expresses a very low level of residual activity results in a severe or moderately severe phenotype.
• Compound heterozygotes with the
• The
• The two other known erythrocyte-specific promoter pathogenic variants,
## Nomenclature
Obsolete terms for CEP are erythropoietic porphyria, congenital porphyria, congenital hematoporphyria, and erythropoietic uroporphyria.
## Prevalence
CEP is an ultra-rare disorder. To date, about 220 affected individuals have been reported.
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
See
Disorders to Consider in the Differential Diagnosis of Congenital Erythropoietic Porphyria
Cutaneous photosensitivity w/blistering & friability of skin in sun-exposed areas
Facial hypertrichosis
Discolored urine
Usually manifests in adulthood
Distinct biochemical porphyrin profile
Phenotype similar to PCT
Manifests in early childhood
Discolored urine
Photosensitivity
Distinct biochemical porphyrin profile
Developmental delay (in some)
Acute (hepatic) porphyria
Acute attacks of abdominal or generalized pain; can be assoc w/neurologic symptoms
Incompletely penetrant in absence of environmental inducers
Usually manifests after puberty
Fragility of skin → nonscarring blisters caused by little/no trauma
Major & minor subtypes share common feature of blistering above dermal-epidermal junction at the ultrastructural level.
Fragility of skin & mucous membranes, manifest by blistering w/little or no trauma
Herlitz JEB (classic severe form): blisters present at birth or become apparent in neonatal period
Non-Herlitz JEB: may be mild w/blistering localized to hands, feet, knees, elbows
Blisters affecting whole body may be present in neonatal period.
Oral involvement
Corneal erosions
Esophageal erosions
Severe nutritional deficiency & secondary problems
"Mitten" hands & feet
>90% lifetime risk of aggressive squamous cell carcinoma
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
80% of persons with porphyria cutanea tarda (PCT) have type I PCT (also referred to as acquired or "sporadic" PCT because it is not known to be associated with an inherited genetic alteration). Type I PCT is characterized by normal URO-decarboxylase activity systemically when affected individuals are asymptomatic. Inhibition of the enzyme activity resulting in PCT can be caused by excessive alcohol intake, hemochromatosis, viral hepatitis (mostly hepatitis C), HIV infection, certain medications, and environmental exposures such as aromatic polyhalogenated hepatotoxins. Treatment consists of eliminating or treating the underlying cause and, if symptoms persist, frequent phlebotomies or therapy with oral low-dose hydroxychloroquine.
Affected individuals had normal erythrocyte URO-synthase activity. Presumably, the CEP-like manifestations resulted from genetic or functional changes associated with the bone marrow disorder.
EBS caused by pathogenic variants in
• Cutaneous photosensitivity w/blistering & friability of skin in sun-exposed areas
• Facial hypertrichosis
• Discolored urine
• Usually manifests in adulthood
• Distinct biochemical porphyrin profile
• Phenotype similar to PCT
• Manifests in early childhood
• Discolored urine
• Photosensitivity
• Distinct biochemical porphyrin profile
• Developmental delay (in some)
• Acute (hepatic) porphyria
• Acute attacks of abdominal or generalized pain; can be assoc w/neurologic symptoms
• Incompletely penetrant in absence of environmental inducers
• Usually manifests after puberty
• Fragility of skin → nonscarring blisters caused by little/no trauma
• Major & minor subtypes share common feature of blistering above dermal-epidermal junction at the ultrastructural level.
• Fragility of skin & mucous membranes, manifest by blistering w/little or no trauma
• Herlitz JEB (classic severe form): blisters present at birth or become apparent in neonatal period
• Non-Herlitz JEB: may be mild w/blistering localized to hands, feet, knees, elbows
• Blisters affecting whole body may be present in neonatal period.
• Oral involvement
• Corneal erosions
• Esophageal erosions
• Severe nutritional deficiency & secondary problems
• "Mitten" hands & feet
• >90% lifetime risk of aggressive squamous cell carcinoma
## Management
A management algorithm for congenital erythropoietic porphyria (CEP) has been published [
To establish the extent of disease and needs in an individual diagnosed with congenital erythropoietic porphyria (CEP), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Hematologic indices including reticulocytes and bilirubin (to assess hemolysis) and iron profile (to assess iron storage)
Serum calcium and vitamin D concentrations; bone densitometry
Hepatic function tests, especially in transfusion-dependent individuals given the risk for liver disease due to iron storage
Dermatologic evaluation to assess photosensitivity, photomutilation, and secondary skin changes (thickening, hyper- or hypopigmentation, hypertrichosis)
Ophthalmologic evaluation for corneal ulcers and scarring and other ocular manifestations
Dental assessment for erythrodontia (reddish-brown color from porphyrin deposition)
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of CEP in order to facilitate medical and personal decision making
Currently the only effective treatment is prevention of blistering by avoidance of light exposure, including the long-wave ultraviolet sunlight that passes through window glass or light emitted by fluorescent sources:
Sun protection using protective clothing including long sleeves, gloves, and wide-brimmed hats
Protective window films for cars and windows at home as well as at school/work to prevent exposure to UV light
Replacement of LED and fluorescent lights with reddish incandescent bulbs or installation of filtering screens
Reflectant sunscreens containing zinc oxide or titanium dioxide. Note, however, that these may be cosmetically unacceptable and, in any case, do not replace strict avoidance of sun/light exposure.
Skin trauma should be avoided.
Wound care is essential to prevent infection of opened blisters. Antiseptic and topical/oral antibiotic treatment may be indicated to avoid progression to osteomyelitis and bone resorption with subsequent mutilation.
Surgical intervention may be indicated for severe mutilation (repair of microstomia, correction of ectropion, reconstruction of the nose).
Laser hair removal can be used to treat facial hypertrichosis.
Vitamin D supplementation is advised as affected individuals are predisposed to vitamin D insufficiency due to sun avoidance.
Immunization for hepatitis A and B is recommended.
Note: (1) Beta-carotene has been tried in some individuals but without significant benefit. (2) Phototherapy with narrowband ultraviolet B radiation did not show any benefit.
Avoidance of damage to the eyelids and cornea by wearing wraparound sunglasses
Topical antibiotics for corneal ulcers, scleritis, and blepharitis
Artificial tears and lubricants to help prevent dry eyes in those with ectropion
Corrective surgery of eyelids to help protect the cornea from injury in those with ectropion [
Consider frozen matched-erythrocyte transfusions when hemolysis is significant, or bone marrow transplantation
Chronic transfusions (every 2-4 weeks) with a target hematocrit greater than 35% can suppress erythropoiesis and decrease porphyrin production, which reduces porphyrin levels and photosensitivity [
Note: In those who receive frequent transfusions, the body iron burden can be reduced with parenteral or oral chelators [
Experimental induction of iron deficiency either using treatment with iron chelators or via phlebotomies improved photosensitivity and hemolysis in a few affected individuals [
Note: Although oral charcoal and cholestyramine were thought to increase fecal loss of porphyrins, a clear clinical benefit has not been shown [
The age of children with CEP receiving BMT ranges from younger than one year to 13 years [
Monitor the following:
Hematologic indices including iron profile, reticulocyte count, and bilirubin to assess hemolysis every six months
Note: Individuals receiving transfusion therapy need closer monitoring.
Iron profile on a regular basis to assess for iron overload for those who are transfusion dependent
Hepatic function every six to twelve months
Vitamin D 25-OH levels in all individuals whether or not they are receiving vitamin D supplements
The following are appropriate:
Avoidance of sunlight and UV light
In individuals with hepatic dysfunction, avoidance of drugs that may induce cholestasis (e.g., estrogens)
In individuals undergoing surgeries, use of protective filters for artificial lights in the operating room to prevent phototoxic damage [
It is appropriate to evaluate at-risk sibs as newborns or infants in order to identify as early as possible those who would benefit from early intervention (no phototherapy, strict sun protection) and future monitoring for signs of hemolytic anemia. Evaluations include:
Molecular genetic testing if the pathogenic variant(s) in the family are known;
Biochemical testing for urinary or erythrocyte uroporphyrin I and coproporphyrin I isomer elevation if the pathogenic variants in the family are not known.
See
Successful pregnancies in women with CEP resulting in healthy and unaffected children have been described [
Protective filters for artificial lights should be used in the delivery/operating room to prevent phototoxic damage to the mother during delivery [
Although there are no clinical trials at the present time, therapeutic approaches under investigation include phlebotomy or iron chelation strategies to reduce the hemolysis and decrease the accumulated porphyrins and, thus, photosensitivity [
A murine CEP model is being used to investigate pharmacologic chaperone therapy (i.e., administration of small-molecule drugs to enhance the residual activity of mutated enzymes that have low activities or are unstable). Specifically, use of the antimicrobial agent ciclopirox as a chaperone-stabilized UROIII-synthase and reversed CEP-related findings such as abnormal URO I levels in the blood, splenomegaly, and liver porphyrins [
Search
• Hematologic indices including reticulocytes and bilirubin (to assess hemolysis) and iron profile (to assess iron storage)
• Serum calcium and vitamin D concentrations; bone densitometry
• Hepatic function tests, especially in transfusion-dependent individuals given the risk for liver disease due to iron storage
• Dermatologic evaluation to assess photosensitivity, photomutilation, and secondary skin changes (thickening, hyper- or hypopigmentation, hypertrichosis)
• Ophthalmologic evaluation for corneal ulcers and scarring and other ocular manifestations
• Dental assessment for erythrodontia (reddish-brown color from porphyrin deposition)
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of CEP in order to facilitate medical and personal decision making
• Sun protection using protective clothing including long sleeves, gloves, and wide-brimmed hats
• Protective window films for cars and windows at home as well as at school/work to prevent exposure to UV light
• Replacement of LED and fluorescent lights with reddish incandescent bulbs or installation of filtering screens
• Reflectant sunscreens containing zinc oxide or titanium dioxide. Note, however, that these may be cosmetically unacceptable and, in any case, do not replace strict avoidance of sun/light exposure.
• Avoidance of damage to the eyelids and cornea by wearing wraparound sunglasses
• Topical antibiotics for corneal ulcers, scleritis, and blepharitis
• Artificial tears and lubricants to help prevent dry eyes in those with ectropion
• Corrective surgery of eyelids to help protect the cornea from injury in those with ectropion [
• Consider frozen matched-erythrocyte transfusions when hemolysis is significant, or bone marrow transplantation
• Chronic transfusions (every 2-4 weeks) with a target hematocrit greater than 35% can suppress erythropoiesis and decrease porphyrin production, which reduces porphyrin levels and photosensitivity [
• Note: In those who receive frequent transfusions, the body iron burden can be reduced with parenteral or oral chelators [
• Experimental induction of iron deficiency either using treatment with iron chelators or via phlebotomies improved photosensitivity and hemolysis in a few affected individuals [
• Hematologic indices including iron profile, reticulocyte count, and bilirubin to assess hemolysis every six months
• Note: Individuals receiving transfusion therapy need closer monitoring.
• Iron profile on a regular basis to assess for iron overload for those who are transfusion dependent
• Hepatic function every six to twelve months
• Vitamin D 25-OH levels in all individuals whether or not they are receiving vitamin D supplements
• Avoidance of sunlight and UV light
• In individuals with hepatic dysfunction, avoidance of drugs that may induce cholestasis (e.g., estrogens)
• In individuals undergoing surgeries, use of protective filters for artificial lights in the operating room to prevent phototoxic damage [
• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Biochemical testing for urinary or erythrocyte uroporphyrin I and coproporphyrin I isomer elevation if the pathogenic variants in the family are not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with congenital erythropoietic porphyria (CEP), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Hematologic indices including reticulocytes and bilirubin (to assess hemolysis) and iron profile (to assess iron storage)
Serum calcium and vitamin D concentrations; bone densitometry
Hepatic function tests, especially in transfusion-dependent individuals given the risk for liver disease due to iron storage
Dermatologic evaluation to assess photosensitivity, photomutilation, and secondary skin changes (thickening, hyper- or hypopigmentation, hypertrichosis)
Ophthalmologic evaluation for corneal ulcers and scarring and other ocular manifestations
Dental assessment for erythrodontia (reddish-brown color from porphyrin deposition)
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of CEP in order to facilitate medical and personal decision making
• Hematologic indices including reticulocytes and bilirubin (to assess hemolysis) and iron profile (to assess iron storage)
• Serum calcium and vitamin D concentrations; bone densitometry
• Hepatic function tests, especially in transfusion-dependent individuals given the risk for liver disease due to iron storage
• Dermatologic evaluation to assess photosensitivity, photomutilation, and secondary skin changes (thickening, hyper- or hypopigmentation, hypertrichosis)
• Ophthalmologic evaluation for corneal ulcers and scarring and other ocular manifestations
• Dental assessment for erythrodontia (reddish-brown color from porphyrin deposition)
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of CEP in order to facilitate medical and personal decision making
## Treatment of Manifestations
Currently the only effective treatment is prevention of blistering by avoidance of light exposure, including the long-wave ultraviolet sunlight that passes through window glass or light emitted by fluorescent sources:
Sun protection using protective clothing including long sleeves, gloves, and wide-brimmed hats
Protective window films for cars and windows at home as well as at school/work to prevent exposure to UV light
Replacement of LED and fluorescent lights with reddish incandescent bulbs or installation of filtering screens
Reflectant sunscreens containing zinc oxide or titanium dioxide. Note, however, that these may be cosmetically unacceptable and, in any case, do not replace strict avoidance of sun/light exposure.
Skin trauma should be avoided.
Wound care is essential to prevent infection of opened blisters. Antiseptic and topical/oral antibiotic treatment may be indicated to avoid progression to osteomyelitis and bone resorption with subsequent mutilation.
Surgical intervention may be indicated for severe mutilation (repair of microstomia, correction of ectropion, reconstruction of the nose).
Laser hair removal can be used to treat facial hypertrichosis.
Vitamin D supplementation is advised as affected individuals are predisposed to vitamin D insufficiency due to sun avoidance.
Immunization for hepatitis A and B is recommended.
Note: (1) Beta-carotene has been tried in some individuals but without significant benefit. (2) Phototherapy with narrowband ultraviolet B radiation did not show any benefit.
Avoidance of damage to the eyelids and cornea by wearing wraparound sunglasses
Topical antibiotics for corneal ulcers, scleritis, and blepharitis
Artificial tears and lubricants to help prevent dry eyes in those with ectropion
Corrective surgery of eyelids to help protect the cornea from injury in those with ectropion [
Consider frozen matched-erythrocyte transfusions when hemolysis is significant, or bone marrow transplantation
Chronic transfusions (every 2-4 weeks) with a target hematocrit greater than 35% can suppress erythropoiesis and decrease porphyrin production, which reduces porphyrin levels and photosensitivity [
Note: In those who receive frequent transfusions, the body iron burden can be reduced with parenteral or oral chelators [
Experimental induction of iron deficiency either using treatment with iron chelators or via phlebotomies improved photosensitivity and hemolysis in a few affected individuals [
Note: Although oral charcoal and cholestyramine were thought to increase fecal loss of porphyrins, a clear clinical benefit has not been shown [
The age of children with CEP receiving BMT ranges from younger than one year to 13 years [
• Sun protection using protective clothing including long sleeves, gloves, and wide-brimmed hats
• Protective window films for cars and windows at home as well as at school/work to prevent exposure to UV light
• Replacement of LED and fluorescent lights with reddish incandescent bulbs or installation of filtering screens
• Reflectant sunscreens containing zinc oxide or titanium dioxide. Note, however, that these may be cosmetically unacceptable and, in any case, do not replace strict avoidance of sun/light exposure.
• Avoidance of damage to the eyelids and cornea by wearing wraparound sunglasses
• Topical antibiotics for corneal ulcers, scleritis, and blepharitis
• Artificial tears and lubricants to help prevent dry eyes in those with ectropion
• Corrective surgery of eyelids to help protect the cornea from injury in those with ectropion [
• Consider frozen matched-erythrocyte transfusions when hemolysis is significant, or bone marrow transplantation
• Chronic transfusions (every 2-4 weeks) with a target hematocrit greater than 35% can suppress erythropoiesis and decrease porphyrin production, which reduces porphyrin levels and photosensitivity [
• Note: In those who receive frequent transfusions, the body iron burden can be reduced with parenteral or oral chelators [
• Experimental induction of iron deficiency either using treatment with iron chelators or via phlebotomies improved photosensitivity and hemolysis in a few affected individuals [
## Surveillance
Monitor the following:
Hematologic indices including iron profile, reticulocyte count, and bilirubin to assess hemolysis every six months
Note: Individuals receiving transfusion therapy need closer monitoring.
Iron profile on a regular basis to assess for iron overload for those who are transfusion dependent
Hepatic function every six to twelve months
Vitamin D 25-OH levels in all individuals whether or not they are receiving vitamin D supplements
• Hematologic indices including iron profile, reticulocyte count, and bilirubin to assess hemolysis every six months
• Note: Individuals receiving transfusion therapy need closer monitoring.
• Iron profile on a regular basis to assess for iron overload for those who are transfusion dependent
• Hepatic function every six to twelve months
• Vitamin D 25-OH levels in all individuals whether or not they are receiving vitamin D supplements
## Agents/Circumstances to Avoid
The following are appropriate:
Avoidance of sunlight and UV light
In individuals with hepatic dysfunction, avoidance of drugs that may induce cholestasis (e.g., estrogens)
In individuals undergoing surgeries, use of protective filters for artificial lights in the operating room to prevent phototoxic damage [
• Avoidance of sunlight and UV light
• In individuals with hepatic dysfunction, avoidance of drugs that may induce cholestasis (e.g., estrogens)
• In individuals undergoing surgeries, use of protective filters for artificial lights in the operating room to prevent phototoxic damage [
## Evaluation of Relatives at Risk
It is appropriate to evaluate at-risk sibs as newborns or infants in order to identify as early as possible those who would benefit from early intervention (no phototherapy, strict sun protection) and future monitoring for signs of hemolytic anemia. Evaluations include:
Molecular genetic testing if the pathogenic variant(s) in the family are known;
Biochemical testing for urinary or erythrocyte uroporphyrin I and coproporphyrin I isomer elevation if the pathogenic variants in the family are not known.
See
• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Biochemical testing for urinary or erythrocyte uroporphyrin I and coproporphyrin I isomer elevation if the pathogenic variants in the family are not known.
## Pregnancy Management
Successful pregnancies in women with CEP resulting in healthy and unaffected children have been described [
Protective filters for artificial lights should be used in the delivery/operating room to prevent phototoxic damage to the mother during delivery [
## Therapies Under Investigation
Although there are no clinical trials at the present time, therapeutic approaches under investigation include phlebotomy or iron chelation strategies to reduce the hemolysis and decrease the accumulated porphyrins and, thus, photosensitivity [
A murine CEP model is being used to investigate pharmacologic chaperone therapy (i.e., administration of small-molecule drugs to enhance the residual activity of mutated enzymes that have low activities or are unstable). Specifically, use of the antimicrobial agent ciclopirox as a chaperone-stabilized UROIII-synthase and reversed CEP-related findings such as abnormal URO I levels in the blood, splenomegaly, and liver porphyrins [
Search
## Genetic Counseling
Congenital erythropoietic porphyria (CEP) caused by biallelic
CEP caused by a hemizygous
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The father of an affected male will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier, the affected male may have a
The frequency of
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
If the mother of the proband has a
Males who inherit the pathogenic variant will be affected;
Females who inherit the pathogenic variant will be heterozygotes and can be either asymptomatic or have a milder phenotype with predominantly hematologic and/or cutaneous abnormalities due to skewed X-chromosome inactivation [
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
Note: Molecular genetic testing may be able to identify the family member in whom a
Identification of female heterozygotes requires either prior identification of the
Note: Females who are heterozygous for this X-linked disorder will be either asymptomatic or have a milder phenotype with predominantly hematologic abnormalities due to skewed X-chromosome inactivation [
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Note: It is assumed that an elevation of uroporphyrin I and coproporphyrin I concentrations in amniotic fluid is also present in
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier, the affected male may have a
• The frequency of
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• If the mother of the proband has a
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygotes and can be either asymptomatic or have a milder phenotype with predominantly hematologic and/or cutaneous abnormalities due to skewed X-chromosome inactivation [
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygotes and can be either asymptomatic or have a milder phenotype with predominantly hematologic and/or cutaneous abnormalities due to skewed X-chromosome inactivation [
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygotes and can be either asymptomatic or have a milder phenotype with predominantly hematologic and/or cutaneous abnormalities due to skewed X-chromosome inactivation [
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Congenital erythropoietic porphyria (CEP) caused by biallelic
CEP caused by a hemizygous
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## X-Linked Inheritance – Risk to Family Members
The father of an affected male will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier, the affected male may have a
The frequency of
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
If the mother of the proband has a
Males who inherit the pathogenic variant will be affected;
Females who inherit the pathogenic variant will be heterozygotes and can be either asymptomatic or have a milder phenotype with predominantly hematologic and/or cutaneous abnormalities due to skewed X-chromosome inactivation [
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
Note: Molecular genetic testing may be able to identify the family member in whom a
Identification of female heterozygotes requires either prior identification of the
Note: Females who are heterozygous for this X-linked disorder will be either asymptomatic or have a milder phenotype with predominantly hematologic abnormalities due to skewed X-chromosome inactivation [
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier, the affected male may have a
• The frequency of
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• If the mother of the proband has a
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygotes and can be either asymptomatic or have a milder phenotype with predominantly hematologic and/or cutaneous abnormalities due to skewed X-chromosome inactivation [
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygotes and can be either asymptomatic or have a milder phenotype with predominantly hematologic and/or cutaneous abnormalities due to skewed X-chromosome inactivation [
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygotes and can be either asymptomatic or have a milder phenotype with predominantly hematologic and/or cutaneous abnormalities due to skewed X-chromosome inactivation [
## Heterozygote Detection
Identification of female heterozygotes requires either prior identification of the
Note: Females who are heterozygous for this X-linked disorder will be either asymptomatic or have a milder phenotype with predominantly hematologic abnormalities due to skewed X-chromosome inactivation [
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Note: It is assumed that an elevation of uroporphyrin I and coproporphyrin I concentrations in amniotic fluid is also present in
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
American Porphyria Foundation
South Africa
Sweden
•
•
•
•
•
•
•
• Canada
•
•
• American Porphyria Foundation
•
•
•
•
•
•
• South Africa
•
•
• Sweden
•
## Molecular Genetics
Congenital Erythropoietic Porphyria: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Congenital Erythropoietic Porphyria (
CEP results from markedly decreased (but not absent) URO-synthase activity (<1% to ~10% of normal). When expressed in vitro, the residual enzyme activity of individual pathogenic variants ranges from less than 1.0% to approximately 35% [
URO-synthase, the fourth enzyme in the heme biosynthesis pathway, normally converts hydroxymethylbilane (HMB) to uroporphyrinogen III. When URO-synthase activity is deficient, HMB accumulates primarily in the erythron and is non-enzymatically converted to uroporphyrinogen I. Decarboxylation of uroporphyrinogen I by URO-decarboxylase leads to formation of hepta-, hexa-, and pentacarboxyl porphyrinogen I isomers, with coproporphyrinogen I being the final product. Since coproporphyrinogen oxidase is specific for the III isomer, coproporphyrinogen I cannot be further metabolized to heme and is therefore non-physiologic. Isomer I porphyrinogens are pathogenic when they accumulate in large amounts and are auto-oxidized to their corresponding porphyrins [
Porphyrinogen I isomers accumulate in bone marrow erythroid precursors; erythrocytes undergo auto-oxidation, which causes damage of the erythrocytes and hemolysis. Porphyrin I isomers are released into the circulation and deposited in skin, bone, and other tissues as well as excreted in urine and feces [
Urinary porphyrin excretion is markedly increased (100-1,000x normal) and consists mainly of uroporphyrin I and coproporphyrin I, with lesser increases in hepta-, hexa-, and pentacarboxyl porphyrin isomers [
Cutaneous photosensitivity with blistering and increased friability occurs because the porphyrins deposited in the skin are photocatalytic and cytotoxic compounds [
The bone marrow contains much larger amounts of porphyrins (mostly uroporphyrin I and coproporphyrin I) than other tissues and hemolysis is almost always present in persons with CEP. Whether it is accompanied by anemia depends on whether erythroid hyperplasia is sufficient to compensate for the increased rate of erythrocyte destruction, which may vary over time. More severely affected individuals are transfusion dependent.
Splenomegaly usually develops secondary to hemolysis and can also lead to thrombocytopenia and leukopenia. In addition, porphyrin deposition also occurs in the spleen and to a lesser degree in the liver.
Congenital Erythropoietic Porphyria: Gene-Specific Laboratory Considerations
Congenital Erythropoietic Porphyria: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
See
## Molecular Pathogenesis
CEP results from markedly decreased (but not absent) URO-synthase activity (<1% to ~10% of normal). When expressed in vitro, the residual enzyme activity of individual pathogenic variants ranges from less than 1.0% to approximately 35% [
URO-synthase, the fourth enzyme in the heme biosynthesis pathway, normally converts hydroxymethylbilane (HMB) to uroporphyrinogen III. When URO-synthase activity is deficient, HMB accumulates primarily in the erythron and is non-enzymatically converted to uroporphyrinogen I. Decarboxylation of uroporphyrinogen I by URO-decarboxylase leads to formation of hepta-, hexa-, and pentacarboxyl porphyrinogen I isomers, with coproporphyrinogen I being the final product. Since coproporphyrinogen oxidase is specific for the III isomer, coproporphyrinogen I cannot be further metabolized to heme and is therefore non-physiologic. Isomer I porphyrinogens are pathogenic when they accumulate in large amounts and are auto-oxidized to their corresponding porphyrins [
Porphyrinogen I isomers accumulate in bone marrow erythroid precursors; erythrocytes undergo auto-oxidation, which causes damage of the erythrocytes and hemolysis. Porphyrin I isomers are released into the circulation and deposited in skin, bone, and other tissues as well as excreted in urine and feces [
Urinary porphyrin excretion is markedly increased (100-1,000x normal) and consists mainly of uroporphyrin I and coproporphyrin I, with lesser increases in hepta-, hexa-, and pentacarboxyl porphyrin isomers [
Cutaneous photosensitivity with blistering and increased friability occurs because the porphyrins deposited in the skin are photocatalytic and cytotoxic compounds [
The bone marrow contains much larger amounts of porphyrins (mostly uroporphyrin I and coproporphyrin I) than other tissues and hemolysis is almost always present in persons with CEP. Whether it is accompanied by anemia depends on whether erythroid hyperplasia is sufficient to compensate for the increased rate of erythrocyte destruction, which may vary over time. More severely affected individuals are transfusion dependent.
Splenomegaly usually develops secondary to hemolysis and can also lead to thrombocytopenia and leukopenia. In addition, porphyrin deposition also occurs in the spleen and to a lesser degree in the liver.
Congenital Erythropoietic Porphyria: Gene-Specific Laboratory Considerations
Congenital Erythropoietic Porphyria: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
See
## Chapter Notes
The
15 April 2021 (bp) Comprehensive update posted live
7 April 2016 (bp) Comprehensive update posted live
12 September 2013 (me) Review posted live
5 March 2013 (ae) Original submission
• 15 April 2021 (bp) Comprehensive update posted live
• 7 April 2016 (bp) Comprehensive update posted live
• 12 September 2013 (me) Review posted live
• 5 March 2013 (ae) Original submission
## Acknowledgments
The
## Revision History
15 April 2021 (bp) Comprehensive update posted live
7 April 2016 (bp) Comprehensive update posted live
12 September 2013 (me) Review posted live
5 March 2013 (ae) Original submission
• 15 April 2021 (bp) Comprehensive update posted live
• 7 April 2016 (bp) Comprehensive update posted live
• 12 September 2013 (me) Review posted live
• 5 March 2013 (ae) Original submission
## References
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"J Frank, X Wang, HM Lam, VM Aita, FK Jugert, G Goerz, HF Merk, MB Poh-Fitzpatrick, AM Christiano. C73R is a hotspot mutation in the uroporphyrinogen III synthase gene in congenital erythropoietic porphyria.. Ann Hum Genet. 1998;62:225-30",
"C Fritsch, K Bolsen, T Ruzicka, G. Goerz. Congenital erythropoietic porphyria.. J Am Acad Dermatol. 1997;36:594-610",
"C Ged, H Mégarbané, E Chouery, M Lalanne, A Mégarbané, H. de Verneuil. Congenital erythropoietic porphyria: report of a novel mutation with absence of clinical manifestations in a homozygous mutant sibling.. J Invest Dermatol. 2004;123:589-91",
"N Hallai, A Anstey, S Mendelsohn, J Williams, G Evans-Jones, S Malick, MN Badminton. Pregnancy in a patient with congenital erythropoietic porphyria.. N Engl J Med. 2007;357:622-3",
"FA Harada, TA Shwayder, RJ Desnick, HW Lim. Treatment of severe congenital erythropoietic porphyria by bone marrow transplantation.. J Am Acad Dermatol. 2001;45:279-82",
"RP Katugampola, AV Anstey, AY Finlay, S Whatley, J Woolf, N Mason, JC Deybach, H Puy, C Ged, H de Verneuil, S Hanneken, E Minder, X Schneider-Yin, MN Badminton. A management algorithm for congenital erythropoietic porphyria derived from a study of 29 cases.. Br J Dermatol. 2012a;167:888-900",
"RP Katugampola, MN Badminton, AY Finlay, S Whatley, J Woolf, N Mason, JC Deybach, H Puy, C Ged, H de Verneuil, S Hanneken, E Minder, X Schneider-Yin, AV Anstey. Congenital erythropoietic porphyria: a single-observer clinical study of 29 cases.. Br J Dermatol. 2012b;167:901-13",
"BM Kaufman, HR Vickers, J Rayne, TJ Ryan. Congenital erythropoietic porphyria. Report of a case.. Br J Dermatol. 1967;79:210-20",
"AP Kontos, D Ozog, C Bichakjian, HW Lim. Congenital erythropoietic porphyria associated with myelodysplasia presenting in a 72-year-old man: report of a case and review of the literature.. Br J Dermatol. 2003;148:160-4",
"A Laorr, A Greenspan. Severe osteopenia in congenital erythropoietic porphyria.. Can Assoc Radiol J. 1994;45:307-9",
"A Mirmiran, A Poli, C Ged, C Schmitt, T Lefebvre, H Manceau, R Daher, B Moulouel, K Peoc'h, S Simonin, JM Blouin, JC Deybach, G Nicolas, H Puy, E Richard, L Gouya. Phlebotomy as an efficient long-term treatment of congenital erythropoietic porphyria.. Haematologica. 2021;106:913-7",
"F Oguz, M Sidal, C Bayram, N Sansoy, N Hekim. Ocular involvement in two symptomatic congenital erythropoietic porphyria.. Eur J Pediatr. 1993;152:671-3",
"RW Pain, FW Welch, AJ Woodroffe, DA Handley, WH Lockwood. Erythropoietic uroporphyria of Gunther first presenting at 58 years with positive family studies.. Br Med J. 1975;3:621-3",
"JD Phillips, DP Steensma, MA Pulsipher, GJ Spangrude, JP Kushner. Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria.. Blood. 2007;109:2618-21",
"S Piomelli, MB Poh-Fitzpatrick, C Seaman, LM Skolnick, WE Berdon. Complete suppression of the symptoms of congenital erythropoietic porphyria by long-term treatment with high-level transfusions.. N Engl J Med. 1986;314:1029-31",
"MB Poh-Fitzpatrick. The erythropoietic porphyrias.. Dermatol Clin. 1986;4:291-6",
"RP Sarkany, SH Ibbotson, SD Whatley, CM Lawrence, P Gover, GJ Mufti, GM Murphy, GS Masters, MN Badminton, GH Elder. Erythropoietic uroporphyria associated with myeloid malignancy is likely distinct from autosomal recessive congenital erythropoietic porphyria.. J Invest Dermatol. 2011;131:1172-5",
"R Schmid, S Schwartz, RD Sundberg. Erythropoietic (congenital) porphyria: a rare abnormality of the normoblasts.. Blood. 1955;10:416-28",
"AA Shady, BR Colby, LF Cunha, KH Astrin, DF Bishop, RJ Desnick. Congenital erythropoietic porphyria: identification and expression of eight novel mutations in the uroporphyrinogen III synthase gene.. Br J Haematol. 2002;117:980-7",
"PH Shaw, AJ Mancini, JP McConnell, D Brown, M Kletzel. Treatment of congenital erythropoietic porphyria in children by allogeneic stem cell transplantation: a case report and review of the literature.. Bone Marrow Transplant. 2001;27:101-5",
"SS Siddique, LA Gonzalez-Gonzalez, P Thakuria, PY Chang, CS Foster. Scleral necrosis in a patient with congenital erythropoietic porphyria.. Cornea. 2011;30:97-9",
"C Solis, GI Aizencang, KH Astrin, DF Bishop, RJ Desnick. Uroporphyrinogen III synthase erythroid promoter mutations in adjacent GATA1 and CP2 elements cause congenital erythropoietic porphyria.. J Clin Invest. 2001;107:753-62",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"SM Taibjee, OE Stevenson, A Abdullah, CY Tan, P Darbyshire, C Moss, H Goodyear, A Heagerty, S Whatley, MN Badminton. Allogeneic bone marrow transplantation in a 7-year-old girl with congenital erythropoietic porphyria: a treatment dilemma.. Br J Dermatol. 2007;156:567-71",
"I Tezcan, W Xu, A Gurgey, M Tuncer, M Cetin, C Oner, S Yetgin, F Ersoy, G Aizencang, KH Astrin, RJ Desnick. Congenital erythropoietic porphyria successfully treated by allogeneic bone marrow transplantation.. Blood. 1998;92:4053-8",
"C Thomas, C Ged, Y Nordmann, H de Verneuil, I Pellier, A Fischer, S Blanche. Correction of congenital erythropoietic porphyria by bone marrow transplantation.. J Pediatr. 1996;129:453-6",
"PV Tishler, SH Winston. Rapid improvement in the chemical pathology of congenital erythropoietic porphyria with treatment with superactivated charcoal.. Methods Find Exp Clin Pharmacol. 1990;12:645-8",
"J To-Figueras, S Ducamp, J Clayton, C Badenas, C Delaby, C Ged, S Lyoumi, L Gouya, H de Verneuil, C Beaumont, GC Ferreira, JC Deybach, C Herrero, H Puy. ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria.. Blood. 2011;118:1443-51",
"P Urquiza, A Lain, A Sanz-Parra, J Moreno, G Bernardo-Seisdedos, P Dubus, E González, V Gutiérrez-de-Juan, S García, H Eraña, I San Juan, I Macías, F Ben Bdira, P Pluta, G Ortega, J Oyarzábal, R González-Muñiz, J Rodríguez-Cuesta, J Anguita, E Díez, JM Blouin, H de Verneuil, JM Mato, E Richard, JM Falcón-Pérez, J Castilla, O Millet. Repurposing ciclopirox as a pharmacological chaperone in a model of congenital erythropoietic porphyria.. Sci Transl Med. 2018;10",
"P Venkatesh, SP Garg, E Kumaran, HK Tewari. Congenital porphyria with necrotizing scleritis in a 9-year-old child.. Clin Experiment Ophthalmol. 2000;28:314-8",
"S Wahlin, N Srikanthan, B Hamre, P Harper, A Brun. Protection from phototoxic injury during surgery and endoscopy in erythropoietic protoporphyria.. Liver Transpl. 2008;14:1340-6",
"CA Warner, HW Yoo, AG Roberts, RJ Desnick. Congenital erythropoietic porphyria: identification and expression of exonic mutations in the uroporphyrinogen III synthase gene.. J Clin Invest. 1992;89:693-700",
"MJ Weston, DC Nicholson, CK Lim, KG Clark, A Macdonald, MA Henderson, R Williams. Congenital erythropoietic uroporphyria (Günther's disease) presenting in a middle aged man.. Int J Biochem. 1978;9:921-6",
"I Zix-Kieffer, B Langer, D Eyer, G Acar, E Racadot, G Schlaeder, F Oberlin, P Lutz. Successful cord blood stem cell transplantation for congenital erythropoietic porphyria (Gunther's disease).. Bone Marrow Transplant. 1996;18:217-20"
] |
12/9/2013
|
15/4/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
cetp-def
|
cetp-def
|
[
"Cholesteryl Ester Transfer Protein (CETP) Deficiency",
"Primary Hyperalphalipoproteinemia",
"Cholesteryl Ester Transfer Protein (CETP) Deficiency",
"Primary Hyperalphalipoproteinemia",
"Biallelic CETP-Related Hyperalphalipoproteinemia (HALP)",
"Heterozygous CETP-Related Hyperalphalipoproteinemia (HALP)",
"Cholesteryl ester transfer protein",
"CETP",
"CETP-Related Hyperalphalipoproteinemia"
] |
John R Burnett, Amanda J Hooper, Robert A Hegele
|
Summary The molecular diagnosis of biallelic Biallelic
|
Biallelic
Heterozygous
For other genetic causes of these phenotypes, see
• Biallelic
• Heterozygous
## Diagnosis
No consensus clinical diagnostic criteria for
Biallelic (homozygous or compound heterozygous)
Plasma total cholesterol level of 220-320 mg/dL (5.7-8.3 mmol/L)
HDL-C level of 100-250 mg/dL (2.6-6.5 mmol/L)
LDL-C level of 30-130 mg/dL (0.8-3.4 mmol/L)
Apolipoprotein (apo) A-I level of 150-280 mg/dL (1.5-2.8 g/L)
Apo B level of 30-80 mg/dL (0.3-0.8 g/L)
Heterozygous
Plasma total cholesterol level of 120-270 mg/dL (3.1-7.0 mmol/L)
HDL-C level of 50-100 mg/dL (1.3-2.6 mmol/L)
Apo A-I level of 110-230 mg/dL (1.1-2.3 g/L)
The molecular diagnosis of biallelic or heterozygous
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
When the laboratory findings suggest the diagnosis of
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
• Plasma total cholesterol level of 220-320 mg/dL (5.7-8.3 mmol/L)
• HDL-C level of 100-250 mg/dL (2.6-6.5 mmol/L)
• LDL-C level of 30-130 mg/dL (0.8-3.4 mmol/L)
• Apolipoprotein (apo) A-I level of 150-280 mg/dL (1.5-2.8 g/L)
• Apo B level of 30-80 mg/dL (0.3-0.8 g/L)
• Plasma total cholesterol level of 120-270 mg/dL (3.1-7.0 mmol/L)
• HDL-C level of 50-100 mg/dL (1.3-2.6 mmol/L)
• Apo A-I level of 110-230 mg/dL (1.1-2.3 g/L)
• For an introduction to multigene panels click
## Suggestive Findings
Biallelic (homozygous or compound heterozygous)
Plasma total cholesterol level of 220-320 mg/dL (5.7-8.3 mmol/L)
HDL-C level of 100-250 mg/dL (2.6-6.5 mmol/L)
LDL-C level of 30-130 mg/dL (0.8-3.4 mmol/L)
Apolipoprotein (apo) A-I level of 150-280 mg/dL (1.5-2.8 g/L)
Apo B level of 30-80 mg/dL (0.3-0.8 g/L)
Heterozygous
Plasma total cholesterol level of 120-270 mg/dL (3.1-7.0 mmol/L)
HDL-C level of 50-100 mg/dL (1.3-2.6 mmol/L)
Apo A-I level of 110-230 mg/dL (1.1-2.3 g/L)
• Plasma total cholesterol level of 220-320 mg/dL (5.7-8.3 mmol/L)
• HDL-C level of 100-250 mg/dL (2.6-6.5 mmol/L)
• LDL-C level of 30-130 mg/dL (0.8-3.4 mmol/L)
• Apolipoprotein (apo) A-I level of 150-280 mg/dL (1.5-2.8 g/L)
• Apo B level of 30-80 mg/dL (0.3-0.8 g/L)
• Plasma total cholesterol level of 120-270 mg/dL (3.1-7.0 mmol/L)
• HDL-C level of 50-100 mg/dL (1.3-2.6 mmol/L)
• Apo A-I level of 110-230 mg/dL (1.1-2.3 g/L)
## Establishing the Diagnosis
The molecular diagnosis of biallelic or heterozygous
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
When the laboratory findings suggest the diagnosis of
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
• For an introduction to multigene panels click
## Clinical Characteristics
To date, more than 1,000 individuals have been reported with biallelic or heterozygous pathogenic variants in
In
It is estimated that between 5% and 7% of individuals of Japanese ancestry are heterozygous for a pathogenic variant in
The milder p.Asp459Gly pathogenic variant is present in other East Asian populations and was identified in 4.5% of the Han Chinese population in Taiwan [
The
## Clinical Description
To date, more than 1,000 individuals have been reported with biallelic or heterozygous pathogenic variants in
## Genotype-Phenotype Correlations
In
## Prevalence
It is estimated that between 5% and 7% of individuals of Japanese ancestry are heterozygous for a pathogenic variant in
The milder p.Asp459Gly pathogenic variant is present in other East Asian populations and was identified in 4.5% of the Han Chinese population in Taiwan [
The
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Other genes associated with primary hyperalphalipoproteinemia (HALP) are listed in
Genes of Interest in the Differential Diagnosis of
Adapted from
apo = apolipoprotein; ASCVD = atherosclerotic cardiovascular disease; HDL-C = high-density lipoprotein cholesterol
## Management
No clinical practice guidelines for
To establish the extent of findings in an individual diagnosed with
Total cholesterol
HDL-C
LDL-C
Triglycerides
Apo A-I
Apo B
apo = apolipoprotein; HALP = hyperalphalipoproteinemia; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
To monitor affected individuals, the evaluations summarized in
See
Search
• Total cholesterol
• HDL-C
• LDL-C
• Triglycerides
• Apo A-I
• Apo B
## Evaluations Following Initial Diagnosis
To establish the extent of findings in an individual diagnosed with
Total cholesterol
HDL-C
LDL-C
Triglycerides
Apo A-I
Apo B
apo = apolipoprotein; HALP = hyperalphalipoproteinemia; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Total cholesterol
• HDL-C
• LDL-C
• Triglycerides
• Apo A-I
• Apo B
## Treatment of Manifestations
## Surveillance
To monitor affected individuals, the evaluations summarized in
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Biallelic
Note: Because markedly increased high-density lipoprotein cholesterol (HDL-C) is associated with biallelic
The parents of an individual with biallelic
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Individuals who are heterozygous for a
If both parents are known to be heterozygous for a
Individuals with heterozygous
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an individual with biallelic
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Individuals who are heterozygous for a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Individuals with heterozygous
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have
## Mode of Inheritance
Biallelic
Note: Because markedly increased high-density lipoprotein cholesterol (HDL-C) is associated with biallelic
## Risk to Family Members (Proband with Biallelic
The parents of an individual with biallelic
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Individuals who are heterozygous for a
If both parents are known to be heterozygous for a
Individuals with heterozygous
• The parents of an individual with biallelic
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Individuals who are heterozygous for a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Individuals with heterozygous
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
No specific resources for
## Molecular Genetics
CETP-Related Hyperalphalipoproteinemia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CETP-Related Hyperalphalipoproteinemia (
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions or was historically different due to changing nomenclature
## Molecular Pathogenesis
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions or was historically different due to changing nomenclature
## Chapter Notes
RAH is supported by the Jacob J Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Research Chair, and the Martha G Blackburn Chair in Cardiovascular Research. RAH holds operating grants from the Canadian Institutes of Health Research (Foundation award) and the Heart and Stroke Foundation of Ontario (G-21-0031455).
8 May 2025 (ma) Review posted live
6 November 2024 (jb) Original submission
• 8 May 2025 (ma) Review posted live
• 6 November 2024 (jb) Original submission
## Author Notes
RAH is supported by the Jacob J Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Research Chair, and the Martha G Blackburn Chair in Cardiovascular Research. RAH holds operating grants from the Canadian Institutes of Health Research (Foundation award) and the Heart and Stroke Foundation of Ontario (G-21-0031455).
## Revision History
8 May 2025 (ma) Review posted live
6 November 2024 (jb) Original submission
• 8 May 2025 (ma) Review posted live
• 6 November 2024 (jb) Original submission
## References
## Literature Cited
|
[] |
8/5/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
cf
|
cf
|
[
"Cystic fibrosis transmembrane conductance regulator",
"CFTR",
"Cystic Fibrosis"
] |
Cystic Fibrosis
|
Adrienne Savant, Benjamin Lyman, Christine Bojanowski, Jariya Upadia
|
Summary Cystic fibrosis (CF) is a multisystem disease affecting epithelia of the respiratory tract, exocrine pancreas, intestine, hepatobiliary system, and exocrine sweat glands. Morbidities include recurrent sinusitis and bronchitis, progressive obstructive pulmonary disease with bronchiectasis, exocrine pancreatic deficiency and malnutrition, pancreatitis, gastrointestinal manifestations (meconium ileus, rectal prolapse, distal intestinal obstructive syndrome), liver disease, diabetes, male infertility due to hypoplasia or aplasia of the vas deferens, and reduced fertility or infertility in some women. Pulmonary disease is the major cause of morbidity and mortality in CF. The diagnosis of CF is established in a proband with (1) elevated immunoreactive trypsinogen on newborn screen, signs and/or symptoms suggestive of CF, or family history of CF; AND (2) evidence of an abnormality in cystic fibrosis transmembrane conductance regulator (CFTR) function: sweat chloride ≥60 mmol/L on sweat chloride testing, biallelic After the newborn period: airway clearance; pulmonary treatment (bronchodilator, hypertonic saline, dornase alfa, airway clearance, inhaled corticosteroids and/or long-acting beta agonist, and aerosolized antibiotic); standard treatments for pneumothorax or hemoptysis; double lung transplant for those with advanced lung disease; routine vaccinations including influenza; contact precautions; antibiotics for bacterial suppression and treatment; antibiotics and/or surgical intervention for nasal/sinus symptoms; nutrition management; pancreatic enzyme replacement; nutrient-dense food and supplements; fat-soluble vitamin supplements; laxative treatment as needed with surgical management for bowel obstruction; standard treatments for gastroesophageal reflux disease; oral ursodiol for biliary sludging/obstruction; liver transplant when indicated; management of CF-related diabetes mellitus by an endocrinologist; assisted reproductive technologies (ART) for infertility; salt and water supplementation; standard treatments for associated mental health issues. CF is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
Consensus clinical diagnostic criteria for cystic fibrosis (CF) have been established [
NBS for CF is based on quantification of immunoreactive trypsinogen (IRT) and subsequent molecular testing including either
Elevated IRT values with or without the presence of
Suggestive clinical and laboratory findings in symptomatic individuals include:
Sinopulmonary: chronic wet or productive cough, recurrent pneumonia, bronchiectasis, nasal polyposis
Musculoskeletal: digital clubbing
Infectious: respiratory infection with
Nutritional/metabolic: poor weight gain, growth deficiency
Pancreatic: exocrine pancreatic insufficiency, recurrent pancreatitis
Intestinal: meconium ileus, rectal prolapse, distal intestinal obstructive syndrome, steatorrhea
Hepatic: protracted neonatal jaundice, biliary cirrhosis
Genitourinary: obstructive azoospermia
Hyponatremia, hypochloremia, hypokalemia, hypoproteinemia, chronic metabolic alkalosis
Deficiency of fat-soluble vitamins (vitamins A, D, E, and K)
The diagnosis of CF
Positive newborn screen (NBS) for CF (elevated immunoreactive trypsinogen [IRT])
Signs and/or symptoms suggestive of CF (See
Family history of CF in a first-degree relative (typically a sib)
Elevated sweat chloride value ≥60 mmol/L on sweat chloride testing
Identification of biallelic
Nasal transmembrane epithelial potential difference measurement consistent with CF (See
Note: (1) A sweat chloride value ≥60 mmol/L establishes the diagnosis; however, an intermediate sweat chloride of 30-59 mmol/L should prompt further evaluation with a CF specialist. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
NBS for CF has been universal in the United States since 2010; IRT is measured in a blood sample in all newborns born in the US. Infants with CF have increased IRT levels as a result of inspissated secretions in pancreatic ducts leading to an increase of trypsinogen in the blood. Further testing for newborns with elevated IRT varies by state NBS program; follow-up testing may include a second IRT, targeted DNA analysis for common CF-causing
Sweat chloride testing, the gold standard for diagnosis of CF, requires appropriate techniques; within the US, it should be performed at a center accredited by the CF Foundation [
Approaches include
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Amish, Ashkenazi Jewish, Faroe Islander, Hutterite, or Zuni ancestry (see
For an introduction to multigene panels click
Molecular Genetic Testing Used in Cystic Fibrosis
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
NPD provides an indirect measurement of CFTR function in nasal epithelium. Currently, NPD is only performed in specialized testing centers [
• NBS for CF is based on quantification of immunoreactive trypsinogen (IRT) and subsequent molecular testing including either
• Elevated IRT values with or without the presence of
• Sinopulmonary: chronic wet or productive cough, recurrent pneumonia, bronchiectasis, nasal polyposis
• Musculoskeletal: digital clubbing
• Infectious: respiratory infection with
• Nutritional/metabolic: poor weight gain, growth deficiency
• Pancreatic: exocrine pancreatic insufficiency, recurrent pancreatitis
• Intestinal: meconium ileus, rectal prolapse, distal intestinal obstructive syndrome, steatorrhea
• Hepatic: protracted neonatal jaundice, biliary cirrhosis
• Genitourinary: obstructive azoospermia
• Sinopulmonary: chronic wet or productive cough, recurrent pneumonia, bronchiectasis, nasal polyposis
• Musculoskeletal: digital clubbing
• Infectious: respiratory infection with
• Nutritional/metabolic: poor weight gain, growth deficiency
• Pancreatic: exocrine pancreatic insufficiency, recurrent pancreatitis
• Intestinal: meconium ileus, rectal prolapse, distal intestinal obstructive syndrome, steatorrhea
• Hepatic: protracted neonatal jaundice, biliary cirrhosis
• Genitourinary: obstructive azoospermia
•
• Hyponatremia, hypochloremia, hypokalemia, hypoproteinemia, chronic metabolic alkalosis
• Deficiency of fat-soluble vitamins (vitamins A, D, E, and K)
• Hyponatremia, hypochloremia, hypokalemia, hypoproteinemia, chronic metabolic alkalosis
• Deficiency of fat-soluble vitamins (vitamins A, D, E, and K)
• Sinopulmonary: chronic wet or productive cough, recurrent pneumonia, bronchiectasis, nasal polyposis
• Musculoskeletal: digital clubbing
• Infectious: respiratory infection with
• Nutritional/metabolic: poor weight gain, growth deficiency
• Pancreatic: exocrine pancreatic insufficiency, recurrent pancreatitis
• Intestinal: meconium ileus, rectal prolapse, distal intestinal obstructive syndrome, steatorrhea
• Hepatic: protracted neonatal jaundice, biliary cirrhosis
• Genitourinary: obstructive azoospermia
• Hyponatremia, hypochloremia, hypokalemia, hypoproteinemia, chronic metabolic alkalosis
• Deficiency of fat-soluble vitamins (vitamins A, D, E, and K)
• Positive newborn screen (NBS) for CF (elevated immunoreactive trypsinogen [IRT])
• Signs and/or symptoms suggestive of CF (See
• Family history of CF in a first-degree relative (typically a sib)
• Elevated sweat chloride value ≥60 mmol/L on sweat chloride testing
• Identification of biallelic
• Nasal transmembrane epithelial potential difference measurement consistent with CF (See
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Amish, Ashkenazi Jewish, Faroe Islander, Hutterite, or Zuni ancestry (see
• For an introduction to multigene panels click
## Suggestive Findings
NBS for CF is based on quantification of immunoreactive trypsinogen (IRT) and subsequent molecular testing including either
Elevated IRT values with or without the presence of
Suggestive clinical and laboratory findings in symptomatic individuals include:
Sinopulmonary: chronic wet or productive cough, recurrent pneumonia, bronchiectasis, nasal polyposis
Musculoskeletal: digital clubbing
Infectious: respiratory infection with
Nutritional/metabolic: poor weight gain, growth deficiency
Pancreatic: exocrine pancreatic insufficiency, recurrent pancreatitis
Intestinal: meconium ileus, rectal prolapse, distal intestinal obstructive syndrome, steatorrhea
Hepatic: protracted neonatal jaundice, biliary cirrhosis
Genitourinary: obstructive azoospermia
Hyponatremia, hypochloremia, hypokalemia, hypoproteinemia, chronic metabolic alkalosis
Deficiency of fat-soluble vitamins (vitamins A, D, E, and K)
• NBS for CF is based on quantification of immunoreactive trypsinogen (IRT) and subsequent molecular testing including either
• Elevated IRT values with or without the presence of
• Sinopulmonary: chronic wet or productive cough, recurrent pneumonia, bronchiectasis, nasal polyposis
• Musculoskeletal: digital clubbing
• Infectious: respiratory infection with
• Nutritional/metabolic: poor weight gain, growth deficiency
• Pancreatic: exocrine pancreatic insufficiency, recurrent pancreatitis
• Intestinal: meconium ileus, rectal prolapse, distal intestinal obstructive syndrome, steatorrhea
• Hepatic: protracted neonatal jaundice, biliary cirrhosis
• Genitourinary: obstructive azoospermia
• Sinopulmonary: chronic wet or productive cough, recurrent pneumonia, bronchiectasis, nasal polyposis
• Musculoskeletal: digital clubbing
• Infectious: respiratory infection with
• Nutritional/metabolic: poor weight gain, growth deficiency
• Pancreatic: exocrine pancreatic insufficiency, recurrent pancreatitis
• Intestinal: meconium ileus, rectal prolapse, distal intestinal obstructive syndrome, steatorrhea
• Hepatic: protracted neonatal jaundice, biliary cirrhosis
• Genitourinary: obstructive azoospermia
•
• Hyponatremia, hypochloremia, hypokalemia, hypoproteinemia, chronic metabolic alkalosis
• Deficiency of fat-soluble vitamins (vitamins A, D, E, and K)
• Hyponatremia, hypochloremia, hypokalemia, hypoproteinemia, chronic metabolic alkalosis
• Deficiency of fat-soluble vitamins (vitamins A, D, E, and K)
• Sinopulmonary: chronic wet or productive cough, recurrent pneumonia, bronchiectasis, nasal polyposis
• Musculoskeletal: digital clubbing
• Infectious: respiratory infection with
• Nutritional/metabolic: poor weight gain, growth deficiency
• Pancreatic: exocrine pancreatic insufficiency, recurrent pancreatitis
• Intestinal: meconium ileus, rectal prolapse, distal intestinal obstructive syndrome, steatorrhea
• Hepatic: protracted neonatal jaundice, biliary cirrhosis
• Genitourinary: obstructive azoospermia
• Hyponatremia, hypochloremia, hypokalemia, hypoproteinemia, chronic metabolic alkalosis
• Deficiency of fat-soluble vitamins (vitamins A, D, E, and K)
## Establishing the Diagnosis
The diagnosis of CF
Positive newborn screen (NBS) for CF (elevated immunoreactive trypsinogen [IRT])
Signs and/or symptoms suggestive of CF (See
Family history of CF in a first-degree relative (typically a sib)
Elevated sweat chloride value ≥60 mmol/L on sweat chloride testing
Identification of biallelic
Nasal transmembrane epithelial potential difference measurement consistent with CF (See
Note: (1) A sweat chloride value ≥60 mmol/L establishes the diagnosis; however, an intermediate sweat chloride of 30-59 mmol/L should prompt further evaluation with a CF specialist. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
NBS for CF has been universal in the United States since 2010; IRT is measured in a blood sample in all newborns born in the US. Infants with CF have increased IRT levels as a result of inspissated secretions in pancreatic ducts leading to an increase of trypsinogen in the blood. Further testing for newborns with elevated IRT varies by state NBS program; follow-up testing may include a second IRT, targeted DNA analysis for common CF-causing
Sweat chloride testing, the gold standard for diagnosis of CF, requires appropriate techniques; within the US, it should be performed at a center accredited by the CF Foundation [
Approaches include
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Amish, Ashkenazi Jewish, Faroe Islander, Hutterite, or Zuni ancestry (see
For an introduction to multigene panels click
Molecular Genetic Testing Used in Cystic Fibrosis
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
NPD provides an indirect measurement of CFTR function in nasal epithelium. Currently, NPD is only performed in specialized testing centers [
• Positive newborn screen (NBS) for CF (elevated immunoreactive trypsinogen [IRT])
• Signs and/or symptoms suggestive of CF (See
• Family history of CF in a first-degree relative (typically a sib)
• Elevated sweat chloride value ≥60 mmol/L on sweat chloride testing
• Identification of biallelic
• Nasal transmembrane epithelial potential difference measurement consistent with CF (See
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Amish, Ashkenazi Jewish, Faroe Islander, Hutterite, or Zuni ancestry (see
• For an introduction to multigene panels click
## Newborn Screening (NBS)
NBS for CF has been universal in the United States since 2010; IRT is measured in a blood sample in all newborns born in the US. Infants with CF have increased IRT levels as a result of inspissated secretions in pancreatic ducts leading to an increase of trypsinogen in the blood. Further testing for newborns with elevated IRT varies by state NBS program; follow-up testing may include a second IRT, targeted DNA analysis for common CF-causing
## Sweat Chloride Testing
Sweat chloride testing, the gold standard for diagnosis of CF, requires appropriate techniques; within the US, it should be performed at a center accredited by the CF Foundation [
## Molecular Genetic Testing
Approaches include
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Amish, Ashkenazi Jewish, Faroe Islander, Hutterite, or Zuni ancestry (see
For an introduction to multigene panels click
Molecular Genetic Testing Used in Cystic Fibrosis
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Amish, Ashkenazi Jewish, Faroe Islander, Hutterite, or Zuni ancestry (see
• For an introduction to multigene panels click
## Nasal Transmembrane Epithelial Potential Difference (NPD)
NPD provides an indirect measurement of CFTR function in nasal epithelium. Currently, NPD is only performed in specialized testing centers [
## Clinical Characteristics
Cystic fibrosis (CF) affects the epithelia in several organs resulting in a complex, multisystem disease primarily involving the respiratory, gastrointestinal, genitourinary, and endocrine systems and the sweat glands.
Cystic Fibrosis: Frequency of Select Features
CF = cystic fibrosis; PS = pancreatic sufficient
Additional endocrine-related complications in individuals with CF include delayed puberty and delayed linear growth with reduced adult height [
Additional musculoskeletal manifestations include arthritis and thoracic postural defects (e.g., thoracic kyphosis, scoliosis) [
Men with CF often have congenital bilateral absence of the vas deferens (CBAVD) [
Women with CF are typically fertile. However, abnormal, pH imbalanced, and thickened cervical mucus contribute to reduced fertility and infertility in some women with CF [
People with CF are at increased risk for excessive sodium chloride loss across various epithelial surfaces. This is particularly true during infancy and during episodes of sweating, vomiting, or diarrhea. Infants are at increased risk during the transition from human milk or infant formulas to baby food because of the lack of added salt in commercially available baby foods. Because of increased salt losses, people with CF are at increased risk for developing hyponatremic, hypochloremic dehydration. Chronically depleted levels of total body sodium can lead to chronic metabolic alkalosis. Children, adolescents, and adults must monitor dietary salt intake particularly in hot and humid climates and during periods of increased sweating (e.g., physical exercise, illness).
Among people with CF born between 2017 and 2021, the median predicted survival is to age 53 years – an increase of ten years compared to those born between 2012 and 2016 [
Individuals with bronchiectasis, allergic bronchopulmonary aspergillosis, asthma, chronic rhinosinusitis / nasal polyposis, atypical mycobacterial infections, and aquagenic palmoplantar keratoderma are more likely to be heterozygous for a
The
The strongest genotype-phenotype correlations have been identified in the context of pancreatic function. The most common
Beyond pancreatic function, genotype does not consistently predict phenotype. Pulmonary disease severity varies widely among individuals with identical genotypes (see Molecular Genetics,
CF affects at least 100,000 individuals worldwide, with 40,000 individuals in the US [
The incidence of CF is increased in several populations (e.g., Amish, Ashkenazi Jewish, Hutterite) due to the presence of pathogenic founder variants (see
## Clinical Description
Cystic fibrosis (CF) affects the epithelia in several organs resulting in a complex, multisystem disease primarily involving the respiratory, gastrointestinal, genitourinary, and endocrine systems and the sweat glands.
Cystic Fibrosis: Frequency of Select Features
CF = cystic fibrosis; PS = pancreatic sufficient
Additional endocrine-related complications in individuals with CF include delayed puberty and delayed linear growth with reduced adult height [
Additional musculoskeletal manifestations include arthritis and thoracic postural defects (e.g., thoracic kyphosis, scoliosis) [
Men with CF often have congenital bilateral absence of the vas deferens (CBAVD) [
Women with CF are typically fertile. However, abnormal, pH imbalanced, and thickened cervical mucus contribute to reduced fertility and infertility in some women with CF [
People with CF are at increased risk for excessive sodium chloride loss across various epithelial surfaces. This is particularly true during infancy and during episodes of sweating, vomiting, or diarrhea. Infants are at increased risk during the transition from human milk or infant formulas to baby food because of the lack of added salt in commercially available baby foods. Because of increased salt losses, people with CF are at increased risk for developing hyponatremic, hypochloremic dehydration. Chronically depleted levels of total body sodium can lead to chronic metabolic alkalosis. Children, adolescents, and adults must monitor dietary salt intake particularly in hot and humid climates and during periods of increased sweating (e.g., physical exercise, illness).
Among people with CF born between 2017 and 2021, the median predicted survival is to age 53 years – an increase of ten years compared to those born between 2012 and 2016 [
## Respiratory
## Pancreatic
## Gastrointestinal
## Endocrine
Additional endocrine-related complications in individuals with CF include delayed puberty and delayed linear growth with reduced adult height [
## Musculoskeletal
Additional musculoskeletal manifestations include arthritis and thoracic postural defects (e.g., thoracic kyphosis, scoliosis) [
## Genitourinary
Men with CF often have congenital bilateral absence of the vas deferens (CBAVD) [
Women with CF are typically fertile. However, abnormal, pH imbalanced, and thickened cervical mucus contribute to reduced fertility and infertility in some women with CF [
## Salt Loss Syndrome
People with CF are at increased risk for excessive sodium chloride loss across various epithelial surfaces. This is particularly true during infancy and during episodes of sweating, vomiting, or diarrhea. Infants are at increased risk during the transition from human milk or infant formulas to baby food because of the lack of added salt in commercially available baby foods. Because of increased salt losses, people with CF are at increased risk for developing hyponatremic, hypochloremic dehydration. Chronically depleted levels of total body sodium can lead to chronic metabolic alkalosis. Children, adolescents, and adults must monitor dietary salt intake particularly in hot and humid climates and during periods of increased sweating (e.g., physical exercise, illness).
## Mental Health
## Prognosis
Among people with CF born between 2017 and 2021, the median predicted survival is to age 53 years – an increase of ten years compared to those born between 2012 and 2016 [
## Heterozygotes
Individuals with bronchiectasis, allergic bronchopulmonary aspergillosis, asthma, chronic rhinosinusitis / nasal polyposis, atypical mycobacterial infections, and aquagenic palmoplantar keratoderma are more likely to be heterozygous for a
## Genotype-Phenotype Correlations
The
The strongest genotype-phenotype correlations have been identified in the context of pancreatic function. The most common
Beyond pancreatic function, genotype does not consistently predict phenotype. Pulmonary disease severity varies widely among individuals with identical genotypes (see Molecular Genetics,
## Prevalence
CF affects at least 100,000 individuals worldwide, with 40,000 individuals in the US [
The incidence of CF is increased in several populations (e.g., Amish, Ashkenazi Jewish, Hutterite) due to the presence of pathogenic founder variants (see
## Genetically Related (Allelic) Disorders
A normal sweat chloride (<30 mmol/L) and biallelic
An intermediate sweat chloride (30-59 mmol/L) and heterozygous or no CF-causing
Individuals with CRMS/CFSPID need to be monitored for features of CF by a CF specialist, as some individuals will become symptomatic and/or develop an elevated sweat chloride test and require treatment for CF [
• A normal sweat chloride (<30 mmol/L) and biallelic
• An intermediate sweat chloride (30-59 mmol/L) and heterozygous or no CF-causing
## Differential Diagnosis
Genetic disorders of interest in the differential diagnosis of cystic fibrosis (CF) are summarized in
Genetic Disorders in the Differential Diagnosis of Cystic Fibrosis
Abnormal ciliary structure & function (→ retention of mucus & bacteria in respiratory tract) & abnormal flagellar structure (→ abnormal sperm motility);
Respiratory distress in infancy; cough & sputum production w/recurrent pneumonias that may progress to chronic bronchiectasis;
Situs inversus is present in 50% of persons w/PCD.
Steatorrhea & poor weight gain are not assoc w/PCD.
Note: 20%-30% of persons w/well-characterized PCD do not have identifiable pathogenic variants in any known PCD-related genes.
Recurrent bacterial infections in affected males in 1st 2 yrs of life – most commonly recurrent otitis media
Conjunctivitis, sinopulmonary infections, diarrhea, & skin infections are also frequently seen.
Recurrent lung, sinus, & ear infection; recurrent lung infections can lead to chronic lung disease (bronchiectasis).
Diarrhea & impaired nutrient absorption
Typical X-SCID: w/universal NBS for SCID, common presentation is asymptomatic, healthy-appearing male infant.
Atypical X-SCID: usually not detected by NBS; can manifest in 1st yrs of life or later w/recurrent upper & lower respiratory tract infections w/bronchiectasis
Persons w/X-SCID are also prone to nonrespiratory infections (e.g., otitis media, cellulitis) not specifically assoc w/CF.
Other features may incl, e.g., hepatosplenomegaly, lymphadenopathy, lymphopenia.
Defect in epithelia sodium channel or mineralcorticoid receptor protein
↑ sweat chloride in some persons
Chronic bronchitis, bronchiectasis, recurrent pulmonary infections
AD = autosomal dominant; AML = acute myelogenous leukemia; AR = autosomal recessive; CF = cystic fibrosis; MDS = myelodysplasia syndrome; MOI = mode of inheritance; NBS = newborn screening; XL = X-linked
PCD is usually inherited in an autosomal recessive manner.
SDS caused by pathogenic variants in
Pseudohypoaldosteronism caused by pathogenic variants in
• Abnormal ciliary structure & function (→ retention of mucus & bacteria in respiratory tract) & abnormal flagellar structure (→ abnormal sperm motility);
• Respiratory distress in infancy; cough & sputum production w/recurrent pneumonias that may progress to chronic bronchiectasis;
• Situs inversus is present in 50% of persons w/PCD.
• Steatorrhea & poor weight gain are not assoc w/PCD.
• Note: 20%-30% of persons w/well-characterized PCD do not have identifiable pathogenic variants in any known PCD-related genes.
• Recurrent bacterial infections in affected males in 1st 2 yrs of life – most commonly recurrent otitis media
• Conjunctivitis, sinopulmonary infections, diarrhea, & skin infections are also frequently seen.
• Recurrent lung, sinus, & ear infection; recurrent lung infections can lead to chronic lung disease (bronchiectasis).
• Diarrhea & impaired nutrient absorption
• Typical X-SCID: w/universal NBS for SCID, common presentation is asymptomatic, healthy-appearing male infant.
• Atypical X-SCID: usually not detected by NBS; can manifest in 1st yrs of life or later w/recurrent upper & lower respiratory tract infections w/bronchiectasis
• Persons w/X-SCID are also prone to nonrespiratory infections (e.g., otitis media, cellulitis) not specifically assoc w/CF.
• Other features may incl, e.g., hepatosplenomegaly, lymphadenopathy, lymphopenia.
• Defect in epithelia sodium channel or mineralcorticoid receptor protein
• ↑ sweat chloride in some persons
• Chronic bronchitis, bronchiectasis, recurrent pulmonary infections
## Other Disorders
## Management
To establish the extent of disease and needs in a newborn diagnosed with cystic fibrosis (CF), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis of Cystic Fibrosis in Newborn Period
Assess growth (weight, length, head circumference).
Refer to CF specialist.
CF = cystic fibrosis; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis of Cystic Fibrosis After the Newborn Period
Assess growth (weight, length, head circumference).
Refer to CF specialist.
Pulmonary function testing
Respiratory culture for CF-specific pathogens by expectorated sputum or deep oropharyngeal swab
alk phos = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CF = cystic fibrosis; GGT = gamma-glutamyl transferase; MOI = mode of inheritance; PT = prothrombin time
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for CF. However, cystic fibrosis transmembrane conductance regulator (CFTR) modulator targeted therapy is available to mitigate manifestations (see
Cystic Fibrosis: Targeted Therapies
CFTR = cystic fibrosis transmembrane conductance regulator
Minimal function variants are
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Treatment of Manifestations in a Newborn with Cystic Fibrosis
Encourage feeding w/breast milk.
Routine vaccinations
Antibiotics (oral, inhaled, or IV) for chronic suppression & to treat pulmonary exacerbations
Treat identified bacteria in affected person & bacteria common in CF.
Consult nutritionist w/experience in CF.
Pancreatic enzyme replacement therapy
Nutrient-dense food & supplements
Fat-soluble vitamin supplements
If obstructed, consult surgery for intervention.
If not obstructed, treat w/laxatives.
Salt supplementation
Extra salt & water for hydration & salt loss in situations w/salt loss (e.g., ↑ heat/humidity, exercise)
CF = cystic fibrosis
Treatment of Manifestations in Individuals with Cystic Fibrosis
Bronchodilator
Hypertonic saline
Dornase alfa
Airway clearance
Inhaled corticosteroids &/or long-acting beta agonist (for select persons)
Aerosolized antibiotic
Antibiotics (oral, inhaled, or IV) for chronic suppression & to treat pulmonary exacerbations
Treat identified bacteria in affected persons & bacteria common in CF.
Standard treatments for rhinosinusitis
Referral to ENT specialist w/CF experience as needed
Sinus surgery as needed to widen ostia &/or clear impacted secretions
Polypectomy as needed for obstructive nasal polyps
Consult w/nutritionist w/experience in CF.
Pancreatic enzyme replacement therapy
Nutrient-dense food & supplements
Fat-soluble vitamin supplements
Consider zinc supplementations.
Consider gastrostomy tube.
If obstructed, consult w/surgeon for intervention.
If not obstructed, use laxatives.
Persistent elevations in liver function tests are treated w/ursodiol.
Refer to hepatologist w/CF experience.
Refer to endocrinologist familiar w/CFRD.
Treat CFRD w/glucose monitoring & insulin therapy.
Counseling regarding partner testing & preimplantation genetic testing
ART, sperm donation, surrogacy, & adoption
Ultrasound to assess for absence of vas deferens
ART involves eval by urologist. 2 techniques are widely used: microsurgical epididymal sperm aspiration or testicular biopsy & sperm extraction.
Once sperm is obtained, IVF w/intracytoplasmic sperm injection is necessary as sperm counts & concentration are often too low for intrauterine insemination.
↓ fertility or infertility can be treated by several options available through ART.
While intrauterine insemination combined w/gonadotropin ovulation induction can be used, IVF is more co mmonly used.
Salt supplementation
Extra salt & water for hydration & salt loss in situations w/salt loss (e.g., ↑ heat/humidity, exercise)
ART = assisted reproductive technology; CF = cystic fibrosis; CFRD = cystic fibrosis-related diabetes; GERD = gastroesophageal reflux disease; IVF = in vitro fertilization
To monitor existing manifestations, the individual's response to targeted therapy and supportive care, and the emergence of new manifestations, partnership with a CF specialist is critical in addition to the following recommended surveillance.
Cystic Fibrosis: Recommended Surveillance
Monthly until age 6 mos
Every 2 mos from age 6-24 mos
Every 3 mos beginning at age 2 yrs
More frequently as indicated
Non-tuberculosis mycobacterium culture
Serum IgE to assess for allergic bronchopulmonary aspergillosis
Weight & height
Weight for length (in those age <2 yrs)
BMI (in those age ≥2 yrs)
Annually beginning at age 10 yrs
Note: Hgb A1C & fructosamine are not indicated in CF.
alk phos = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; BUN = blood urea nitrogen; CBC = complete blood count; CF = cystic fibrosis; CFRD = cystic fibrosis-related diabetes; DXA = dual-energy x-ray absorptiometry; GAD-7 = General Anxiety Disorder-7; GGT = gamma-glutamyl transferase; PHQ-9 = Patient Health Questionnaire-9; PT = prothrombin time
Avoid the following:
Environmental smoke
Exposure to respiratory infections
Dehydration
It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband and at-risk relatives to identify as early as possible those who should be referred to a CF center for initiation of treatment. Evaluations can include the following:
If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
If the pathogenic variants in the family are not known, sweat chloride testing can be used to clarify the disease status of at-risk sibs.
See
Women with CF tolerate pregnancy well. Key factors for an optimal pregnancy include nutrition management, pulmonary clearance treatments, aggressive management of infections, and treatment by a multidisciplinary care team, especially in women with mild-to-moderate disease [
Females with CF of reproductive age should receive preconception counseling and take steps to optimize health prior to pregnancy.
Maternal and fetal complications are high in women with CF who have received lung transplantation. Open and extensive discussions should be held between the transplant recipient and her care team prior to conception [
As in pregnancies of women with other forms of diabetes mellitus, fetal outcome is optimized when glycemic control is achieved prior to pregnancy.
The management of pregnancy and the immediate postpartum period for a woman with CF requires a maternal fetal medicine specialist, CF pulmonologist, dietician, and other members of the CF team [
Special attention should also be paid to supplementation of the fat-soluble vitamin A during pregnancy, as supratherapeutic levels may be teratogenic. Iron and folate supplementation recommendations in pregnant women with CF are similar to those in women without CF [
While there are no concerning signals in animal reproductive models for CFTR modulator therapy, human data are currently limited to case reports and physician surveys [
Maternal nutritional status and weight gain should be monitored and optimized aggressively, and pulmonary exacerbations should be treated early.
Gestational diabetes is common in pregnancies of women with CF. Traditional screening paradigms for gestational diabetes mellitus may not be useful in pregnancies of women with CF; therefore, screening at each trimester of pregnancy has been suggested to improve the detection of diabetes mellitus [
Mode of delivery is based on usual obstetric indications, with vaginal delivery being the most common mode of delivery in women with CF [
During the postpartum period, it is important to support early mobilization and maintain good airway clearance practices, which can continue to be challenging with the demands of childcare [
Review medications for risk of transfer in breast milk. Most medications used in the long-term management of CF are considered safe. The major exceptions to this are immunosuppressants (importantly, in transplant recipients), azoles, and tetracyclines. Animal reproductive models have shown the presence of modulators in the breast milk of lactating animals [
Women with CF will need to consider the choice of breastfeeding based on the ability to maintain weight in the face of the high caloric demands associated with breastfeeding and the need to resume medications that may be transferred to the infant through breast milk [
Therapeutic interventions for CF are continually evolving (see
Therapies under study that focus specifically on the approximately 10% of individuals who are not eligible for current therapy due to nonsense or rare variants that do not produce any CFTR protein include read-through agents and gene therapy. Read-through agents are particularly interesting as a treatment for those with nonsense variants. Gene therapy is an area of active research, ranging from DNA based (both integrating and nonintegrating), RNA therapy, gene editing (such as CRISPR), and antisense oligonucleotide therapy.
The Infection Research Initiative from the Cystic Fibrosis Foundation is investigating a range of topics, including understanding CF-specific microorganisms, improving diagnosis and detection, optimizing current treatment, developing new antimicrobials, and evaluating the long-term effects of antimicrobial use. One exciting area of infection research related to bacteriophage therapy is the use of viruses to target difficult-to-treat bacteria.
Many other areas of CF research are also under way, such as mucociliary clearance modalities, anti-inflammatory agents, and nutritional treatments.
Search
• Assess growth (weight, length, head circumference).
• Refer to CF specialist.
• Assess growth (weight, length, head circumference).
• Refer to CF specialist.
• Pulmonary function testing
• Respiratory culture for CF-specific pathogens by expectorated sputum or deep oropharyngeal swab
• Encourage feeding w/breast milk.
• Routine vaccinations
• Antibiotics (oral, inhaled, or IV) for chronic suppression & to treat pulmonary exacerbations
• Treat identified bacteria in affected person & bacteria common in CF.
• Consult nutritionist w/experience in CF.
• Pancreatic enzyme replacement therapy
• Nutrient-dense food & supplements
• Fat-soluble vitamin supplements
• If obstructed, consult surgery for intervention.
• If not obstructed, treat w/laxatives.
• Salt supplementation
• Extra salt & water for hydration & salt loss in situations w/salt loss (e.g., ↑ heat/humidity, exercise)
• Bronchodilator
• Hypertonic saline
• Dornase alfa
• Airway clearance
• Inhaled corticosteroids &/or long-acting beta agonist (for select persons)
• Aerosolized antibiotic
• Antibiotics (oral, inhaled, or IV) for chronic suppression & to treat pulmonary exacerbations
• Treat identified bacteria in affected persons & bacteria common in CF.
• Standard treatments for rhinosinusitis
• Referral to ENT specialist w/CF experience as needed
• Sinus surgery as needed to widen ostia &/or clear impacted secretions
• Polypectomy as needed for obstructive nasal polyps
• Consult w/nutritionist w/experience in CF.
• Pancreatic enzyme replacement therapy
• Nutrient-dense food & supplements
• Fat-soluble vitamin supplements
• Consider zinc supplementations.
• Consider gastrostomy tube.
• If obstructed, consult w/surgeon for intervention.
• If not obstructed, use laxatives.
• Persistent elevations in liver function tests are treated w/ursodiol.
• Refer to hepatologist w/CF experience.
• Refer to endocrinologist familiar w/CFRD.
• Treat CFRD w/glucose monitoring & insulin therapy.
• Counseling regarding partner testing & preimplantation genetic testing
• ART, sperm donation, surrogacy, & adoption
• Ultrasound to assess for absence of vas deferens
• ART involves eval by urologist. 2 techniques are widely used: microsurgical epididymal sperm aspiration or testicular biopsy & sperm extraction.
• Once sperm is obtained, IVF w/intracytoplasmic sperm injection is necessary as sperm counts & concentration are often too low for intrauterine insemination.
• ↓ fertility or infertility can be treated by several options available through ART.
• While intrauterine insemination combined w/gonadotropin ovulation induction can be used, IVF is more co mmonly used.
• Salt supplementation
• Extra salt & water for hydration & salt loss in situations w/salt loss (e.g., ↑ heat/humidity, exercise)
• Monthly until age 6 mos
• Every 2 mos from age 6-24 mos
• Every 3 mos beginning at age 2 yrs
• More frequently as indicated
• Non-tuberculosis mycobacterium culture
• Serum IgE to assess for allergic bronchopulmonary aspergillosis
• Weight & height
• Weight for length (in those age <2 yrs)
• BMI (in those age ≥2 yrs)
• Annually beginning at age 10 yrs
• Note: Hgb A1C & fructosamine are not indicated in CF.
• Environmental smoke
• Exposure to respiratory infections
• Dehydration
• If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
• If the pathogenic variants in the family are not known, sweat chloride testing can be used to clarify the disease status of at-risk sibs.
• Females with CF of reproductive age should receive preconception counseling and take steps to optimize health prior to pregnancy.
• Maternal and fetal complications are high in women with CF who have received lung transplantation. Open and extensive discussions should be held between the transplant recipient and her care team prior to conception [
• As in pregnancies of women with other forms of diabetes mellitus, fetal outcome is optimized when glycemic control is achieved prior to pregnancy.
• The management of pregnancy and the immediate postpartum period for a woman with CF requires a maternal fetal medicine specialist, CF pulmonologist, dietician, and other members of the CF team [
• Special attention should also be paid to supplementation of the fat-soluble vitamin A during pregnancy, as supratherapeutic levels may be teratogenic. Iron and folate supplementation recommendations in pregnant women with CF are similar to those in women without CF [
• While there are no concerning signals in animal reproductive models for CFTR modulator therapy, human data are currently limited to case reports and physician surveys [
• Maternal nutritional status and weight gain should be monitored and optimized aggressively, and pulmonary exacerbations should be treated early.
• Gestational diabetes is common in pregnancies of women with CF. Traditional screening paradigms for gestational diabetes mellitus may not be useful in pregnancies of women with CF; therefore, screening at each trimester of pregnancy has been suggested to improve the detection of diabetes mellitus [
• Mode of delivery is based on usual obstetric indications, with vaginal delivery being the most common mode of delivery in women with CF [
• During the postpartum period, it is important to support early mobilization and maintain good airway clearance practices, which can continue to be challenging with the demands of childcare [
• Review medications for risk of transfer in breast milk. Most medications used in the long-term management of CF are considered safe. The major exceptions to this are immunosuppressants (importantly, in transplant recipients), azoles, and tetracyclines. Animal reproductive models have shown the presence of modulators in the breast milk of lactating animals [
• Women with CF will need to consider the choice of breastfeeding based on the ability to maintain weight in the face of the high caloric demands associated with breastfeeding and the need to resume medications that may be transferred to the infant through breast milk [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in a newborn diagnosed with cystic fibrosis (CF), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis of Cystic Fibrosis in Newborn Period
Assess growth (weight, length, head circumference).
Refer to CF specialist.
CF = cystic fibrosis; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis of Cystic Fibrosis After the Newborn Period
Assess growth (weight, length, head circumference).
Refer to CF specialist.
Pulmonary function testing
Respiratory culture for CF-specific pathogens by expectorated sputum or deep oropharyngeal swab
alk phos = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CF = cystic fibrosis; GGT = gamma-glutamyl transferase; MOI = mode of inheritance; PT = prothrombin time
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Assess growth (weight, length, head circumference).
• Refer to CF specialist.
• Assess growth (weight, length, head circumference).
• Refer to CF specialist.
• Pulmonary function testing
• Respiratory culture for CF-specific pathogens by expectorated sputum or deep oropharyngeal swab
## Treatment of Manifestations
There is no cure for CF. However, cystic fibrosis transmembrane conductance regulator (CFTR) modulator targeted therapy is available to mitigate manifestations (see
Cystic Fibrosis: Targeted Therapies
CFTR = cystic fibrosis transmembrane conductance regulator
Minimal function variants are
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Treatment of Manifestations in a Newborn with Cystic Fibrosis
Encourage feeding w/breast milk.
Routine vaccinations
Antibiotics (oral, inhaled, or IV) for chronic suppression & to treat pulmonary exacerbations
Treat identified bacteria in affected person & bacteria common in CF.
Consult nutritionist w/experience in CF.
Pancreatic enzyme replacement therapy
Nutrient-dense food & supplements
Fat-soluble vitamin supplements
If obstructed, consult surgery for intervention.
If not obstructed, treat w/laxatives.
Salt supplementation
Extra salt & water for hydration & salt loss in situations w/salt loss (e.g., ↑ heat/humidity, exercise)
CF = cystic fibrosis
Treatment of Manifestations in Individuals with Cystic Fibrosis
Bronchodilator
Hypertonic saline
Dornase alfa
Airway clearance
Inhaled corticosteroids &/or long-acting beta agonist (for select persons)
Aerosolized antibiotic
Antibiotics (oral, inhaled, or IV) for chronic suppression & to treat pulmonary exacerbations
Treat identified bacteria in affected persons & bacteria common in CF.
Standard treatments for rhinosinusitis
Referral to ENT specialist w/CF experience as needed
Sinus surgery as needed to widen ostia &/or clear impacted secretions
Polypectomy as needed for obstructive nasal polyps
Consult w/nutritionist w/experience in CF.
Pancreatic enzyme replacement therapy
Nutrient-dense food & supplements
Fat-soluble vitamin supplements
Consider zinc supplementations.
Consider gastrostomy tube.
If obstructed, consult w/surgeon for intervention.
If not obstructed, use laxatives.
Persistent elevations in liver function tests are treated w/ursodiol.
Refer to hepatologist w/CF experience.
Refer to endocrinologist familiar w/CFRD.
Treat CFRD w/glucose monitoring & insulin therapy.
Counseling regarding partner testing & preimplantation genetic testing
ART, sperm donation, surrogacy, & adoption
Ultrasound to assess for absence of vas deferens
ART involves eval by urologist. 2 techniques are widely used: microsurgical epididymal sperm aspiration or testicular biopsy & sperm extraction.
Once sperm is obtained, IVF w/intracytoplasmic sperm injection is necessary as sperm counts & concentration are often too low for intrauterine insemination.
↓ fertility or infertility can be treated by several options available through ART.
While intrauterine insemination combined w/gonadotropin ovulation induction can be used, IVF is more co mmonly used.
Salt supplementation
Extra salt & water for hydration & salt loss in situations w/salt loss (e.g., ↑ heat/humidity, exercise)
ART = assisted reproductive technology; CF = cystic fibrosis; CFRD = cystic fibrosis-related diabetes; GERD = gastroesophageal reflux disease; IVF = in vitro fertilization
• Encourage feeding w/breast milk.
• Routine vaccinations
• Antibiotics (oral, inhaled, or IV) for chronic suppression & to treat pulmonary exacerbations
• Treat identified bacteria in affected person & bacteria common in CF.
• Consult nutritionist w/experience in CF.
• Pancreatic enzyme replacement therapy
• Nutrient-dense food & supplements
• Fat-soluble vitamin supplements
• If obstructed, consult surgery for intervention.
• If not obstructed, treat w/laxatives.
• Salt supplementation
• Extra salt & water for hydration & salt loss in situations w/salt loss (e.g., ↑ heat/humidity, exercise)
• Bronchodilator
• Hypertonic saline
• Dornase alfa
• Airway clearance
• Inhaled corticosteroids &/or long-acting beta agonist (for select persons)
• Aerosolized antibiotic
• Antibiotics (oral, inhaled, or IV) for chronic suppression & to treat pulmonary exacerbations
• Treat identified bacteria in affected persons & bacteria common in CF.
• Standard treatments for rhinosinusitis
• Referral to ENT specialist w/CF experience as needed
• Sinus surgery as needed to widen ostia &/or clear impacted secretions
• Polypectomy as needed for obstructive nasal polyps
• Consult w/nutritionist w/experience in CF.
• Pancreatic enzyme replacement therapy
• Nutrient-dense food & supplements
• Fat-soluble vitamin supplements
• Consider zinc supplementations.
• Consider gastrostomy tube.
• If obstructed, consult w/surgeon for intervention.
• If not obstructed, use laxatives.
• Persistent elevations in liver function tests are treated w/ursodiol.
• Refer to hepatologist w/CF experience.
• Refer to endocrinologist familiar w/CFRD.
• Treat CFRD w/glucose monitoring & insulin therapy.
• Counseling regarding partner testing & preimplantation genetic testing
• ART, sperm donation, surrogacy, & adoption
• Ultrasound to assess for absence of vas deferens
• ART involves eval by urologist. 2 techniques are widely used: microsurgical epididymal sperm aspiration or testicular biopsy & sperm extraction.
• Once sperm is obtained, IVF w/intracytoplasmic sperm injection is necessary as sperm counts & concentration are often too low for intrauterine insemination.
• ↓ fertility or infertility can be treated by several options available through ART.
• While intrauterine insemination combined w/gonadotropin ovulation induction can be used, IVF is more co mmonly used.
• Salt supplementation
• Extra salt & water for hydration & salt loss in situations w/salt loss (e.g., ↑ heat/humidity, exercise)
## Targeted Therapies
There is no cure for CF. However, cystic fibrosis transmembrane conductance regulator (CFTR) modulator targeted therapy is available to mitigate manifestations (see
Cystic Fibrosis: Targeted Therapies
CFTR = cystic fibrosis transmembrane conductance regulator
Minimal function variants are
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Treatment of Manifestations in a Newborn with Cystic Fibrosis
Encourage feeding w/breast milk.
Routine vaccinations
Antibiotics (oral, inhaled, or IV) for chronic suppression & to treat pulmonary exacerbations
Treat identified bacteria in affected person & bacteria common in CF.
Consult nutritionist w/experience in CF.
Pancreatic enzyme replacement therapy
Nutrient-dense food & supplements
Fat-soluble vitamin supplements
If obstructed, consult surgery for intervention.
If not obstructed, treat w/laxatives.
Salt supplementation
Extra salt & water for hydration & salt loss in situations w/salt loss (e.g., ↑ heat/humidity, exercise)
CF = cystic fibrosis
Treatment of Manifestations in Individuals with Cystic Fibrosis
Bronchodilator
Hypertonic saline
Dornase alfa
Airway clearance
Inhaled corticosteroids &/or long-acting beta agonist (for select persons)
Aerosolized antibiotic
Antibiotics (oral, inhaled, or IV) for chronic suppression & to treat pulmonary exacerbations
Treat identified bacteria in affected persons & bacteria common in CF.
Standard treatments for rhinosinusitis
Referral to ENT specialist w/CF experience as needed
Sinus surgery as needed to widen ostia &/or clear impacted secretions
Polypectomy as needed for obstructive nasal polyps
Consult w/nutritionist w/experience in CF.
Pancreatic enzyme replacement therapy
Nutrient-dense food & supplements
Fat-soluble vitamin supplements
Consider zinc supplementations.
Consider gastrostomy tube.
If obstructed, consult w/surgeon for intervention.
If not obstructed, use laxatives.
Persistent elevations in liver function tests are treated w/ursodiol.
Refer to hepatologist w/CF experience.
Refer to endocrinologist familiar w/CFRD.
Treat CFRD w/glucose monitoring & insulin therapy.
Counseling regarding partner testing & preimplantation genetic testing
ART, sperm donation, surrogacy, & adoption
Ultrasound to assess for absence of vas deferens
ART involves eval by urologist. 2 techniques are widely used: microsurgical epididymal sperm aspiration or testicular biopsy & sperm extraction.
Once sperm is obtained, IVF w/intracytoplasmic sperm injection is necessary as sperm counts & concentration are often too low for intrauterine insemination.
↓ fertility or infertility can be treated by several options available through ART.
While intrauterine insemination combined w/gonadotropin ovulation induction can be used, IVF is more co mmonly used.
Salt supplementation
Extra salt & water for hydration & salt loss in situations w/salt loss (e.g., ↑ heat/humidity, exercise)
ART = assisted reproductive technology; CF = cystic fibrosis; CFRD = cystic fibrosis-related diabetes; GERD = gastroesophageal reflux disease; IVF = in vitro fertilization
• Encourage feeding w/breast milk.
• Routine vaccinations
• Antibiotics (oral, inhaled, or IV) for chronic suppression & to treat pulmonary exacerbations
• Treat identified bacteria in affected person & bacteria common in CF.
• Consult nutritionist w/experience in CF.
• Pancreatic enzyme replacement therapy
• Nutrient-dense food & supplements
• Fat-soluble vitamin supplements
• If obstructed, consult surgery for intervention.
• If not obstructed, treat w/laxatives.
• Salt supplementation
• Extra salt & water for hydration & salt loss in situations w/salt loss (e.g., ↑ heat/humidity, exercise)
• Bronchodilator
• Hypertonic saline
• Dornase alfa
• Airway clearance
• Inhaled corticosteroids &/or long-acting beta agonist (for select persons)
• Aerosolized antibiotic
• Antibiotics (oral, inhaled, or IV) for chronic suppression & to treat pulmonary exacerbations
• Treat identified bacteria in affected persons & bacteria common in CF.
• Standard treatments for rhinosinusitis
• Referral to ENT specialist w/CF experience as needed
• Sinus surgery as needed to widen ostia &/or clear impacted secretions
• Polypectomy as needed for obstructive nasal polyps
• Consult w/nutritionist w/experience in CF.
• Pancreatic enzyme replacement therapy
• Nutrient-dense food & supplements
• Fat-soluble vitamin supplements
• Consider zinc supplementations.
• Consider gastrostomy tube.
• If obstructed, consult w/surgeon for intervention.
• If not obstructed, use laxatives.
• Persistent elevations in liver function tests are treated w/ursodiol.
• Refer to hepatologist w/CF experience.
• Refer to endocrinologist familiar w/CFRD.
• Treat CFRD w/glucose monitoring & insulin therapy.
• Counseling regarding partner testing & preimplantation genetic testing
• ART, sperm donation, surrogacy, & adoption
• Ultrasound to assess for absence of vas deferens
• ART involves eval by urologist. 2 techniques are widely used: microsurgical epididymal sperm aspiration or testicular biopsy & sperm extraction.
• Once sperm is obtained, IVF w/intracytoplasmic sperm injection is necessary as sperm counts & concentration are often too low for intrauterine insemination.
• ↓ fertility or infertility can be treated by several options available through ART.
• While intrauterine insemination combined w/gonadotropin ovulation induction can be used, IVF is more co mmonly used.
• Salt supplementation
• Extra salt & water for hydration & salt loss in situations w/salt loss (e.g., ↑ heat/humidity, exercise)
## Surveillance
To monitor existing manifestations, the individual's response to targeted therapy and supportive care, and the emergence of new manifestations, partnership with a CF specialist is critical in addition to the following recommended surveillance.
Cystic Fibrosis: Recommended Surveillance
Monthly until age 6 mos
Every 2 mos from age 6-24 mos
Every 3 mos beginning at age 2 yrs
More frequently as indicated
Non-tuberculosis mycobacterium culture
Serum IgE to assess for allergic bronchopulmonary aspergillosis
Weight & height
Weight for length (in those age <2 yrs)
BMI (in those age ≥2 yrs)
Annually beginning at age 10 yrs
Note: Hgb A1C & fructosamine are not indicated in CF.
alk phos = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; BUN = blood urea nitrogen; CBC = complete blood count; CF = cystic fibrosis; CFRD = cystic fibrosis-related diabetes; DXA = dual-energy x-ray absorptiometry; GAD-7 = General Anxiety Disorder-7; GGT = gamma-glutamyl transferase; PHQ-9 = Patient Health Questionnaire-9; PT = prothrombin time
• Monthly until age 6 mos
• Every 2 mos from age 6-24 mos
• Every 3 mos beginning at age 2 yrs
• More frequently as indicated
• Non-tuberculosis mycobacterium culture
• Serum IgE to assess for allergic bronchopulmonary aspergillosis
• Weight & height
• Weight for length (in those age <2 yrs)
• BMI (in those age ≥2 yrs)
• Annually beginning at age 10 yrs
• Note: Hgb A1C & fructosamine are not indicated in CF.
## Agents/Circumstances to Avoid
Avoid the following:
Environmental smoke
Exposure to respiratory infections
Dehydration
• Environmental smoke
• Exposure to respiratory infections
• Dehydration
## Evaluation of Relatives at Risk
It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband and at-risk relatives to identify as early as possible those who should be referred to a CF center for initiation of treatment. Evaluations can include the following:
If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
If the pathogenic variants in the family are not known, sweat chloride testing can be used to clarify the disease status of at-risk sibs.
See
• If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
• If the pathogenic variants in the family are not known, sweat chloride testing can be used to clarify the disease status of at-risk sibs.
## Pregnancy Management
Women with CF tolerate pregnancy well. Key factors for an optimal pregnancy include nutrition management, pulmonary clearance treatments, aggressive management of infections, and treatment by a multidisciplinary care team, especially in women with mild-to-moderate disease [
Females with CF of reproductive age should receive preconception counseling and take steps to optimize health prior to pregnancy.
Maternal and fetal complications are high in women with CF who have received lung transplantation. Open and extensive discussions should be held between the transplant recipient and her care team prior to conception [
As in pregnancies of women with other forms of diabetes mellitus, fetal outcome is optimized when glycemic control is achieved prior to pregnancy.
The management of pregnancy and the immediate postpartum period for a woman with CF requires a maternal fetal medicine specialist, CF pulmonologist, dietician, and other members of the CF team [
Special attention should also be paid to supplementation of the fat-soluble vitamin A during pregnancy, as supratherapeutic levels may be teratogenic. Iron and folate supplementation recommendations in pregnant women with CF are similar to those in women without CF [
While there are no concerning signals in animal reproductive models for CFTR modulator therapy, human data are currently limited to case reports and physician surveys [
Maternal nutritional status and weight gain should be monitored and optimized aggressively, and pulmonary exacerbations should be treated early.
Gestational diabetes is common in pregnancies of women with CF. Traditional screening paradigms for gestational diabetes mellitus may not be useful in pregnancies of women with CF; therefore, screening at each trimester of pregnancy has been suggested to improve the detection of diabetes mellitus [
Mode of delivery is based on usual obstetric indications, with vaginal delivery being the most common mode of delivery in women with CF [
During the postpartum period, it is important to support early mobilization and maintain good airway clearance practices, which can continue to be challenging with the demands of childcare [
Review medications for risk of transfer in breast milk. Most medications used in the long-term management of CF are considered safe. The major exceptions to this are immunosuppressants (importantly, in transplant recipients), azoles, and tetracyclines. Animal reproductive models have shown the presence of modulators in the breast milk of lactating animals [
Women with CF will need to consider the choice of breastfeeding based on the ability to maintain weight in the face of the high caloric demands associated with breastfeeding and the need to resume medications that may be transferred to the infant through breast milk [
• Females with CF of reproductive age should receive preconception counseling and take steps to optimize health prior to pregnancy.
• Maternal and fetal complications are high in women with CF who have received lung transplantation. Open and extensive discussions should be held between the transplant recipient and her care team prior to conception [
• As in pregnancies of women with other forms of diabetes mellitus, fetal outcome is optimized when glycemic control is achieved prior to pregnancy.
• The management of pregnancy and the immediate postpartum period for a woman with CF requires a maternal fetal medicine specialist, CF pulmonologist, dietician, and other members of the CF team [
• Special attention should also be paid to supplementation of the fat-soluble vitamin A during pregnancy, as supratherapeutic levels may be teratogenic. Iron and folate supplementation recommendations in pregnant women with CF are similar to those in women without CF [
• While there are no concerning signals in animal reproductive models for CFTR modulator therapy, human data are currently limited to case reports and physician surveys [
• Maternal nutritional status and weight gain should be monitored and optimized aggressively, and pulmonary exacerbations should be treated early.
• Gestational diabetes is common in pregnancies of women with CF. Traditional screening paradigms for gestational diabetes mellitus may not be useful in pregnancies of women with CF; therefore, screening at each trimester of pregnancy has been suggested to improve the detection of diabetes mellitus [
• Mode of delivery is based on usual obstetric indications, with vaginal delivery being the most common mode of delivery in women with CF [
• During the postpartum period, it is important to support early mobilization and maintain good airway clearance practices, which can continue to be challenging with the demands of childcare [
• Review medications for risk of transfer in breast milk. Most medications used in the long-term management of CF are considered safe. The major exceptions to this are immunosuppressants (importantly, in transplant recipients), azoles, and tetracyclines. Animal reproductive models have shown the presence of modulators in the breast milk of lactating animals [
• Women with CF will need to consider the choice of breastfeeding based on the ability to maintain weight in the face of the high caloric demands associated with breastfeeding and the need to resume medications that may be transferred to the infant through breast milk [
## Therapies Under Investigation
Therapeutic interventions for CF are continually evolving (see
Therapies under study that focus specifically on the approximately 10% of individuals who are not eligible for current therapy due to nonsense or rare variants that do not produce any CFTR protein include read-through agents and gene therapy. Read-through agents are particularly interesting as a treatment for those with nonsense variants. Gene therapy is an area of active research, ranging from DNA based (both integrating and nonintegrating), RNA therapy, gene editing (such as CRISPR), and antisense oligonucleotide therapy.
The Infection Research Initiative from the Cystic Fibrosis Foundation is investigating a range of topics, including understanding CF-specific microorganisms, improving diagnosis and detection, optimizing current treatment, developing new antimicrobials, and evaluating the long-term effects of antimicrobial use. One exciting area of infection research related to bacteriophage therapy is the use of viruses to target difficult-to-treat bacteria.
Many other areas of CF research are also under way, such as mucociliary clearance modalities, anti-inflammatory agents, and nutritional treatments.
Search
## Genetic Counseling
Cystic fibrosis (CF) is inherited in an autosomal recessive manner.
The parents of an affected individual are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband not detected by sequence analysis that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes are at increased risk for bronchiectasis, allergic bronchopulmonary aspergillosis, asthma, chronic rhinosinusitis / nasal polyposis, aquagenic palmoplantar keratoderma, acute recurrent pancreatitis, chronic pancreatitis, atypical mycobacterial infections, and bronchiectasis [
If both parents are known to be heterozygous for a
Heterozygotes are at increased risk for bronchiectasis, allergic bronchopulmonary aspergillosis, asthma, chronic rhinosinusitis / nasal polyposis, aquagenic palmoplantar keratoderma, acute recurrent pancreatitis, chronic pancreatitis, atypical mycobacterial infections, and bronchiectasis [
An individual with CF will transmit a
If the reproductive partner of a proband is heterozygous for a
It is appropriate to offer carrier testing to the reproductive partner of an individual with CF (see
Note: While CF occurs in individuals of all ethnicities, the incidence of CF is increased in several populations (e.g., Amish, Ashkenazi Jewish, Hutterite) due to the presence of pathogenic founder variants (see
Targeted heterozygote testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of carrier testing, potential risks to offspring, and reproductive options) to young adults who are affected, are carriers (heterozygotes), or are at risk of being carriers.
Females with CF of reproductive age should receive preconception counseling and take steps to optimize health prior to pregnancy (see
Carrier screening for CF is offered to all women who are pregnant.
Per
A core panel of 23
Note: Noninvasive prenatal testing for CF is also becoming more common.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband not detected by sequence analysis that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband not detected by sequence analysis that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes are at increased risk for bronchiectasis, allergic bronchopulmonary aspergillosis, asthma, chronic rhinosinusitis / nasal polyposis, aquagenic palmoplantar keratoderma, acute recurrent pancreatitis, chronic pancreatitis, atypical mycobacterial infections, and bronchiectasis [
• A single- or multiexon deletion in the proband not detected by sequence analysis that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes are at increased risk for bronchiectasis, allergic bronchopulmonary aspergillosis, asthma, chronic rhinosinusitis / nasal polyposis, aquagenic palmoplantar keratoderma, acute recurrent pancreatitis, chronic pancreatitis, atypical mycobacterial infections, and bronchiectasis [
• An individual with CF will transmit a
• If the reproductive partner of a proband is heterozygous for a
• It is appropriate to offer carrier testing to the reproductive partner of an individual with CF (see
• Note: While CF occurs in individuals of all ethnicities, the incidence of CF is increased in several populations (e.g., Amish, Ashkenazi Jewish, Hutterite) due to the presence of pathogenic founder variants (see
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of carrier testing, potential risks to offspring, and reproductive options) to young adults who are affected, are carriers (heterozygotes), or are at risk of being carriers.
• Females with CF of reproductive age should receive preconception counseling and take steps to optimize health prior to pregnancy (see
## Mode of Inheritance
Cystic fibrosis (CF) is inherited in an autosomal recessive manner.
## Risk to Family Members of a Proband with CF
The parents of an affected individual are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband not detected by sequence analysis that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes are at increased risk for bronchiectasis, allergic bronchopulmonary aspergillosis, asthma, chronic rhinosinusitis / nasal polyposis, aquagenic palmoplantar keratoderma, acute recurrent pancreatitis, chronic pancreatitis, atypical mycobacterial infections, and bronchiectasis [
If both parents are known to be heterozygous for a
Heterozygotes are at increased risk for bronchiectasis, allergic bronchopulmonary aspergillosis, asthma, chronic rhinosinusitis / nasal polyposis, aquagenic palmoplantar keratoderma, acute recurrent pancreatitis, chronic pancreatitis, atypical mycobacterial infections, and bronchiectasis [
An individual with CF will transmit a
If the reproductive partner of a proband is heterozygous for a
It is appropriate to offer carrier testing to the reproductive partner of an individual with CF (see
Note: While CF occurs in individuals of all ethnicities, the incidence of CF is increased in several populations (e.g., Amish, Ashkenazi Jewish, Hutterite) due to the presence of pathogenic founder variants (see
• The parents of an affected individual are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband not detected by sequence analysis that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband not detected by sequence analysis that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes are at increased risk for bronchiectasis, allergic bronchopulmonary aspergillosis, asthma, chronic rhinosinusitis / nasal polyposis, aquagenic palmoplantar keratoderma, acute recurrent pancreatitis, chronic pancreatitis, atypical mycobacterial infections, and bronchiectasis [
• A single- or multiexon deletion in the proband not detected by sequence analysis that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes are at increased risk for bronchiectasis, allergic bronchopulmonary aspergillosis, asthma, chronic rhinosinusitis / nasal polyposis, aquagenic palmoplantar keratoderma, acute recurrent pancreatitis, chronic pancreatitis, atypical mycobacterial infections, and bronchiectasis [
• An individual with CF will transmit a
• If the reproductive partner of a proband is heterozygous for a
• It is appropriate to offer carrier testing to the reproductive partner of an individual with CF (see
• Note: While CF occurs in individuals of all ethnicities, the incidence of CF is increased in several populations (e.g., Amish, Ashkenazi Jewish, Hutterite) due to the presence of pathogenic founder variants (see
## Heterozygote Detection
Targeted heterozygote testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of carrier testing, potential risks to offspring, and reproductive options) to young adults who are affected, are carriers (heterozygotes), or are at risk of being carriers.
Females with CF of reproductive age should receive preconception counseling and take steps to optimize health prior to pregnancy (see
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of carrier testing, potential risks to offspring, and reproductive options) to young adults who are affected, are carriers (heterozygotes), or are at risk of being carriers.
• Females with CF of reproductive age should receive preconception counseling and take steps to optimize health prior to pregnancy (see
## Population Screening
Carrier screening for CF is offered to all women who are pregnant.
Per
A core panel of 23
## Prenatal Testing and Preimplantation Genetic Testing
Note: Noninvasive prenatal testing for CF is also becoming more common.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
Health Resources & Services Administration
•
• Canada
•
•
•
•
•
•
•
•
• Health Resources & Services Administration
•
## Molecular Genetics
Cystic Fibrosis: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Cystic Fibrosis (
Loss-of-function
The CFTR chloride channel is unique in the sweat glands, as it is reversed. In a person unaffected by CF, the CFTR chloride channel in sweat glands helps to reabsorb chloride (and thus salt and water). In people with CF, the channel is not functional, chloride is not reabsorbed, and the sweat is salty (resulting in an abnormal sweat test).
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
## Molecular Pathogenesis
Loss-of-function
The CFTR chloride channel is unique in the sweat glands, as it is reversed. In a person unaffected by CF, the CFTR chloride channel in sweat glands helps to reabsorb chloride (and thus salt and water). In people with CF, the channel is not functional, chloride is not reabsorbed, and the sweat is salty (resulting in an abnormal sweat test).
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
## Genetic Modifiers
## Chapter Notes
The authors would like to acknowledge the Cystic Fibrosis Foundation and most importantly all of the people with CF and their families who have contributed to improving care for those with CF.
Christine Bojanowski, MD, MSCR (2022-present)Edith Cheng, MS, MD; University of Washington School of Medicine (2001-2022) James F Chmiel, MD; Case Western Reserve University School of Medicine (2008-2017) Garry R Cutting, MD; Johns Hopkins University School of Medicine (2001-2022) Ronald L Gibson, MD, PhD; University of Washington (2001-2008) Barbara A Karczeski, MS, CGC, MA; Johns Hopkins University School of Medicine (2017-2022)Benjamin Lyman, DO (2022-present)Susan G Marshall, MD; Seattle Children's Hospital (2001-2004; 2017-2022)Samuel M Moskowitz, MD; Massachusetts General Hospital (2004-2017) Thida Ong, MD; Seattle Children's Hospital (2017-2022)Adrienne Savant, MD, MS (2022-present)Darci Sternen, MS, LGC; Seattle Children's Hospital (2001-2022)Jonathan F Tait, MD, PhD; University of Washington (2001-2004)Jariya Upadia, MD (2022-present)
8 August 2024 (aa) Revision: White-Sutton syndrome added to
9 March 2023 (aa) Revision:
10 November 2022 (sw) Comprehensive update posted live
2 February 2017 (sw) Comprehensive update posted live
19 February 2008 (me) Comprehensive update posted live
24 August 2004 (me) Comprehensive update posted live
26 March 2001 (me) Review posted live
6 October 1998 (jt) Original submission
• 8 August 2024 (aa) Revision: White-Sutton syndrome added to
• 9 March 2023 (aa) Revision:
• 10 November 2022 (sw) Comprehensive update posted live
• 2 February 2017 (sw) Comprehensive update posted live
• 19 February 2008 (me) Comprehensive update posted live
• 24 August 2004 (me) Comprehensive update posted live
• 26 March 2001 (me) Review posted live
• 6 October 1998 (jt) Original submission
## Acknowledgments
The authors would like to acknowledge the Cystic Fibrosis Foundation and most importantly all of the people with CF and their families who have contributed to improving care for those with CF.
## Author History
Christine Bojanowski, MD, MSCR (2022-present)Edith Cheng, MS, MD; University of Washington School of Medicine (2001-2022) James F Chmiel, MD; Case Western Reserve University School of Medicine (2008-2017) Garry R Cutting, MD; Johns Hopkins University School of Medicine (2001-2022) Ronald L Gibson, MD, PhD; University of Washington (2001-2008) Barbara A Karczeski, MS, CGC, MA; Johns Hopkins University School of Medicine (2017-2022)Benjamin Lyman, DO (2022-present)Susan G Marshall, MD; Seattle Children's Hospital (2001-2004; 2017-2022)Samuel M Moskowitz, MD; Massachusetts General Hospital (2004-2017) Thida Ong, MD; Seattle Children's Hospital (2017-2022)Adrienne Savant, MD, MS (2022-present)Darci Sternen, MS, LGC; Seattle Children's Hospital (2001-2022)Jonathan F Tait, MD, PhD; University of Washington (2001-2004)Jariya Upadia, MD (2022-present)
## Revision History
8 August 2024 (aa) Revision: White-Sutton syndrome added to
9 March 2023 (aa) Revision:
10 November 2022 (sw) Comprehensive update posted live
2 February 2017 (sw) Comprehensive update posted live
19 February 2008 (me) Comprehensive update posted live
24 August 2004 (me) Comprehensive update posted live
26 March 2001 (me) Review posted live
6 October 1998 (jt) Original submission
• 8 August 2024 (aa) Revision: White-Sutton syndrome added to
• 9 March 2023 (aa) Revision:
• 10 November 2022 (sw) Comprehensive update posted live
• 2 February 2017 (sw) Comprehensive update posted live
• 19 February 2008 (me) Comprehensive update posted live
• 24 August 2004 (me) Comprehensive update posted live
• 26 March 2001 (me) Review posted live
• 6 October 1998 (jt) Original submission
## Key Sections in this
## References
Barben J, Castellani C, Munck A, Davies JC, de Winter-de Groot KM, Gartner S, Kashirskaya N, Linnane B, Mayell SJ, McColley S, Ooi CY, Proesmans M, Ren CL, Salinas D, Sands D, Sermet-Gaudelus I, Sommerburg O, Southern KW, et al. Updated guidance on the management of children with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID). J Cyst Fibros. 2021;20:810-9. [
Borowitz DS, Grant RJ Durie PR. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr. 1995;127:681-84. [
Cystic Fibrosis Foundation, Borowitz D, Parad RB, Sharp JK, Sabadosa KA, Robinson KA, et al. Cystic Fibrosis Foundation practice guidelines for the management of infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome during the first two years of life and beyond. J Pediatr. 2009;155:S106-16. [
Cystic Fibrosis Foundation, Borowitz D, Robinson KA, Rosenfeld M, Davis SD, Sabadosa KA, et al. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr. 2009;155:S73-93. [
Floto RA, Olivier KN, Saiman L, Daley CL, Herrmann JL, Nick JA, Noone PG, Bilton D, Corris P, Gibson RL, Hempstead SE, Koetz K, Sabadosa KA, Sermet-Gaudelus I, Smyth AR, van Ingen J, Wallace RJ, Winthrop KL, Marshall BC, Haworth CS. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis. Thorax. 2016;71:i1-22. [
Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, Holland SM, Horsburgh R, Huitt G, Iademarco MF, Iseman M, Olivier K, Ruoss S, von Reyn CF, Wallace RJ Jr, Winthrop K, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175:367-416. [
Moran A, Becker D, Casella SJ, Gottlieb PA, Kirkman MS, Marshall BC, Slovis B, et al. Epidemiology, pathophysiology, and prognostic implications of cystic fibrosis-related diabetes: a technical review. Diabetes Care. 2010;33:2677-83. [
Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, Robinson KA, Sabadosa KA, Stecenko A, Slovis B, et al. Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care. 2010;33:2697-708. [
Robinson KA, Saldanha IJ, McKoy NA. Management of infants with cystic fibrosis: a summary of the evidence for the Cystic Fibrosis Foundation Working Group on care of infants with cystic fibrosis. J Pediatr. 2009;155:S94-S105. [
Sosnay PR, Salinas DB, White TB, Ren CL, Farrell PM, Raraigh KS, Girodon E, Castellani C. Applying cystic fibrosis transmembrane conductance regulator genetics and CFTR2 data to facilitate diagnoses. J Pediatr. 2017;181S:S27-S32.e1. [
Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H, et al. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc. 2008;108:832-9. [
• Barben J, Castellani C, Munck A, Davies JC, de Winter-de Groot KM, Gartner S, Kashirskaya N, Linnane B, Mayell SJ, McColley S, Ooi CY, Proesmans M, Ren CL, Salinas D, Sands D, Sermet-Gaudelus I, Sommerburg O, Southern KW, et al. Updated guidance on the management of children with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID). J Cyst Fibros. 2021;20:810-9. [
• Borowitz DS, Grant RJ Durie PR. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr. 1995;127:681-84. [
• Cystic Fibrosis Foundation, Borowitz D, Parad RB, Sharp JK, Sabadosa KA, Robinson KA, et al. Cystic Fibrosis Foundation practice guidelines for the management of infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome during the first two years of life and beyond. J Pediatr. 2009;155:S106-16. [
• Cystic Fibrosis Foundation, Borowitz D, Robinson KA, Rosenfeld M, Davis SD, Sabadosa KA, et al. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr. 2009;155:S73-93. [
• Floto RA, Olivier KN, Saiman L, Daley CL, Herrmann JL, Nick JA, Noone PG, Bilton D, Corris P, Gibson RL, Hempstead SE, Koetz K, Sabadosa KA, Sermet-Gaudelus I, Smyth AR, van Ingen J, Wallace RJ, Winthrop KL, Marshall BC, Haworth CS. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis. Thorax. 2016;71:i1-22. [
• Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, Holland SM, Horsburgh R, Huitt G, Iademarco MF, Iseman M, Olivier K, Ruoss S, von Reyn CF, Wallace RJ Jr, Winthrop K, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175:367-416. [
• Moran A, Becker D, Casella SJ, Gottlieb PA, Kirkman MS, Marshall BC, Slovis B, et al. Epidemiology, pathophysiology, and prognostic implications of cystic fibrosis-related diabetes: a technical review. Diabetes Care. 2010;33:2677-83. [
• Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, Robinson KA, Sabadosa KA, Stecenko A, Slovis B, et al. Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care. 2010;33:2697-708. [
• Robinson KA, Saldanha IJ, McKoy NA. Management of infants with cystic fibrosis: a summary of the evidence for the Cystic Fibrosis Foundation Working Group on care of infants with cystic fibrosis. J Pediatr. 2009;155:S94-S105. [
• Sosnay PR, Salinas DB, White TB, Ren CL, Farrell PM, Raraigh KS, Girodon E, Castellani C. Applying cystic fibrosis transmembrane conductance regulator genetics and CFTR2 data to facilitate diagnoses. J Pediatr. 2017;181S:S27-S32.e1. [
• Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H, et al. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc. 2008;108:832-9. [
## Published Guidelines / Consensus Statements
Barben J, Castellani C, Munck A, Davies JC, de Winter-de Groot KM, Gartner S, Kashirskaya N, Linnane B, Mayell SJ, McColley S, Ooi CY, Proesmans M, Ren CL, Salinas D, Sands D, Sermet-Gaudelus I, Sommerburg O, Southern KW, et al. Updated guidance on the management of children with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID). J Cyst Fibros. 2021;20:810-9. [
Borowitz DS, Grant RJ Durie PR. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr. 1995;127:681-84. [
Cystic Fibrosis Foundation, Borowitz D, Parad RB, Sharp JK, Sabadosa KA, Robinson KA, et al. Cystic Fibrosis Foundation practice guidelines for the management of infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome during the first two years of life and beyond. J Pediatr. 2009;155:S106-16. [
Cystic Fibrosis Foundation, Borowitz D, Robinson KA, Rosenfeld M, Davis SD, Sabadosa KA, et al. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr. 2009;155:S73-93. [
Floto RA, Olivier KN, Saiman L, Daley CL, Herrmann JL, Nick JA, Noone PG, Bilton D, Corris P, Gibson RL, Hempstead SE, Koetz K, Sabadosa KA, Sermet-Gaudelus I, Smyth AR, van Ingen J, Wallace RJ, Winthrop KL, Marshall BC, Haworth CS. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis. Thorax. 2016;71:i1-22. [
Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, Holland SM, Horsburgh R, Huitt G, Iademarco MF, Iseman M, Olivier K, Ruoss S, von Reyn CF, Wallace RJ Jr, Winthrop K, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175:367-416. [
Moran A, Becker D, Casella SJ, Gottlieb PA, Kirkman MS, Marshall BC, Slovis B, et al. Epidemiology, pathophysiology, and prognostic implications of cystic fibrosis-related diabetes: a technical review. Diabetes Care. 2010;33:2677-83. [
Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, Robinson KA, Sabadosa KA, Stecenko A, Slovis B, et al. Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care. 2010;33:2697-708. [
Robinson KA, Saldanha IJ, McKoy NA. Management of infants with cystic fibrosis: a summary of the evidence for the Cystic Fibrosis Foundation Working Group on care of infants with cystic fibrosis. J Pediatr. 2009;155:S94-S105. [
Sosnay PR, Salinas DB, White TB, Ren CL, Farrell PM, Raraigh KS, Girodon E, Castellani C. Applying cystic fibrosis transmembrane conductance regulator genetics and CFTR2 data to facilitate diagnoses. J Pediatr. 2017;181S:S27-S32.e1. [
Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H, et al. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc. 2008;108:832-9. [
• Barben J, Castellani C, Munck A, Davies JC, de Winter-de Groot KM, Gartner S, Kashirskaya N, Linnane B, Mayell SJ, McColley S, Ooi CY, Proesmans M, Ren CL, Salinas D, Sands D, Sermet-Gaudelus I, Sommerburg O, Southern KW, et al. Updated guidance on the management of children with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID). J Cyst Fibros. 2021;20:810-9. [
• Borowitz DS, Grant RJ Durie PR. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr. 1995;127:681-84. [
• Cystic Fibrosis Foundation, Borowitz D, Parad RB, Sharp JK, Sabadosa KA, Robinson KA, et al. Cystic Fibrosis Foundation practice guidelines for the management of infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome during the first two years of life and beyond. J Pediatr. 2009;155:S106-16. [
• Cystic Fibrosis Foundation, Borowitz D, Robinson KA, Rosenfeld M, Davis SD, Sabadosa KA, et al. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr. 2009;155:S73-93. [
• Floto RA, Olivier KN, Saiman L, Daley CL, Herrmann JL, Nick JA, Noone PG, Bilton D, Corris P, Gibson RL, Hempstead SE, Koetz K, Sabadosa KA, Sermet-Gaudelus I, Smyth AR, van Ingen J, Wallace RJ, Winthrop KL, Marshall BC, Haworth CS. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis. Thorax. 2016;71:i1-22. [
• Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, Holland SM, Horsburgh R, Huitt G, Iademarco MF, Iseman M, Olivier K, Ruoss S, von Reyn CF, Wallace RJ Jr, Winthrop K, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175:367-416. [
• Moran A, Becker D, Casella SJ, Gottlieb PA, Kirkman MS, Marshall BC, Slovis B, et al. Epidemiology, pathophysiology, and prognostic implications of cystic fibrosis-related diabetes: a technical review. Diabetes Care. 2010;33:2677-83. [
• Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, Robinson KA, Sabadosa KA, Stecenko A, Slovis B, et al. Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care. 2010;33:2697-708. [
• Robinson KA, Saldanha IJ, McKoy NA. Management of infants with cystic fibrosis: a summary of the evidence for the Cystic Fibrosis Foundation Working Group on care of infants with cystic fibrosis. J Pediatr. 2009;155:S94-S105. [
• Sosnay PR, Salinas DB, White TB, Ren CL, Farrell PM, Raraigh KS, Girodon E, Castellani C. Applying cystic fibrosis transmembrane conductance regulator genetics and CFTR2 data to facilitate diagnoses. J Pediatr. 2017;181S:S27-S32.e1. [
• Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H, et al. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc. 2008;108:832-9. [
## Literature Cited
|
[] |
26/3/2001
|
10/11/2022
|
8/8/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cfc
|
cfc
|
[
"CFC Syndrome",
"CFC Syndrome",
"Dual specificity mitogen-activated protein kinase kinase 1",
"Dual specificity mitogen-activated protein kinase kinase 2",
"GTPase KRas",
"Serine/threonine-protein kinase B-raf",
"BRAF",
"KRAS",
"MAP2K1",
"MAP2K2",
"Cardiofaciocutaneous Syndrome"
] |
Cardiofaciocutaneous Syndrome
|
Katherine A Rauen
|
Summary Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, and woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Affected individuals typically have some form of neurologic and/or cognitive delay (ranging from mild to severe). Most individuals have severe feeding issues, which can contribute to poor growth, and many require nasogastric or gastrostomy tube feeding. Many affected individuals have eye findings, including strabismus, nystagmus, refractive errors, and optic nerve hypoplasia. Seizures may be present and can be refractory to therapy. The diagnosis of CFC syndrome is established in a proband with suggestive clinical findings by the identification of a heterozygous pathogenic variant in CFC syndrome is inherited in an autosomal dominant manner. The majority of individuals with CFC syndrome reported to date have the disorder as the result of a
|
## Diagnosis
Cardiofaciocutaneous (CFC) syndrome is one the RASopathies: a group of syndromes having overlapping clinical features resulting from a common pathogenetic mechanism [
Cardiofaciocutaneous (CFC) syndrome
Dysmorphic facial features (see
Cardiac anomalies and rhythm disturbance, including pulmonic stenosis, hypertrophic cardiomyopathy, septal defects, and heart valve anomalies
Severe feeding issues (gastroesophageal reflux disease, aspiration, vomiting, and oral aversion) and poor growth with relative macrocephaly
Ectodermal findings, such as xerosis; sparse, curly, and woolly or brittle hair; and dystrophic nails
Lymphedema and/or chylothorax
Eye anomalies, including strabismus, nystagmus, and/or optic nerve hypoplasia
Hypotonia
Developmental delay and cognitive impairment (mild to severe)
Seizure disorder
Cryptorchidism in males
The diagnosis of CFC syndrome
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cardiofaciocutaneous (CFC) Syndrome
NA = not applicable
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
A single report of a
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Dysmorphic facial features (see
• Cardiac anomalies and rhythm disturbance, including pulmonic stenosis, hypertrophic cardiomyopathy, septal defects, and heart valve anomalies
• Severe feeding issues (gastroesophageal reflux disease, aspiration, vomiting, and oral aversion) and poor growth with relative macrocephaly
• Ectodermal findings, such as xerosis; sparse, curly, and woolly or brittle hair; and dystrophic nails
• Lymphedema and/or chylothorax
• Eye anomalies, including strabismus, nystagmus, and/or optic nerve hypoplasia
• Hypotonia
• Developmental delay and cognitive impairment (mild to severe)
• Seizure disorder
• Cryptorchidism in males
## Suggestive Findings
Cardiofaciocutaneous (CFC) syndrome
Dysmorphic facial features (see
Cardiac anomalies and rhythm disturbance, including pulmonic stenosis, hypertrophic cardiomyopathy, septal defects, and heart valve anomalies
Severe feeding issues (gastroesophageal reflux disease, aspiration, vomiting, and oral aversion) and poor growth with relative macrocephaly
Ectodermal findings, such as xerosis; sparse, curly, and woolly or brittle hair; and dystrophic nails
Lymphedema and/or chylothorax
Eye anomalies, including strabismus, nystagmus, and/or optic nerve hypoplasia
Hypotonia
Developmental delay and cognitive impairment (mild to severe)
Seizure disorder
Cryptorchidism in males
• Dysmorphic facial features (see
• Cardiac anomalies and rhythm disturbance, including pulmonic stenosis, hypertrophic cardiomyopathy, septal defects, and heart valve anomalies
• Severe feeding issues (gastroesophageal reflux disease, aspiration, vomiting, and oral aversion) and poor growth with relative macrocephaly
• Ectodermal findings, such as xerosis; sparse, curly, and woolly or brittle hair; and dystrophic nails
• Lymphedema and/or chylothorax
• Eye anomalies, including strabismus, nystagmus, and/or optic nerve hypoplasia
• Hypotonia
• Developmental delay and cognitive impairment (mild to severe)
• Seizure disorder
• Cryptorchidism in males
## Establishing the Diagnosis
The diagnosis of CFC syndrome
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cardiofaciocutaneous (CFC) Syndrome
NA = not applicable
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
A single report of a
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cardiofaciocutaneous (CFC) Syndrome
NA = not applicable
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
A single report of a
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Clinical Characteristics
Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly disorder in which individuals may have dysmorphic craniofacial features, cardiac issues, skin and hair abnormalities, hypotonia, eye abnormalities, gastrointestinal dysfunction, seizures, and varying degrees of neurocognitive delay [
Polyhydramnios is present in the vast majority of fetal cases diagnosed in utero. Maternal hyperemesis gravidarum, gestational diabetes, gestational hypertension, and preeclampsia may occur, and subjective decrease in fetal movement may be observed prenatally. Second- and third-trimester ultrasound abnormalities may include polyhydramnios, macrocephaly, macrosomia, and renal and cardiac abnormalities. Operative delivery is not uncommon.
Neonatal outcomes of CFC individuals may include irregular heartbeat, intubation, need for feeding tube, edema, chylothorax, and hyperbilirubinemia, which may be confounded by the increased rate of prematurity [
Cardiofaciocutaneous Syndrome: Frequency of Select Features
Relative macrocephaly
Triangular facies
Bitemporal narrowing
High anterior hairline
Hypoplasia of the supraorbital ridges
Widely spaced eyes
Telecanthus
Downslanted palpebral fissures
Epicanthal folds
Ptosis
Short nose with depressed bridge and anteverted nares
Ear lobe creases
Low-set ears that may be posteriorly rotated
Deep philtrum
Cupid's bow configuration of the upper lip
High-arched palate
Relative micrognathia
Pulmonic stenosis
Atrial septal defects and/or ventricular septal defects
Hypertrophic cardiomyopathy
Heart valve anomalies (mitral valve dysplasia, tricuspid valve dysplasia, and bicuspid aortic valve)
Rhythm disturbances
Aspiration or swallowing problems, which may improve with age
Recurrent vomiting, which may be association with gastroesophageal reflux disease or malrotation
Oral aversion
Dysmotility
Intestinal malrotation
Umbilical and inguinal hernia
Xerosis
Hyperkeratosis of arms, legs, and face
Keratosis pilaris
Ichthyosis
Ulerythema ophryogenes
Eczema
Hemangiomas
Café au lait macules
Erythema, both on the face or generalized
Pigmented moles that may be progressive in number
Palmoplantar hyperkeratosis over pressure zones
The vast majority of affected individuals have hypotonia due to a skeletal muscle myopathy, causing motor delays. The average age of walking in those who become ambulatory is around three years; however, many never achieve this goal.
A significant number of affected individuals remain nonverbal. In those who develop verbal language skills, the first word is said on average by age two years.
Some young adults participate in assisted living programs and may have supervised employment.
Strabismus
Nystagmus
Optic nerve hypoplasia
Astigmatism
Myopia
Hyperopia
Hyperacusis and hearing loss have been reported.
Pulmonic stenosis is more common in individuals with CFC syndrome due to a pathogenic variant in
The frequency of seizures is higher among individuals with
No genotype-phenotype correlations have been identified for specific pathogenic variants in
Hundreds of individuals with CFC syndrome have been reported in the literature. Overall prevalence is not known; prevalence in Japan is estimated at one in 810,000 [
• Relative macrocephaly
• Triangular facies
• Bitemporal narrowing
• High anterior hairline
• Hypoplasia of the supraorbital ridges
• Widely spaced eyes
• Telecanthus
• Downslanted palpebral fissures
• Epicanthal folds
• Ptosis
• Short nose with depressed bridge and anteverted nares
• Ear lobe creases
• Low-set ears that may be posteriorly rotated
• Deep philtrum
• Cupid's bow configuration of the upper lip
• High-arched palate
• Relative micrognathia
• Pulmonic stenosis
• Atrial septal defects and/or ventricular septal defects
• Hypertrophic cardiomyopathy
• Heart valve anomalies (mitral valve dysplasia, tricuspid valve dysplasia, and bicuspid aortic valve)
• Rhythm disturbances
• Aspiration or swallowing problems, which may improve with age
• Recurrent vomiting, which may be association with gastroesophageal reflux disease or malrotation
• Oral aversion
• Dysmotility
• Intestinal malrotation
• Umbilical and inguinal hernia
• Xerosis
• Hyperkeratosis of arms, legs, and face
• Keratosis pilaris
• Ichthyosis
• Ulerythema ophryogenes
• Eczema
• Hemangiomas
• Café au lait macules
• Erythema, both on the face or generalized
• Pigmented moles that may be progressive in number
• Palmoplantar hyperkeratosis over pressure zones
• Xerosis
• Hyperkeratosis of arms, legs, and face
• Keratosis pilaris
• Ichthyosis
• Ulerythema ophryogenes
• Eczema
• Hemangiomas
• Café au lait macules
• Erythema, both on the face or generalized
• Pigmented moles that may be progressive in number
• Palmoplantar hyperkeratosis over pressure zones
• Xerosis
• Hyperkeratosis of arms, legs, and face
• Keratosis pilaris
• Ichthyosis
• Ulerythema ophryogenes
• Eczema
• Hemangiomas
• Café au lait macules
• Erythema, both on the face or generalized
• Pigmented moles that may be progressive in number
• Palmoplantar hyperkeratosis over pressure zones
• The vast majority of affected individuals have hypotonia due to a skeletal muscle myopathy, causing motor delays. The average age of walking in those who become ambulatory is around three years; however, many never achieve this goal.
• A significant number of affected individuals remain nonverbal. In those who develop verbal language skills, the first word is said on average by age two years.
• Some young adults participate in assisted living programs and may have supervised employment.
• Strabismus
• Nystagmus
• Optic nerve hypoplasia
• Astigmatism
• Myopia
• Hyperopia
• Pulmonic stenosis is more common in individuals with CFC syndrome due to a pathogenic variant in
• The frequency of seizures is higher among individuals with
## Clinical Description
Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly disorder in which individuals may have dysmorphic craniofacial features, cardiac issues, skin and hair abnormalities, hypotonia, eye abnormalities, gastrointestinal dysfunction, seizures, and varying degrees of neurocognitive delay [
Polyhydramnios is present in the vast majority of fetal cases diagnosed in utero. Maternal hyperemesis gravidarum, gestational diabetes, gestational hypertension, and preeclampsia may occur, and subjective decrease in fetal movement may be observed prenatally. Second- and third-trimester ultrasound abnormalities may include polyhydramnios, macrocephaly, macrosomia, and renal and cardiac abnormalities. Operative delivery is not uncommon.
Neonatal outcomes of CFC individuals may include irregular heartbeat, intubation, need for feeding tube, edema, chylothorax, and hyperbilirubinemia, which may be confounded by the increased rate of prematurity [
Cardiofaciocutaneous Syndrome: Frequency of Select Features
Relative macrocephaly
Triangular facies
Bitemporal narrowing
High anterior hairline
Hypoplasia of the supraorbital ridges
Widely spaced eyes
Telecanthus
Downslanted palpebral fissures
Epicanthal folds
Ptosis
Short nose with depressed bridge and anteverted nares
Ear lobe creases
Low-set ears that may be posteriorly rotated
Deep philtrum
Cupid's bow configuration of the upper lip
High-arched palate
Relative micrognathia
Pulmonic stenosis
Atrial septal defects and/or ventricular septal defects
Hypertrophic cardiomyopathy
Heart valve anomalies (mitral valve dysplasia, tricuspid valve dysplasia, and bicuspid aortic valve)
Rhythm disturbances
Aspiration or swallowing problems, which may improve with age
Recurrent vomiting, which may be association with gastroesophageal reflux disease or malrotation
Oral aversion
Dysmotility
Intestinal malrotation
Umbilical and inguinal hernia
Xerosis
Hyperkeratosis of arms, legs, and face
Keratosis pilaris
Ichthyosis
Ulerythema ophryogenes
Eczema
Hemangiomas
Café au lait macules
Erythema, both on the face or generalized
Pigmented moles that may be progressive in number
Palmoplantar hyperkeratosis over pressure zones
The vast majority of affected individuals have hypotonia due to a skeletal muscle myopathy, causing motor delays. The average age of walking in those who become ambulatory is around three years; however, many never achieve this goal.
A significant number of affected individuals remain nonverbal. In those who develop verbal language skills, the first word is said on average by age two years.
Some young adults participate in assisted living programs and may have supervised employment.
Strabismus
Nystagmus
Optic nerve hypoplasia
Astigmatism
Myopia
Hyperopia
Hyperacusis and hearing loss have been reported.
• Relative macrocephaly
• Triangular facies
• Bitemporal narrowing
• High anterior hairline
• Hypoplasia of the supraorbital ridges
• Widely spaced eyes
• Telecanthus
• Downslanted palpebral fissures
• Epicanthal folds
• Ptosis
• Short nose with depressed bridge and anteverted nares
• Ear lobe creases
• Low-set ears that may be posteriorly rotated
• Deep philtrum
• Cupid's bow configuration of the upper lip
• High-arched palate
• Relative micrognathia
• Pulmonic stenosis
• Atrial septal defects and/or ventricular septal defects
• Hypertrophic cardiomyopathy
• Heart valve anomalies (mitral valve dysplasia, tricuspid valve dysplasia, and bicuspid aortic valve)
• Rhythm disturbances
• Aspiration or swallowing problems, which may improve with age
• Recurrent vomiting, which may be association with gastroesophageal reflux disease or malrotation
• Oral aversion
• Dysmotility
• Intestinal malrotation
• Umbilical and inguinal hernia
• Xerosis
• Hyperkeratosis of arms, legs, and face
• Keratosis pilaris
• Ichthyosis
• Ulerythema ophryogenes
• Eczema
• Hemangiomas
• Café au lait macules
• Erythema, both on the face or generalized
• Pigmented moles that may be progressive in number
• Palmoplantar hyperkeratosis over pressure zones
• Xerosis
• Hyperkeratosis of arms, legs, and face
• Keratosis pilaris
• Ichthyosis
• Ulerythema ophryogenes
• Eczema
• Hemangiomas
• Café au lait macules
• Erythema, both on the face or generalized
• Pigmented moles that may be progressive in number
• Palmoplantar hyperkeratosis over pressure zones
• Xerosis
• Hyperkeratosis of arms, legs, and face
• Keratosis pilaris
• Ichthyosis
• Ulerythema ophryogenes
• Eczema
• Hemangiomas
• Café au lait macules
• Erythema, both on the face or generalized
• Pigmented moles that may be progressive in number
• Palmoplantar hyperkeratosis over pressure zones
• The vast majority of affected individuals have hypotonia due to a skeletal muscle myopathy, causing motor delays. The average age of walking in those who become ambulatory is around three years; however, many never achieve this goal.
• A significant number of affected individuals remain nonverbal. In those who develop verbal language skills, the first word is said on average by age two years.
• Some young adults participate in assisted living programs and may have supervised employment.
• Strabismus
• Nystagmus
• Optic nerve hypoplasia
• Astigmatism
• Myopia
• Hyperopia
## Phenotype Correlations by Gene
Pulmonic stenosis is more common in individuals with CFC syndrome due to a pathogenic variant in
The frequency of seizures is higher among individuals with
• Pulmonic stenosis is more common in individuals with CFC syndrome due to a pathogenic variant in
• The frequency of seizures is higher among individuals with
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified for specific pathogenic variants in
## Nomenclature
## Prevalence
Hundreds of individuals with CFC syndrome have been reported in the literature. Overall prevalence is not known; prevalence in Japan is estimated at one in 810,000 [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Other phenotypes associated with
Allelic Disorders Due to Germline Pathogenic Variants
## Differential Diagnosis
Slow growth in infancy as a result of severe postnatal feeding difficulties
Short stature
Developmental delay or intellectual disability
Coarse facial features (full lips, large mouth, full nasal tip)
Hair that may be curly, sparse, and fine with synophrys, trichomegaly, and abnormalities of the scalp hair shafts
Loose, soft skin with deep palmar and plantar creases
Papillomata of the face and perianal region
Diffuse hypotonia and joint laxity with ulnar deviation of the wrists and fingers
Tight Achilles (calcaneal) tendons
Cardiac involvement including cardiac hypertrophy (usually typical hypertrophic cardiomyopathy [HCM]), congenital heart defect (usually valvar pulmonic stenosis), and arrhythmia (usually supraventricular tachycardia, especially chaotic atrial rhythm / multifocal atrial tachycardia or ectopic atrial tachycardia)
Relative or absolute macrocephaly (typically). Postnatal cerebellar overgrowth can result in the development of a Chiari I malformation with associated anomalies including hydrocephalus or syringomyelia.
Individuals with Costello syndrome are at an approximately 15% lifetime risk for malignant tumors including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults.
Although
Characteristic facies that includes features similar to CFC, such as triangular facies, macrocephaly, broad forehead, downslanting palpebral fissures, short nose with depressed nasal bridge and anteverted nares, a high-arched palate, and low-set, posteriorly rotated ears.
Short stature. Although birth length is usually normal, final adult height approaches the lower limit of normal.
Congenital heart defect. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 25%-71% of individuals. Hypertrophic cardiomyopathy, found in 20%-29% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot.
Developmental delay of variable degree. Up to one third of affected individuals have mild intellectual disability.
Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities.
More than ten genes are known to be associated with Noonan syndrome. More commonly involved genes include
Craniofacial findings in CFC syndrome are reminiscent of those described in Noonan syndrome (macrocephaly, broad forehead, bitemporal narrowing, hypoplasia of the supraorbital ridges, downslanting palpebral fissures with ptosis, short nose with depressed nasal bridge and anteverted nares, low-set ears with prominent helices that may be posteriorly rotated, and high-arched palate), underscoring the importance of molecular genetic testing to establish the correct diagnosis.
Noonan syndrome is most often inherited in an autosomal dominant manner. While many individuals with autosomal dominant Noonan syndrome have a
• Slow growth in infancy as a result of severe postnatal feeding difficulties
• Short stature
• Developmental delay or intellectual disability
• Coarse facial features (full lips, large mouth, full nasal tip)
• Hair that may be curly, sparse, and fine with synophrys, trichomegaly, and abnormalities of the scalp hair shafts
• Loose, soft skin with deep palmar and plantar creases
• Papillomata of the face and perianal region
• Diffuse hypotonia and joint laxity with ulnar deviation of the wrists and fingers
• Tight Achilles (calcaneal) tendons
• Cardiac involvement including cardiac hypertrophy (usually typical hypertrophic cardiomyopathy [HCM]), congenital heart defect (usually valvar pulmonic stenosis), and arrhythmia (usually supraventricular tachycardia, especially chaotic atrial rhythm / multifocal atrial tachycardia or ectopic atrial tachycardia)
• Relative or absolute macrocephaly (typically). Postnatal cerebellar overgrowth can result in the development of a Chiari I malformation with associated anomalies including hydrocephalus or syringomyelia.
• Characteristic facies that includes features similar to CFC, such as triangular facies, macrocephaly, broad forehead, downslanting palpebral fissures, short nose with depressed nasal bridge and anteverted nares, a high-arched palate, and low-set, posteriorly rotated ears.
• Short stature. Although birth length is usually normal, final adult height approaches the lower limit of normal.
• Congenital heart defect. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 25%-71% of individuals. Hypertrophic cardiomyopathy, found in 20%-29% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot.
• Developmental delay of variable degree. Up to one third of affected individuals have mild intellectual disability.
• Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities.
## Management
Clinical practice guidelines for cardiofaciocutaneous (CFC) syndrome have been published [
To establish the extent of disease and needs in an individual diagnosed with CFC syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Cardiofaciocutaneous (CFC) Syndrome
To incl brain MRI in persons w/rapid ↑ in head growth, regression of developmental skills, seizures, changes in neurologic findings, or concerns about optic nerve hypoplasia on ophthalmologic eval
Consider EEG if seizures are a concern.
Consider nerve conduction velocities & electromyogram in those w/suspected peripheral neuropathy.
Education about ↑ risk for development of infantile spasms, seizures, hydrocephalus, & Type 1 Chiari malformation
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl eval of aspiration risk & nutritional status
Consider swallowing study &/or studies for GERD.
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Be mindful of possible malrotation.
Assessment for signs/symptoms of constipation
Gross motor & fine motor skills
Contractures, hip dysplasia, & kyphoscoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
With special assessment for pulmonary stenosis, hypertrophic cardiomyopathy, &/or septal defects
If there are concerns about arrhythmia, then consider 24-hour Holter eval.
Skin issues typically evolve over time.
If there is significant lymphedema or large hemangiomas, consider referral to vascular anomalies specialist or clinic.
In persons w/history of bruising or bleeding problems, consider referral to hematologist if there are abnormalities on these screening blood tests.
Eval for bleeding issues should be done prior to any invasive or surgical procedure.
Community or
Social work involvement for parental support;
Home nursing referral.
Adapted in part from
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; CBC = complete blood count; DXA = dual-energy x-ray absorptiometry; GERD = gastroesophageal reflux disease; IGF-1 = insulin-like growth factor 1; IGFBP-3 = insulin-like growth factor binding protein 3; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; T4 = thyroxine; TSH = thyroid-stimulating hormone
Affected individuals are also at risk for the development of neuropathy and complaints of pain.
Skin issues may include keratosis pilaris, ulerythema ophryogenes, eczema, progressive multiple pigmented nevi, dystrophic nails, lymphedema, hemangiomas, hyperkeratosis, and generalized hyperpigmentation.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Consensus clinical management guidelines have been published [
There is no cure for CFC syndrome.
Treatment of Manifestations in Individuals with Cardiofaciocutaneous Syndrome
↑ caloric intake may be considered.
Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues.
Children w/severe gastroesophageal reflux may require a Nissen fundoplication.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Seizures may be refractory to single-agent therapy & may require polytherapy.
In those w/infantile spasms, consult w/cardiologist prior to starting steroid medication because of baseline risk of developing cardiomyopathy.
Education of parents/caregivers
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Scoliosis, hip dysplasia, joint contractures, or pectus deformity managed as in general population.
Eval for bleeding issues should be done prior to any invasive or surgical procedure.
Xerosis & pruritus may be relieved by ↑ ambient humidity or using hydrating lotions.
Hyperkeratoses, lymphedema, & hemangiomas are treated as in general population.
Antibiotic treatment for skin infection, esp in presence of lymphedema
Nevi may be progressive.
For those w/significant lymphedema, mgmt through lymphedema or vascular anomalies clinic may be indicated.
Growth hormone therapy may be considered.
Persons w/diagnosis of hypertrophic cardiomyopathy must be monitored closely while on growth hormone therapy.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement and/or home nursing
Consider involvement in adaptive sports or Special Olympics.
Adapted in part from
ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; OT = occupational therapy; PE = pressure equalizer; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder or anxiety, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in
Recommended Surveillance for Individuals with Cardiofaciocutaneous Syndrome
Measurement of growth parameters, incl weight, length/height, & head circumference
Refer to endocrinologist at age 2-3 yrs (or earlier if there are concerns about growth) to monitor growth velocity.
Adapted in part from
DXA = dual-energy x-ray absorptiometry
Growth failure may be a sign of growth hormone deficiency or thyroid hormone deficiency.
Affected individuals are at risk of developing Chari I malformation.
Perform spine MRI prior to any spinal surgery to assess for Chiari malformation and/or spinal abnormalities [
Evaluation for bleeding issues should be done prior to any invasive or surgical procedure [
Periodic echocardiogram and electrocardiogram are necessary throughout life, as hypertrophic cardiomyopathy and rhythm disturbances may develop later in life.
Individuals with CFC syndrome report heat intolerance; therefore, overexposure to heat and strenuous activity should be avoided. Hydrate as needed.
In individuals with evidence of peripheral neuropathy, drugs with a neurotoxic effect should be avoided, per standard supportive treatment according to the individual's neurologist or rehabilitation medicine specialist.
See
A pregnant female suspected of having CFC syndrome warrants high-risk obstetric care from a trained maternal-fetal medicine physician due to possible polyhydramnios, maternal cardiac issues, and/or maternal hypertension.
Search
• To incl brain MRI in persons w/rapid ↑ in head growth, regression of developmental skills, seizures, changes in neurologic findings, or concerns about optic nerve hypoplasia on ophthalmologic eval
• Consider EEG if seizures are a concern.
• Consider nerve conduction velocities & electromyogram in those w/suspected peripheral neuropathy.
• Education about ↑ risk for development of infantile spasms, seizures, hydrocephalus, & Type 1 Chiari malformation
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl eval of aspiration risk & nutritional status
• Consider swallowing study &/or studies for GERD.
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Be mindful of possible malrotation.
• Assessment for signs/symptoms of constipation
• Gross motor & fine motor skills
• Contractures, hip dysplasia, & kyphoscoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• With special assessment for pulmonary stenosis, hypertrophic cardiomyopathy, &/or septal defects
• If there are concerns about arrhythmia, then consider 24-hour Holter eval.
• Skin issues typically evolve over time.
• If there is significant lymphedema or large hemangiomas, consider referral to vascular anomalies specialist or clinic.
• In persons w/history of bruising or bleeding problems, consider referral to hematologist if there are abnormalities on these screening blood tests.
• Eval for bleeding issues should be done prior to any invasive or surgical procedure.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• ↑ caloric intake may be considered.
• Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues.
• Children w/severe gastroesophageal reflux may require a Nissen fundoplication.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Seizures may be refractory to single-agent therapy & may require polytherapy.
• In those w/infantile spasms, consult w/cardiologist prior to starting steroid medication because of baseline risk of developing cardiomyopathy.
• Education of parents/caregivers
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Scoliosis, hip dysplasia, joint contractures, or pectus deformity managed as in general population.
• Eval for bleeding issues should be done prior to any invasive or surgical procedure.
• Xerosis & pruritus may be relieved by ↑ ambient humidity or using hydrating lotions.
• Hyperkeratoses, lymphedema, & hemangiomas are treated as in general population.
• Antibiotic treatment for skin infection, esp in presence of lymphedema
• Nevi may be progressive.
• For those w/significant lymphedema, mgmt through lymphedema or vascular anomalies clinic may be indicated.
• Growth hormone therapy may be considered.
• Persons w/diagnosis of hypertrophic cardiomyopathy must be monitored closely while on growth hormone therapy.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement and/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Measurement of growth parameters, incl weight, length/height, & head circumference
• Refer to endocrinologist at age 2-3 yrs (or earlier if there are concerns about growth) to monitor growth velocity.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CFC syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Cardiofaciocutaneous (CFC) Syndrome
To incl brain MRI in persons w/rapid ↑ in head growth, regression of developmental skills, seizures, changes in neurologic findings, or concerns about optic nerve hypoplasia on ophthalmologic eval
Consider EEG if seizures are a concern.
Consider nerve conduction velocities & electromyogram in those w/suspected peripheral neuropathy.
Education about ↑ risk for development of infantile spasms, seizures, hydrocephalus, & Type 1 Chiari malformation
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl eval of aspiration risk & nutritional status
Consider swallowing study &/or studies for GERD.
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Be mindful of possible malrotation.
Assessment for signs/symptoms of constipation
Gross motor & fine motor skills
Contractures, hip dysplasia, & kyphoscoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
With special assessment for pulmonary stenosis, hypertrophic cardiomyopathy, &/or septal defects
If there are concerns about arrhythmia, then consider 24-hour Holter eval.
Skin issues typically evolve over time.
If there is significant lymphedema or large hemangiomas, consider referral to vascular anomalies specialist or clinic.
In persons w/history of bruising or bleeding problems, consider referral to hematologist if there are abnormalities on these screening blood tests.
Eval for bleeding issues should be done prior to any invasive or surgical procedure.
Community or
Social work involvement for parental support;
Home nursing referral.
Adapted in part from
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; CBC = complete blood count; DXA = dual-energy x-ray absorptiometry; GERD = gastroesophageal reflux disease; IGF-1 = insulin-like growth factor 1; IGFBP-3 = insulin-like growth factor binding protein 3; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; T4 = thyroxine; TSH = thyroid-stimulating hormone
Affected individuals are also at risk for the development of neuropathy and complaints of pain.
Skin issues may include keratosis pilaris, ulerythema ophryogenes, eczema, progressive multiple pigmented nevi, dystrophic nails, lymphedema, hemangiomas, hyperkeratosis, and generalized hyperpigmentation.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl brain MRI in persons w/rapid ↑ in head growth, regression of developmental skills, seizures, changes in neurologic findings, or concerns about optic nerve hypoplasia on ophthalmologic eval
• Consider EEG if seizures are a concern.
• Consider nerve conduction velocities & electromyogram in those w/suspected peripheral neuropathy.
• Education about ↑ risk for development of infantile spasms, seizures, hydrocephalus, & Type 1 Chiari malformation
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl eval of aspiration risk & nutritional status
• Consider swallowing study &/or studies for GERD.
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Be mindful of possible malrotation.
• Assessment for signs/symptoms of constipation
• Gross motor & fine motor skills
• Contractures, hip dysplasia, & kyphoscoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• With special assessment for pulmonary stenosis, hypertrophic cardiomyopathy, &/or septal defects
• If there are concerns about arrhythmia, then consider 24-hour Holter eval.
• Skin issues typically evolve over time.
• If there is significant lymphedema or large hemangiomas, consider referral to vascular anomalies specialist or clinic.
• In persons w/history of bruising or bleeding problems, consider referral to hematologist if there are abnormalities on these screening blood tests.
• Eval for bleeding issues should be done prior to any invasive or surgical procedure.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Consensus clinical management guidelines have been published [
There is no cure for CFC syndrome.
Treatment of Manifestations in Individuals with Cardiofaciocutaneous Syndrome
↑ caloric intake may be considered.
Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues.
Children w/severe gastroesophageal reflux may require a Nissen fundoplication.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Seizures may be refractory to single-agent therapy & may require polytherapy.
In those w/infantile spasms, consult w/cardiologist prior to starting steroid medication because of baseline risk of developing cardiomyopathy.
Education of parents/caregivers
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Scoliosis, hip dysplasia, joint contractures, or pectus deformity managed as in general population.
Eval for bleeding issues should be done prior to any invasive or surgical procedure.
Xerosis & pruritus may be relieved by ↑ ambient humidity or using hydrating lotions.
Hyperkeratoses, lymphedema, & hemangiomas are treated as in general population.
Antibiotic treatment for skin infection, esp in presence of lymphedema
Nevi may be progressive.
For those w/significant lymphedema, mgmt through lymphedema or vascular anomalies clinic may be indicated.
Growth hormone therapy may be considered.
Persons w/diagnosis of hypertrophic cardiomyopathy must be monitored closely while on growth hormone therapy.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement and/or home nursing
Consider involvement in adaptive sports or Special Olympics.
Adapted in part from
ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; OT = occupational therapy; PE = pressure equalizer; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder or anxiety, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• ↑ caloric intake may be considered.
• Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues.
• Children w/severe gastroesophageal reflux may require a Nissen fundoplication.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Seizures may be refractory to single-agent therapy & may require polytherapy.
• In those w/infantile spasms, consult w/cardiologist prior to starting steroid medication because of baseline risk of developing cardiomyopathy.
• Education of parents/caregivers
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Scoliosis, hip dysplasia, joint contractures, or pectus deformity managed as in general population.
• Eval for bleeding issues should be done prior to any invasive or surgical procedure.
• Xerosis & pruritus may be relieved by ↑ ambient humidity or using hydrating lotions.
• Hyperkeratoses, lymphedema, & hemangiomas are treated as in general population.
• Antibiotic treatment for skin infection, esp in presence of lymphedema
• Nevi may be progressive.
• For those w/significant lymphedema, mgmt through lymphedema or vascular anomalies clinic may be indicated.
• Growth hormone therapy may be considered.
• Persons w/diagnosis of hypertrophic cardiomyopathy must be monitored closely while on growth hormone therapy.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement and/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder or anxiety, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in
Recommended Surveillance for Individuals with Cardiofaciocutaneous Syndrome
Measurement of growth parameters, incl weight, length/height, & head circumference
Refer to endocrinologist at age 2-3 yrs (or earlier if there are concerns about growth) to monitor growth velocity.
Adapted in part from
DXA = dual-energy x-ray absorptiometry
Growth failure may be a sign of growth hormone deficiency or thyroid hormone deficiency.
Affected individuals are at risk of developing Chari I malformation.
Perform spine MRI prior to any spinal surgery to assess for Chiari malformation and/or spinal abnormalities [
Evaluation for bleeding issues should be done prior to any invasive or surgical procedure [
Periodic echocardiogram and electrocardiogram are necessary throughout life, as hypertrophic cardiomyopathy and rhythm disturbances may develop later in life.
• Measurement of growth parameters, incl weight, length/height, & head circumference
• Refer to endocrinologist at age 2-3 yrs (or earlier if there are concerns about growth) to monitor growth velocity.
## Agents/Circumstances to Avoid
Individuals with CFC syndrome report heat intolerance; therefore, overexposure to heat and strenuous activity should be avoided. Hydrate as needed.
In individuals with evidence of peripheral neuropathy, drugs with a neurotoxic effect should be avoided, per standard supportive treatment according to the individual's neurologist or rehabilitation medicine specialist.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
A pregnant female suspected of having CFC syndrome warrants high-risk obstetric care from a trained maternal-fetal medicine physician due to possible polyhydramnios, maternal cardiac issues, and/or maternal hypertension.
## Therapies Under Investigation
Search
## Genetic Counseling
Cardiofaciocutaneous (CFC) syndrome is inherited in an autosomal dominant manner.
The majority of individuals with CFC syndrome reported to date have the disorder as the result of a
Individuals diagnosed with CFC syndrome may have an affected parent; instances of familial recurrence of CFC are increasingly reported in the medical literature [
Molecular genetic testing for the pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
The family history of some individuals diagnosed with CFC syndrome may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
If the CFC-causing pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected and to the parents of an affected child.
Once the CFC syndrome-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for CFC are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The majority of individuals with CFC syndrome reported to date have the disorder as the result of a
• Individuals diagnosed with CFC syndrome may have an affected parent; instances of familial recurrence of CFC are increasingly reported in the medical literature [
• Molecular genetic testing for the pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• The family history of some individuals diagnosed with CFC syndrome may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the CFC-causing pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected and to the parents of an affected child.
## Mode of Inheritance
Cardiofaciocutaneous (CFC) syndrome is inherited in an autosomal dominant manner.
## Risk to Family Members
The majority of individuals with CFC syndrome reported to date have the disorder as the result of a
Individuals diagnosed with CFC syndrome may have an affected parent; instances of familial recurrence of CFC are increasingly reported in the medical literature [
Molecular genetic testing for the pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
The family history of some individuals diagnosed with CFC syndrome may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
If the CFC-causing pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [
• The majority of individuals with CFC syndrome reported to date have the disorder as the result of a
• Individuals diagnosed with CFC syndrome may have an affected parent; instances of familial recurrence of CFC are increasingly reported in the medical literature [
• Molecular genetic testing for the pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• The family history of some individuals diagnosed with CFC syndrome may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the CFC-causing pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected and to the parents of an affected child.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected and to the parents of an affected child.
## Prenatal Testing and Preimplantation Genetic Testing
Once the CFC syndrome-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for CFC are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
16716 Cory Cactus Drive
Austin TX 78738
•
• 16716 Cory Cactus Drive
• Austin TX 78738
•
•
•
## Molecular Genetics
Cardiofaciocutaneous Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Cardiofaciocutaneous Syndrome (
The four genes currently known to be associated with cardiofaciocutaneous (CFC) syndrome are in the Ras/mitogen-activated protein kinase (MAPK) signaling cascade. The MAPK signaling cascade of dual-specificity kinases [
Cardiofaciocutaneous (CFC) Syndrome: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the author.
Genes from
## Molecular Pathogenesis
The four genes currently known to be associated with cardiofaciocutaneous (CFC) syndrome are in the Ras/mitogen-activated protein kinase (MAPK) signaling cascade. The MAPK signaling cascade of dual-specificity kinases [
Cardiofaciocutaneous (CFC) Syndrome: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the author.
Genes from
## Cancer and Benign Tumors
## Chapter Notes
Dr Rauen serves on the Medical Advisory Board for CFC International, Inc, and is codirector and member of the Professional Advisory Board for the Costello Syndrome Family Network. She also is a member of the RASopathies Network Scientific Advisory Board and the Global Genes Advisory Board.
Special thanks to CFC International, the Costello Syndrome Family Network, and RASopathiesNet for their ongoing support of research in genomic medicine.
9 February 2023 (ma) Comprehensive update posted live
3 March 2016 (ha) Comprehensive update posted live
6 September 2012 (cd) Revision: multigene panels for Noonan / Costello / LEOPARD / cardiofaciocutaneous syndrome(s) (RAS/MAPK pathway) available clinically
23 December 2010 (me) Comprehensive update posted live
18 January 2007 (me) Review posted live
14 September 2006 (kar) Original submission
• 9 February 2023 (ma) Comprehensive update posted live
• 3 March 2016 (ha) Comprehensive update posted live
• 6 September 2012 (cd) Revision: multigene panels for Noonan / Costello / LEOPARD / cardiofaciocutaneous syndrome(s) (RAS/MAPK pathway) available clinically
• 23 December 2010 (me) Comprehensive update posted live
• 18 January 2007 (me) Review posted live
• 14 September 2006 (kar) Original submission
## Author Notes
Dr Rauen serves on the Medical Advisory Board for CFC International, Inc, and is codirector and member of the Professional Advisory Board for the Costello Syndrome Family Network. She also is a member of the RASopathies Network Scientific Advisory Board and the Global Genes Advisory Board.
## Acknowledgments
Special thanks to CFC International, the Costello Syndrome Family Network, and RASopathiesNet for their ongoing support of research in genomic medicine.
## Revision History
9 February 2023 (ma) Comprehensive update posted live
3 March 2016 (ha) Comprehensive update posted live
6 September 2012 (cd) Revision: multigene panels for Noonan / Costello / LEOPARD / cardiofaciocutaneous syndrome(s) (RAS/MAPK pathway) available clinically
23 December 2010 (me) Comprehensive update posted live
18 January 2007 (me) Review posted live
14 September 2006 (kar) Original submission
• 9 February 2023 (ma) Comprehensive update posted live
• 3 March 2016 (ha) Comprehensive update posted live
• 6 September 2012 (cd) Revision: multigene panels for Noonan / Costello / LEOPARD / cardiofaciocutaneous syndrome(s) (RAS/MAPK pathway) available clinically
• 23 December 2010 (me) Comprehensive update posted live
• 18 January 2007 (me) Review posted live
• 14 September 2006 (kar) Original submission
## References
## Literature Cited
Children with CFC syndrome
A. Three young children with
B. Two boys, age 12 and eight years, with
C. Two boys age six years, with
Courtesy of CFC International
|
[] |
18/1/2007
|
9/2/2023
|
6/9/2012
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cfeom
|
cfeom
|
[
"CFEOM",
"CFEOM",
"Tukel Syndrome",
"Kinesin-like protein KIF21A",
"Paired mesoderm homeobox protein 2A",
"Tubulin beta-2B chain",
"Tubulin beta-3 chain",
"KIF21A",
"PHOX2A",
"TUBB2B",
"TUBB3",
"Congenital Fibrosis of the Extraocular Muscles",
"Overview"
] |
Congenital Fibrosis of the Extraocular Muscles Overview
|
Mary C Whitman, Julie A Jurgens, David G Hunter, Elizabeth C Engle
|
Summary The purpose of this overview is to: Describe the Review the Review the disorders to consider the Provide an Review Inform
|
## Clinical Characteristics of Congenital Fibrosis of the Extraocular Muscles
Congenital fibrosis of the extraocular muscles (CFEOM) is diagnosed based on characteristic eye findings: congenital non-progressive ophthalmoplegia (inability to move the eyes) with or without ptosis (droopy eyelids) affecting part or all of the oculomotor nucleus and nerve (cranial nerve III) and its innervated muscles (superior, medial, and inferior recti, inferior oblique, and levator palpabrae superioris) and sometimes the trochlear and abducens nuclei and nerves (cranial nerves IV and VI) and their innervated muscles (superior oblique muscle and lateral rectus muscle, respectively).
In general, affected individuals have severe limitation of vertical gaze (usually upgaze) and variable limitation of horizontal gaze. Individuals with CFEOM frequently compensate for the ophthalmoplegia by maintaining abnormal head positions (chin up) at rest and by moving their heads rather than their eyes to track objects. Binocular vision is typically absent. Refractive errors are common.
Although once felt to result from primary fibrosis of the extraocular muscles, neuroanatomic, genetic, and neuroimaging findings suggest that the various forms of CFEOM result from abnormal development of oculomotor neurons and their processes [
Congenital Fibrosis of the Extraocular Muscles: Phenotypes
CNS = central nervous system; ID = intellectual disability; nl = normal
This phenotype, caused by
## Genetic Causes of CFEOM
CFEOM: Associated Genes
Genes are listed alphabetically.
CFEOM: Gene-Phenotype Correlations
DD = developmental delay; ID = intellectual disability; nl = normal
Genes are listed alphabetically.
Allelic w/
Allelic w/
Recently, one specific
## Genotype-Phenotype Correlations
Recently, one specific
## Differential Diagnosis of CFEOM
The term "congenital cranial dysinnervation disorders (CCDDs)" was coined to refer to disorders of innervation of cranial musculature [
Genetic disorders with ophthalmoplegia in the differential diagnosis of CFEOM are summarized in
Genetic Disorders with Ophthalmoplegia in the Differential Diagnosis of Congenital Fibrosis of the Extraocular Muscles
DRRS: uni- or bilateral Duane anomaly & radial ray malformation
AROS: radial ray malformations, renal abnormalities, ocular coloboma, & Duane anomaly
AD = autosomal dominant; AR = autosomal recessive; CFEOM = congenital fibrosis of the extraocular muscles; ID = intellectual disability; Mat = maternal; MOI = mode of inheritance; mtDNA = mitochondrial DNA; SNHL = sensorineural hearing loss
Duane syndrome is characterized by horizontal eye movement limitation, usually of abduction, with retraction of the globe and narrowing of the palpebral fissure on attempted adduction. It is believed to result from abnormal development of the abducens nucleus and nerve (cranial nerve VI). Although the majority of cases of Duane syndrome are simplex and isolated (i.e., not associated with other malformations), rare families with autosomal dominant or autosomal recessive inheritance of Duane syndrome with or without accompanying anomalies have been reported.
Hereditary congenital facial paresis 1 (HCFP1) maps to chromosome 3q21-q22 (OMIM
• DRRS: uni- or bilateral Duane anomaly & radial ray malformation
• AROS: radial ray malformations, renal abnormalities, ocular coloboma, & Duane anomaly
## Evaluation Strategy to Identify the Genetic Cause of CFEOM in a Proband (When Possible)
Establishing a specific genetic cause of CFEOM:
Can aid in discussions of prognosis (which are beyond the scope of this
Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.
Bilateral CFEOM with ptosis and upgaze restriction without other physical findings can be caused by pathogenic variants in
Unilateral CFEOM or CFEOM without ptosis is most often caused by pathogenic variants in
The combination of CFEOM3 with facial weakness, other cranial nerve dysfunction, peripheral neuropathy, microphallus and/or cryptorchidism, or congenital joint contractures strongly suggests specific
Testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved (see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
• Can aid in discussions of prognosis (which are beyond the scope of this
• Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.
• Bilateral CFEOM with ptosis and upgaze restriction without other physical findings can be caused by pathogenic variants in
• Unilateral CFEOM or CFEOM without ptosis is most often caused by pathogenic variants in
• The combination of CFEOM3 with facial weakness, other cranial nerve dysfunction, peripheral neuropathy, microphallus and/or cryptorchidism, or congenital joint contractures strongly suggests specific
## Molecular Genetic Testing
Testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved (see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
## Management of CFEOM
To establish the extent of ophthalmologic involvement and needs in an individual diagnosed with congenital fibrosis of the extraocular muscles, the following evaluations are recommended:
Consultation with a clinical geneticist and/or genetic counselor
Ophthalmologic examination:
Determination of resting gaze position, head position with eyes in resting gaze position, and vertical and horizontal gaze restrictions
Evaluation for aberrant movements including synergistic convergence and divergence, globe retraction, Marcus Gunn jaw wink
Measurement of palpebral fissure size
Anterior segment evaluation to detect corneal exposure
Levator function testing
Optional forced duction testing
Refraction, including cycloplegic refraction in children
Photographic documentation for future comparison
Strongly recommended if eye muscle surgery is planned:
Brain and brain stem MRI scan to determine the size and/or course of the oculomotor and trochlear nerves
High-resolution orbital MRI (1- to 3-mm cuts) to detect abnormalities in the size and/or course of the extraocular muscle(s) and atrophy of the superior rectus-levator complex
Referral to relevant specialists regarding evaluation of associated CNS findings/malformations and/or non-ocular findings
Refractive errors may be managed with spectacles or contact lenses. Specialist examination is required to detect refractive errors early in life, when affected individuals may be asymptomatic, to prevent amblyopia and avoid compounding the motility problem with a focusing problem.
Amblyopia can be treated effectively with occlusion or penalization of the better-seeing eye. Early detection (in the first years of life) maximizes the likelihood of a good response to treatment.
Lubrication of ocular surface (particularly cornea) may be required. In cases of severe exposure, a PROSE lens can be of significant benefit [
Correction of ptosis
Eye muscle surgery
To correct or improve a compensatory head posture
To improve alignment in primary gaze position
To improve ambulation and gross motor development in young children
Principles of surgical approach:
Orbital imaging is recommended before surgery to assess muscle size and position.
Extraocular muscles may be found at surgery to be attached in unexpected locations.
Resections or plications may be helpful in some cases to provide traction against large recessions during healing.
Surgery is likely to be technically difficult because of tightness of rectus muscles.
Recessions need to be larger – sometimes considerably larger – than indicated by standard tables, especially recessions of the inferior rectus muscles.
Dysinnervation causing esotropia in attempted upgaze may mask an underlying exotropia that will be unmasked after inferior rectus muscle weakening.
Inferior rectus muscle weakening may be enhanced by superior oblique weakening.
Most individuals with CFEOM have abnormally inserted superior oblique tendons and/or tight muscles or abnormally thin tendons [
Profound weakening procedures (e.g., suturing muscle to orbital rim, rectus muscle myectomy) may be necessary.
Botulinum toxin may be helpful for residual misalignment in some cases.
CFEOM is congenital and is believed to be non-progressive.
Surveillance is important for prevention of amblyopia, and to treat amblyopia and complications of corneal exposure [
Routine ophthalmologic care is indicated, with visits every three to four months during the first years of life, and annual or biannual examinations in affected individuals not at risk for amblyopia.
In individuals with specific
• Consultation with a clinical geneticist and/or genetic counselor
• Ophthalmologic examination:
• Determination of resting gaze position, head position with eyes in resting gaze position, and vertical and horizontal gaze restrictions
• Evaluation for aberrant movements including synergistic convergence and divergence, globe retraction, Marcus Gunn jaw wink
• Measurement of palpebral fissure size
• Anterior segment evaluation to detect corneal exposure
• Levator function testing
• Optional forced duction testing
• Refraction, including cycloplegic refraction in children
• Photographic documentation for future comparison
• Determination of resting gaze position, head position with eyes in resting gaze position, and vertical and horizontal gaze restrictions
• Evaluation for aberrant movements including synergistic convergence and divergence, globe retraction, Marcus Gunn jaw wink
• Measurement of palpebral fissure size
• Anterior segment evaluation to detect corneal exposure
• Levator function testing
• Optional forced duction testing
• Refraction, including cycloplegic refraction in children
• Photographic documentation for future comparison
• Strongly recommended if eye muscle surgery is planned:
• Brain and brain stem MRI scan to determine the size and/or course of the oculomotor and trochlear nerves
• High-resolution orbital MRI (1- to 3-mm cuts) to detect abnormalities in the size and/or course of the extraocular muscle(s) and atrophy of the superior rectus-levator complex
• Brain and brain stem MRI scan to determine the size and/or course of the oculomotor and trochlear nerves
• High-resolution orbital MRI (1- to 3-mm cuts) to detect abnormalities in the size and/or course of the extraocular muscle(s) and atrophy of the superior rectus-levator complex
• Referral to relevant specialists regarding evaluation of associated CNS findings/malformations and/or non-ocular findings
• Determination of resting gaze position, head position with eyes in resting gaze position, and vertical and horizontal gaze restrictions
• Evaluation for aberrant movements including synergistic convergence and divergence, globe retraction, Marcus Gunn jaw wink
• Measurement of palpebral fissure size
• Anterior segment evaluation to detect corneal exposure
• Levator function testing
• Optional forced duction testing
• Refraction, including cycloplegic refraction in children
• Photographic documentation for future comparison
• Brain and brain stem MRI scan to determine the size and/or course of the oculomotor and trochlear nerves
• High-resolution orbital MRI (1- to 3-mm cuts) to detect abnormalities in the size and/or course of the extraocular muscle(s) and atrophy of the superior rectus-levator complex
• Refractive errors may be managed with spectacles or contact lenses. Specialist examination is required to detect refractive errors early in life, when affected individuals may be asymptomatic, to prevent amblyopia and avoid compounding the motility problem with a focusing problem.
• Amblyopia can be treated effectively with occlusion or penalization of the better-seeing eye. Early detection (in the first years of life) maximizes the likelihood of a good response to treatment.
• Lubrication of ocular surface (particularly cornea) may be required. In cases of severe exposure, a PROSE lens can be of significant benefit [
• Correction of ptosis
• Eye muscle surgery
• To correct or improve a compensatory head posture
• To improve alignment in primary gaze position
• To improve ambulation and gross motor development in young children
• To correct or improve a compensatory head posture
• To improve alignment in primary gaze position
• To improve ambulation and gross motor development in young children
• Principles of surgical approach:
• Orbital imaging is recommended before surgery to assess muscle size and position.
• Extraocular muscles may be found at surgery to be attached in unexpected locations.
• Resections or plications may be helpful in some cases to provide traction against large recessions during healing.
• Surgery is likely to be technically difficult because of tightness of rectus muscles.
• Recessions need to be larger – sometimes considerably larger – than indicated by standard tables, especially recessions of the inferior rectus muscles.
• Dysinnervation causing esotropia in attempted upgaze may mask an underlying exotropia that will be unmasked after inferior rectus muscle weakening.
• Inferior rectus muscle weakening may be enhanced by superior oblique weakening.
• Most individuals with CFEOM have abnormally inserted superior oblique tendons and/or tight muscles or abnormally thin tendons [
• Profound weakening procedures (e.g., suturing muscle to orbital rim, rectus muscle myectomy) may be necessary.
• Botulinum toxin may be helpful for residual misalignment in some cases.
• Orbital imaging is recommended before surgery to assess muscle size and position.
• Extraocular muscles may be found at surgery to be attached in unexpected locations.
• Resections or plications may be helpful in some cases to provide traction against large recessions during healing.
• Surgery is likely to be technically difficult because of tightness of rectus muscles.
• Recessions need to be larger – sometimes considerably larger – than indicated by standard tables, especially recessions of the inferior rectus muscles.
• Dysinnervation causing esotropia in attempted upgaze may mask an underlying exotropia that will be unmasked after inferior rectus muscle weakening.
• Inferior rectus muscle weakening may be enhanced by superior oblique weakening.
• Most individuals with CFEOM have abnormally inserted superior oblique tendons and/or tight muscles or abnormally thin tendons [
• Profound weakening procedures (e.g., suturing muscle to orbital rim, rectus muscle myectomy) may be necessary.
• Botulinum toxin may be helpful for residual misalignment in some cases.
• To correct or improve a compensatory head posture
• To improve alignment in primary gaze position
• To improve ambulation and gross motor development in young children
• Orbital imaging is recommended before surgery to assess muscle size and position.
• Extraocular muscles may be found at surgery to be attached in unexpected locations.
• Resections or plications may be helpful in some cases to provide traction against large recessions during healing.
• Surgery is likely to be technically difficult because of tightness of rectus muscles.
• Recessions need to be larger – sometimes considerably larger – than indicated by standard tables, especially recessions of the inferior rectus muscles.
• Dysinnervation causing esotropia in attempted upgaze may mask an underlying exotropia that will be unmasked after inferior rectus muscle weakening.
• Inferior rectus muscle weakening may be enhanced by superior oblique weakening.
• Most individuals with CFEOM have abnormally inserted superior oblique tendons and/or tight muscles or abnormally thin tendons [
• Profound weakening procedures (e.g., suturing muscle to orbital rim, rectus muscle myectomy) may be necessary.
• Botulinum toxin may be helpful for residual misalignment in some cases.
## Evaluations Following Initial Diagnosis
To establish the extent of ophthalmologic involvement and needs in an individual diagnosed with congenital fibrosis of the extraocular muscles, the following evaluations are recommended:
Consultation with a clinical geneticist and/or genetic counselor
Ophthalmologic examination:
Determination of resting gaze position, head position with eyes in resting gaze position, and vertical and horizontal gaze restrictions
Evaluation for aberrant movements including synergistic convergence and divergence, globe retraction, Marcus Gunn jaw wink
Measurement of palpebral fissure size
Anterior segment evaluation to detect corneal exposure
Levator function testing
Optional forced duction testing
Refraction, including cycloplegic refraction in children
Photographic documentation for future comparison
Strongly recommended if eye muscle surgery is planned:
Brain and brain stem MRI scan to determine the size and/or course of the oculomotor and trochlear nerves
High-resolution orbital MRI (1- to 3-mm cuts) to detect abnormalities in the size and/or course of the extraocular muscle(s) and atrophy of the superior rectus-levator complex
Referral to relevant specialists regarding evaluation of associated CNS findings/malformations and/or non-ocular findings
• Consultation with a clinical geneticist and/or genetic counselor
• Ophthalmologic examination:
• Determination of resting gaze position, head position with eyes in resting gaze position, and vertical and horizontal gaze restrictions
• Evaluation for aberrant movements including synergistic convergence and divergence, globe retraction, Marcus Gunn jaw wink
• Measurement of palpebral fissure size
• Anterior segment evaluation to detect corneal exposure
• Levator function testing
• Optional forced duction testing
• Refraction, including cycloplegic refraction in children
• Photographic documentation for future comparison
• Determination of resting gaze position, head position with eyes in resting gaze position, and vertical and horizontal gaze restrictions
• Evaluation for aberrant movements including synergistic convergence and divergence, globe retraction, Marcus Gunn jaw wink
• Measurement of palpebral fissure size
• Anterior segment evaluation to detect corneal exposure
• Levator function testing
• Optional forced duction testing
• Refraction, including cycloplegic refraction in children
• Photographic documentation for future comparison
• Strongly recommended if eye muscle surgery is planned:
• Brain and brain stem MRI scan to determine the size and/or course of the oculomotor and trochlear nerves
• High-resolution orbital MRI (1- to 3-mm cuts) to detect abnormalities in the size and/or course of the extraocular muscle(s) and atrophy of the superior rectus-levator complex
• Brain and brain stem MRI scan to determine the size and/or course of the oculomotor and trochlear nerves
• High-resolution orbital MRI (1- to 3-mm cuts) to detect abnormalities in the size and/or course of the extraocular muscle(s) and atrophy of the superior rectus-levator complex
• Referral to relevant specialists regarding evaluation of associated CNS findings/malformations and/or non-ocular findings
• Determination of resting gaze position, head position with eyes in resting gaze position, and vertical and horizontal gaze restrictions
• Evaluation for aberrant movements including synergistic convergence and divergence, globe retraction, Marcus Gunn jaw wink
• Measurement of palpebral fissure size
• Anterior segment evaluation to detect corneal exposure
• Levator function testing
• Optional forced duction testing
• Refraction, including cycloplegic refraction in children
• Photographic documentation for future comparison
• Brain and brain stem MRI scan to determine the size and/or course of the oculomotor and trochlear nerves
• High-resolution orbital MRI (1- to 3-mm cuts) to detect abnormalities in the size and/or course of the extraocular muscle(s) and atrophy of the superior rectus-levator complex
## Treatment of Manifestations
Refractive errors may be managed with spectacles or contact lenses. Specialist examination is required to detect refractive errors early in life, when affected individuals may be asymptomatic, to prevent amblyopia and avoid compounding the motility problem with a focusing problem.
Amblyopia can be treated effectively with occlusion or penalization of the better-seeing eye. Early detection (in the first years of life) maximizes the likelihood of a good response to treatment.
Lubrication of ocular surface (particularly cornea) may be required. In cases of severe exposure, a PROSE lens can be of significant benefit [
Correction of ptosis
Eye muscle surgery
To correct or improve a compensatory head posture
To improve alignment in primary gaze position
To improve ambulation and gross motor development in young children
Principles of surgical approach:
Orbital imaging is recommended before surgery to assess muscle size and position.
Extraocular muscles may be found at surgery to be attached in unexpected locations.
Resections or plications may be helpful in some cases to provide traction against large recessions during healing.
Surgery is likely to be technically difficult because of tightness of rectus muscles.
Recessions need to be larger – sometimes considerably larger – than indicated by standard tables, especially recessions of the inferior rectus muscles.
Dysinnervation causing esotropia in attempted upgaze may mask an underlying exotropia that will be unmasked after inferior rectus muscle weakening.
Inferior rectus muscle weakening may be enhanced by superior oblique weakening.
Most individuals with CFEOM have abnormally inserted superior oblique tendons and/or tight muscles or abnormally thin tendons [
Profound weakening procedures (e.g., suturing muscle to orbital rim, rectus muscle myectomy) may be necessary.
Botulinum toxin may be helpful for residual misalignment in some cases.
• Refractive errors may be managed with spectacles or contact lenses. Specialist examination is required to detect refractive errors early in life, when affected individuals may be asymptomatic, to prevent amblyopia and avoid compounding the motility problem with a focusing problem.
• Amblyopia can be treated effectively with occlusion or penalization of the better-seeing eye. Early detection (in the first years of life) maximizes the likelihood of a good response to treatment.
• Lubrication of ocular surface (particularly cornea) may be required. In cases of severe exposure, a PROSE lens can be of significant benefit [
• Correction of ptosis
• Eye muscle surgery
• To correct or improve a compensatory head posture
• To improve alignment in primary gaze position
• To improve ambulation and gross motor development in young children
• To correct or improve a compensatory head posture
• To improve alignment in primary gaze position
• To improve ambulation and gross motor development in young children
• Principles of surgical approach:
• Orbital imaging is recommended before surgery to assess muscle size and position.
• Extraocular muscles may be found at surgery to be attached in unexpected locations.
• Resections or plications may be helpful in some cases to provide traction against large recessions during healing.
• Surgery is likely to be technically difficult because of tightness of rectus muscles.
• Recessions need to be larger – sometimes considerably larger – than indicated by standard tables, especially recessions of the inferior rectus muscles.
• Dysinnervation causing esotropia in attempted upgaze may mask an underlying exotropia that will be unmasked after inferior rectus muscle weakening.
• Inferior rectus muscle weakening may be enhanced by superior oblique weakening.
• Most individuals with CFEOM have abnormally inserted superior oblique tendons and/or tight muscles or abnormally thin tendons [
• Profound weakening procedures (e.g., suturing muscle to orbital rim, rectus muscle myectomy) may be necessary.
• Botulinum toxin may be helpful for residual misalignment in some cases.
• Orbital imaging is recommended before surgery to assess muscle size and position.
• Extraocular muscles may be found at surgery to be attached in unexpected locations.
• Resections or plications may be helpful in some cases to provide traction against large recessions during healing.
• Surgery is likely to be technically difficult because of tightness of rectus muscles.
• Recessions need to be larger – sometimes considerably larger – than indicated by standard tables, especially recessions of the inferior rectus muscles.
• Dysinnervation causing esotropia in attempted upgaze may mask an underlying exotropia that will be unmasked after inferior rectus muscle weakening.
• Inferior rectus muscle weakening may be enhanced by superior oblique weakening.
• Most individuals with CFEOM have abnormally inserted superior oblique tendons and/or tight muscles or abnormally thin tendons [
• Profound weakening procedures (e.g., suturing muscle to orbital rim, rectus muscle myectomy) may be necessary.
• Botulinum toxin may be helpful for residual misalignment in some cases.
• To correct or improve a compensatory head posture
• To improve alignment in primary gaze position
• To improve ambulation and gross motor development in young children
• Orbital imaging is recommended before surgery to assess muscle size and position.
• Extraocular muscles may be found at surgery to be attached in unexpected locations.
• Resections or plications may be helpful in some cases to provide traction against large recessions during healing.
• Surgery is likely to be technically difficult because of tightness of rectus muscles.
• Recessions need to be larger – sometimes considerably larger – than indicated by standard tables, especially recessions of the inferior rectus muscles.
• Dysinnervation causing esotropia in attempted upgaze may mask an underlying exotropia that will be unmasked after inferior rectus muscle weakening.
• Inferior rectus muscle weakening may be enhanced by superior oblique weakening.
• Most individuals with CFEOM have abnormally inserted superior oblique tendons and/or tight muscles or abnormally thin tendons [
• Profound weakening procedures (e.g., suturing muscle to orbital rim, rectus muscle myectomy) may be necessary.
• Botulinum toxin may be helpful for residual misalignment in some cases.
## Surveillance
CFEOM is congenital and is believed to be non-progressive.
Surveillance is important for prevention of amblyopia, and to treat amblyopia and complications of corneal exposure [
Routine ophthalmologic care is indicated, with visits every three to four months during the first years of life, and annual or biannual examinations in affected individuals not at risk for amblyopia.
In individuals with specific
## Genetic Counseling of Family Members of an Individual with CFEOM
Congenital fibrosis of the extraocular muscles (CFEOM) caused by pathogenic variants
CFEOM caused by pathogenic variants in
Tukel syndrome (a disorder of unknown genetic cause) is thought to be inherited in an autosomal recessive manner.
Some individuals diagnosed with autosomal dominant CFEOM have an affected parent.
A proband with autosomal dominant CFEOM may have the disorder as the result of a
The frequency of
The frequency of
If the proband appears to be the only affected family member (i.e., a simplex case), ophthalmologic examination and/or molecular genetic testing (for the
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
Presumed parental germline mosaicism has been reported in
The family history of some individuals diagnosed with autosomal dominant CFEOM may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (e.g., ocular examination and/or molecular genetic testing) have been performed on the parents of the proband.
If a parent has clinical characteristics consistent with CFEOM and/or a known
If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [
If the parents of a proband with autosomal dominant CFEOM are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for CFEOM because of the possibility of reduced penetrance in a heterozygous parent or of parental germline mosaicism.
The parents of an individual with autosomal recessive CFEOM are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history).
If biallelic
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) of
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an autosomal recessive CFEOM-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing is not possible for relatives of a proband with Tukel syndrome because the associated gene has not been identified.
If the pathogenic variant(s) in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
If the pathogenic variant(s) in the family are not known, clinical ophthalmologic exam can be used to clarify the disease status of at-risk relatives.
Once the CFEOM-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for CFEOM are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Some individuals diagnosed with autosomal dominant CFEOM have an affected parent.
• A proband with autosomal dominant CFEOM may have the disorder as the result of a
• The frequency of
• The frequency of
• The frequency of
• The frequency of
• If the proband appears to be the only affected family member (i.e., a simplex case), ophthalmologic examination and/or molecular genetic testing (for the
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• Presumed parental germline mosaicism has been reported in
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• Presumed parental germline mosaicism has been reported in
• The family history of some individuals diagnosed with autosomal dominant CFEOM may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (e.g., ocular examination and/or molecular genetic testing) have been performed on the parents of the proband.
• The frequency of
• The frequency of
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• Presumed parental germline mosaicism has been reported in
• If a parent has clinical characteristics consistent with CFEOM and/or a known
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [
• If the parents of a proband with autosomal dominant CFEOM are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for CFEOM because of the possibility of reduced penetrance in a heterozygous parent or of parental germline mosaicism.
• The parents of an individual with autosomal recessive CFEOM are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history).
• If biallelic
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) of
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an autosomal recessive CFEOM-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If the pathogenic variant(s) in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
• If the pathogenic variant(s) in the family are not known, clinical ophthalmologic exam can be used to clarify the disease status of at-risk relatives.
## Mode of Inheritance
Congenital fibrosis of the extraocular muscles (CFEOM) caused by pathogenic variants
CFEOM caused by pathogenic variants in
Tukel syndrome (a disorder of unknown genetic cause) is thought to be inherited in an autosomal recessive manner.
## Autosomal Dominant Inheritance – Risk to Family Members
Some individuals diagnosed with autosomal dominant CFEOM have an affected parent.
A proband with autosomal dominant CFEOM may have the disorder as the result of a
The frequency of
The frequency of
If the proband appears to be the only affected family member (i.e., a simplex case), ophthalmologic examination and/or molecular genetic testing (for the
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
Presumed parental germline mosaicism has been reported in
The family history of some individuals diagnosed with autosomal dominant CFEOM may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (e.g., ocular examination and/or molecular genetic testing) have been performed on the parents of the proband.
If a parent has clinical characteristics consistent with CFEOM and/or a known
If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [
If the parents of a proband with autosomal dominant CFEOM are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for CFEOM because of the possibility of reduced penetrance in a heterozygous parent or of parental germline mosaicism.
• Some individuals diagnosed with autosomal dominant CFEOM have an affected parent.
• A proband with autosomal dominant CFEOM may have the disorder as the result of a
• The frequency of
• The frequency of
• The frequency of
• The frequency of
• If the proband appears to be the only affected family member (i.e., a simplex case), ophthalmologic examination and/or molecular genetic testing (for the
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• Presumed parental germline mosaicism has been reported in
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• Presumed parental germline mosaicism has been reported in
• The family history of some individuals diagnosed with autosomal dominant CFEOM may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (e.g., ocular examination and/or molecular genetic testing) have been performed on the parents of the proband.
• The frequency of
• The frequency of
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• Presumed parental germline mosaicism has been reported in
• If a parent has clinical characteristics consistent with CFEOM and/or a known
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [
• If the parents of a proband with autosomal dominant CFEOM are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for CFEOM because of the possibility of reduced penetrance in a heterozygous parent or of parental germline mosaicism.
## Autosomal Recessive – Inheritance Risk to Family Members
The parents of an individual with autosomal recessive CFEOM are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history).
If biallelic
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) of
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an autosomal recessive CFEOM-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing is not possible for relatives of a proband with Tukel syndrome because the associated gene has not been identified.
• The parents of an individual with autosomal recessive CFEOM are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history).
• If biallelic
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) of
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an autosomal recessive CFEOM-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Related Genetic Counseling Issues
If the pathogenic variant(s) in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
If the pathogenic variant(s) in the family are not known, clinical ophthalmologic exam can be used to clarify the disease status of at-risk relatives.
• If the pathogenic variant(s) in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
• If the pathogenic variant(s) in the family are not known, clinical ophthalmologic exam can be used to clarify the disease status of at-risk relatives.
## Prenatal Testing and Preimplantation Genetic Testing
Once the CFEOM-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for CFEOM are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
211 West Wacker Drive
Suite 1700
Chicago IL 60606
•
•
•
•
•
•
• 211 West Wacker Drive
• Suite 1700
• Chicago IL 60606
•
## Chapter Notes
Dr Engle's websites:
Dr Whitman’s website:
We thank the many individuals with these disorders and their family members for participating in these studies. Our work has been supported by NEI R01EY027421 and NHLBI X01HL132377 (ECE); the Broad Institute of MIT and Harvard Center for Mendelian Genomics (NHGRI/NEI/NHLBI UM1HG008900); the Ocular Genomics Institute Genomics Core (Massachusetts Eye and Ear Infirmary/Harvard Medical School, NEI 2P30EY014104); NHGRI R01HG009141, T32GM007748-42, 5T32NS007473-19, 5T32EY007145-16; the William Randolph Hearst Fund, NEI 5K08EY027850; the Boston Children’s Hospital Ophthalmology Foundation Faculty Discovery Award; Children's Hospital Ophthalmology Foundation, Inc, Boston, MA; and Howard Hughes Medical Institute.
Caroline Andrews, MSc; Howard Hughes Medical Institute (2004-2016) Jigar Desai, PhD; Children’s Hospital Boston (2006-2011) Elizabeth C Engle, MD (2004-present) David G Hunter, MD, PhD (2006-present) Julie A Jurgens, PhD (2021-present)Mary C Whitman, MD, PhD (2016-present)Koki Yamada, MD, PhD; Children's Hospital Boston (2004-2006)
12 August 2021 (bp) Comprehensive update posted live; scope changed to overview
14 January 2016 (me) Comprehensive update posted live
21 April 2011 (me) Comprehensive update posted live
22 September 2006 (me) Comprehensive update posted live
27 April 2004 (me) Review posted live
7 January 2004 (ee) Original submission
• 12 August 2021 (bp) Comprehensive update posted live; scope changed to overview
• 14 January 2016 (me) Comprehensive update posted live
• 21 April 2011 (me) Comprehensive update posted live
• 22 September 2006 (me) Comprehensive update posted live
• 27 April 2004 (me) Review posted live
• 7 January 2004 (ee) Original submission
## Author Notes
Dr Engle's websites:
Dr Whitman’s website:
## Acknowledgments
We thank the many individuals with these disorders and their family members for participating in these studies. Our work has been supported by NEI R01EY027421 and NHLBI X01HL132377 (ECE); the Broad Institute of MIT and Harvard Center for Mendelian Genomics (NHGRI/NEI/NHLBI UM1HG008900); the Ocular Genomics Institute Genomics Core (Massachusetts Eye and Ear Infirmary/Harvard Medical School, NEI 2P30EY014104); NHGRI R01HG009141, T32GM007748-42, 5T32NS007473-19, 5T32EY007145-16; the William Randolph Hearst Fund, NEI 5K08EY027850; the Boston Children’s Hospital Ophthalmology Foundation Faculty Discovery Award; Children's Hospital Ophthalmology Foundation, Inc, Boston, MA; and Howard Hughes Medical Institute.
## Author History
Caroline Andrews, MSc; Howard Hughes Medical Institute (2004-2016) Jigar Desai, PhD; Children’s Hospital Boston (2006-2011) Elizabeth C Engle, MD (2004-present) David G Hunter, MD, PhD (2006-present) Julie A Jurgens, PhD (2021-present)Mary C Whitman, MD, PhD (2016-present)Koki Yamada, MD, PhD; Children's Hospital Boston (2004-2006)
## Revision History
12 August 2021 (bp) Comprehensive update posted live; scope changed to overview
14 January 2016 (me) Comprehensive update posted live
21 April 2011 (me) Comprehensive update posted live
22 September 2006 (me) Comprehensive update posted live
27 April 2004 (me) Review posted live
7 January 2004 (ee) Original submission
• 12 August 2021 (bp) Comprehensive update posted live; scope changed to overview
• 14 January 2016 (me) Comprehensive update posted live
• 21 April 2011 (me) Comprehensive update posted live
• 22 September 2006 (me) Comprehensive update posted live
• 27 April 2004 (me) Review posted live
• 7 January 2004 (ee) Original submission
## References
## Literature Cited
|
[] |
27/4/2004
|
12/8/2021
|
29/12/2011
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cftd
|
cftd
|
[
"CFTDM",
"Congenital Myopathy with Fiber-Type Disproportion",
"CFTDM",
"Congenital Myopathy with Fiber-Type Disproportion",
"Actin, alpha skeletal muscle",
"Myosin-7",
"Ryanodine receptor 1",
"Selenoprotein N",
"Tropomyosin alpha-3 chain",
"Tropomyosin beta chain",
"ACTA1",
"MYH7",
"RYR1",
"SELENON",
"TPM2",
"TPM3",
"Congenital Fiber-Type Disproportion"
] |
Congenital Fiber-Type Disproportion – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Elizabeth Taylor DeChene, Peter B Kang, Alan H Beggs
|
Summary Congenital fiber-type disproportion (CFTD) is usually characterized by hypotonia and mild-to-severe generalized muscle weakness at birth or within the first year of life. Although some individuals remain non-ambulatory throughout life, many eventually develop the ability to walk. In more than 90% of affected individuals, muscle weakness is static or improves; in the remainder it is usually slowly progressive. Mild-to-severe respiratory involvement is seen in approximately 30% of affected individuals; respiratory failure may occur at any age. Ophthalmoplegia, ptosis, and facial and/or bulbar weakness with severe limb/respiratory weakness may predict a poor prognosis. Mild-to-severe feeding difficulties occur in nearly 30% of children. Contractures of the hips, knees, ankles, elbows, and fingers occur in approximately 25% and may be present at birth or occur in older persons with decreased mobility secondary to severe weakness. Spinal deformities including scoliosis, kyphoscoliosis, and lordosis are seen in 25% or more of individuals. Diagnosis is based on a combination of clinical presentation and morphologic features observed on skeletal muscle histology. The pathologic and clinical manifestations of CFTD overlap with other neuromuscular and non-neuromuscular diseases that must be ruled out prior to making a diagnosis of CFTD. To date, pathogenic variants have been identified in six genes: CFTD is a genetically heterogeneous condition that can be inherited in an autosomal recessive, autosomal dominant, or X-linked manner. To date, all identified cases of
|
## Diagnosis
Diagnosis of congenital fiber-type disproportion (CFTD), a genetically and clinically heterogeneous congenital myopathy, is based on a combination of the following [
Morphologic features observed on
The original criteria presented by Brooke in 1973 required that type 1 fibers be at least 12% smaller than the mean diameter of type 2A and/or type 2B fibers in the absence of other significant pathologic findings (e.g., many nemaline bodies, cores, or central nuclei; see
More recent studies suggest that affected individuals with true congenital fiber size disproportion (i.e., those who do not have another defined neuromuscular condition such as myotonic dystrophy or Ullrich muscular dystrophy) have type 1 fibers that are generally at least 40% to over 80% smaller than type 2 fibers, particularly when the condition is associated with pathogenic variants in
Note: Multiple males and at least one female without significant muscle weakness have been noted to have fiber-type disproportion on muscle biopsy that was performed in infancy, adolescence, or adulthood [
Additional findings that may also be present:
Type 1 fiber numeric predominance (
Decreased presence of 2B/2X fibers
One type of type 2 fibers (2A or 2B/2X) possibly larger than the other(s)
Less frequent abnormalities: central myonuclei, moth-eaten fibers, occasional nemaline rods [
Ultrastructural findings on electron microscopy (EM) are generally normal; however, fiber size variation may be present. Architectural abnormalities reported in some individuals include: infrequent multiminicores; nemaline bodies; and sub-sarcolemmal sarcomere disarray or glycogen accumulation.
Pathologic findings may change over time, allowing the refinement of the diagnosis through a second biopsy at a later age. Some individuals with a diagnosis of CFTD on first biopsy are later found to have additional findings on second biopsies [
Nerve conduction studies are generally normal.
In a kindred of seven males with severe congenital myopathy, biopsies in four of six were suggestive of CFTD. Linkage to the intervals Xp22.13 to Xp11.4 and Xq13.1 to Xq22.1 was found. Of note, Xq28, the locus of
A Japanese girl with deletion 1p36, developmental delay, dysmorphic features, and hypotonia had CFTD on muscle biopsy, suggesting that a gene involved in CFTD may exist at this locus [
Molecular Genetic Testing Used in Congenital Fiber-Type Disproportion
See
See
Heterozygous pathogenic missense variants were observed in 6% of individuals with CFTD in one series [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
No large deletions or duplications that were causative of CFTD have been reported in
A
Heterozygous
Molecular genetic testing can be used to confirm the diagnosis of CFTD in some individuals, but some individuals will have normal testing for all six currently associated genes.
Muscle imaging, including ultrasound or MRI, may be helpful in guiding genetic testing, since some genes are associated with characteristic muscle involvement [
Those with
Affected individuals with
Those with
Those with pathogenic variants in
Based on variant frequency and gene size, it is recommended that sequence analysis be performed sequentially or in tiers of two to three genes at a time unless there are clinical/pathologic features or family history suggesting a different testing order.
Sequential testing may be considered in the following order:
In individuals with ophthalmoplegia and/or a personal or family history of malignant hyperthermia,
In individuals with cardiomyopathy,
In individuals with spinal rigidity or early-onset scoliosis,
To date, no large deletions or duplications in the six known genes have been identified to be causative of CFTD; however, disease-causing
Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. However, the risk for malignant hyperthermia (MH) in individuals with a heterozygous pathogenic variant in
• Morphologic features observed on
• The original criteria presented by Brooke in 1973 required that type 1 fibers be at least 12% smaller than the mean diameter of type 2A and/or type 2B fibers in the absence of other significant pathologic findings (e.g., many nemaline bodies, cores, or central nuclei; see
• More recent studies suggest that affected individuals with true congenital fiber size disproportion (i.e., those who do not have another defined neuromuscular condition such as myotonic dystrophy or Ullrich muscular dystrophy) have type 1 fibers that are generally at least 40% to over 80% smaller than type 2 fibers, particularly when the condition is associated with pathogenic variants in
• Note: Multiple males and at least one female without significant muscle weakness have been noted to have fiber-type disproportion on muscle biopsy that was performed in infancy, adolescence, or adulthood [
• Additional findings that may also be present:
• Type 1 fiber numeric predominance (
• Decreased presence of 2B/2X fibers
• One type of type 2 fibers (2A or 2B/2X) possibly larger than the other(s)
• Type 1 fiber numeric predominance (
• Decreased presence of 2B/2X fibers
• One type of type 2 fibers (2A or 2B/2X) possibly larger than the other(s)
• Less frequent abnormalities: central myonuclei, moth-eaten fibers, occasional nemaline rods [
• Type 1 fiber numeric predominance (
• Decreased presence of 2B/2X fibers
• One type of type 2 fibers (2A or 2B/2X) possibly larger than the other(s)
• Nerve conduction studies are generally normal.
• Those with
• Affected individuals with
• Those with
• Those with pathogenic variants in
• Sequential testing may be considered in the following order:
• In individuals with ophthalmoplegia and/or a personal or family history of malignant hyperthermia,
• In individuals with cardiomyopathy,
• In individuals with spinal rigidity or early-onset scoliosis,
• To date, no large deletions or duplications in the six known genes have been identified to be causative of CFTD; however, disease-causing
## Clinical Diagnosis
Diagnosis of congenital fiber-type disproportion (CFTD), a genetically and clinically heterogeneous congenital myopathy, is based on a combination of the following [
Morphologic features observed on
The original criteria presented by Brooke in 1973 required that type 1 fibers be at least 12% smaller than the mean diameter of type 2A and/or type 2B fibers in the absence of other significant pathologic findings (e.g., many nemaline bodies, cores, or central nuclei; see
More recent studies suggest that affected individuals with true congenital fiber size disproportion (i.e., those who do not have another defined neuromuscular condition such as myotonic dystrophy or Ullrich muscular dystrophy) have type 1 fibers that are generally at least 40% to over 80% smaller than type 2 fibers, particularly when the condition is associated with pathogenic variants in
Note: Multiple males and at least one female without significant muscle weakness have been noted to have fiber-type disproportion on muscle biopsy that was performed in infancy, adolescence, or adulthood [
Additional findings that may also be present:
Type 1 fiber numeric predominance (
Decreased presence of 2B/2X fibers
One type of type 2 fibers (2A or 2B/2X) possibly larger than the other(s)
Less frequent abnormalities: central myonuclei, moth-eaten fibers, occasional nemaline rods [
Ultrastructural findings on electron microscopy (EM) are generally normal; however, fiber size variation may be present. Architectural abnormalities reported in some individuals include: infrequent multiminicores; nemaline bodies; and sub-sarcolemmal sarcomere disarray or glycogen accumulation.
Pathologic findings may change over time, allowing the refinement of the diagnosis through a second biopsy at a later age. Some individuals with a diagnosis of CFTD on first biopsy are later found to have additional findings on second biopsies [
Nerve conduction studies are generally normal.
• Morphologic features observed on
• The original criteria presented by Brooke in 1973 required that type 1 fibers be at least 12% smaller than the mean diameter of type 2A and/or type 2B fibers in the absence of other significant pathologic findings (e.g., many nemaline bodies, cores, or central nuclei; see
• More recent studies suggest that affected individuals with true congenital fiber size disproportion (i.e., those who do not have another defined neuromuscular condition such as myotonic dystrophy or Ullrich muscular dystrophy) have type 1 fibers that are generally at least 40% to over 80% smaller than type 2 fibers, particularly when the condition is associated with pathogenic variants in
• Note: Multiple males and at least one female without significant muscle weakness have been noted to have fiber-type disproportion on muscle biopsy that was performed in infancy, adolescence, or adulthood [
• Additional findings that may also be present:
• Type 1 fiber numeric predominance (
• Decreased presence of 2B/2X fibers
• One type of type 2 fibers (2A or 2B/2X) possibly larger than the other(s)
• Type 1 fiber numeric predominance (
• Decreased presence of 2B/2X fibers
• One type of type 2 fibers (2A or 2B/2X) possibly larger than the other(s)
• Less frequent abnormalities: central myonuclei, moth-eaten fibers, occasional nemaline rods [
• Type 1 fiber numeric predominance (
• Decreased presence of 2B/2X fibers
• One type of type 2 fibers (2A or 2B/2X) possibly larger than the other(s)
• Nerve conduction studies are generally normal.
## Molecular Genetic Testing
In a kindred of seven males with severe congenital myopathy, biopsies in four of six were suggestive of CFTD. Linkage to the intervals Xp22.13 to Xp11.4 and Xq13.1 to Xq22.1 was found. Of note, Xq28, the locus of
A Japanese girl with deletion 1p36, developmental delay, dysmorphic features, and hypotonia had CFTD on muscle biopsy, suggesting that a gene involved in CFTD may exist at this locus [
Molecular Genetic Testing Used in Congenital Fiber-Type Disproportion
See
See
Heterozygous pathogenic missense variants were observed in 6% of individuals with CFTD in one series [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
No large deletions or duplications that were causative of CFTD have been reported in
A
Heterozygous
## Testing Strategy
Molecular genetic testing can be used to confirm the diagnosis of CFTD in some individuals, but some individuals will have normal testing for all six currently associated genes.
Muscle imaging, including ultrasound or MRI, may be helpful in guiding genetic testing, since some genes are associated with characteristic muscle involvement [
Those with
Affected individuals with
Those with
Those with pathogenic variants in
Based on variant frequency and gene size, it is recommended that sequence analysis be performed sequentially or in tiers of two to three genes at a time unless there are clinical/pathologic features or family history suggesting a different testing order.
Sequential testing may be considered in the following order:
In individuals with ophthalmoplegia and/or a personal or family history of malignant hyperthermia,
In individuals with cardiomyopathy,
In individuals with spinal rigidity or early-onset scoliosis,
To date, no large deletions or duplications in the six known genes have been identified to be causative of CFTD; however, disease-causing
Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. However, the risk for malignant hyperthermia (MH) in individuals with a heterozygous pathogenic variant in
• Those with
• Affected individuals with
• Those with
• Those with pathogenic variants in
• Sequential testing may be considered in the following order:
• In individuals with ophthalmoplegia and/or a personal or family history of malignant hyperthermia,
• In individuals with cardiomyopathy,
• In individuals with spinal rigidity or early-onset scoliosis,
• To date, no large deletions or duplications in the six known genes have been identified to be causative of CFTD; however, disease-causing
## Clinical Characteristics
Most children present with hypotonia, mild-to-severe generalized muscle weakness, and/or delayed motor milestones at birth or within the first year of life. Poor head control is also common. Limb weakness may be greatest in the limb girdle and proximal limb muscles, but weakness is not usually solely distal. Facial weakness is often present, resulting in a long face, high-arched palate, and tented upper lip. Ptosis, ophthalmoplegia, and bulbar weakness can be seen. Tendon reflexes are often decreased or absent.
Motor milestones are often delayed. Although some individuals remain non-ambulatory throughout life, many eventually develop the ability to walk. In more than 90% of affected individuals, muscle weakness becomes static or shows improvement, and in 9% it is slowly progressive [
Clinical Features Seen in CFTD Based on Frequency of Occurrence
At least 30% of individuals with CFTD have mild-to-severe respiratory involvement, which may not develop until adulthood. The majority of severely affected children develop significant respiratory weakness; however, the severity of respiratory muscle weakness and limb muscle weakness do not always correlate. Respiratory failure may occur at any age with some affected children succumbing to respiratory failure during infancy or childhood. Respiratory failure can occur without evidence of respiratory distress. In more mildly affected individuals, respiratory insufficiency may manifest as nocturnal hypoxia, potentially resulting in frequent chest infections, morning headaches, daytime fatigue, decreased appetite, reduced weight gain, and/or sleep disturbances. Severe respiratory involvement in infancy does not always predict poor prognosis.
Approximately 25% of individuals with CFTD show a more severe clinical course with significant and persistent weakness of limb or respiratory muscles at birth. The association in particular of ophthalmoplegia, ptosis, and facial and/or bulbar weakness with severe limb and respiratory weakness has previously been suggested to predict a poor prognosis.
Mild-to-severe feeding difficulties occur in almost 30% of children with CFTD. Bulbar weakness may result in chewing and swallowing problems and aspiration of secretions. Infants with severe facial and bulbar weakness may have significant feeding issues and may require intervention (gavage feeding, and/or gastrostomy with or without fundoplication) if symptoms continue beyond the first few months of life. Milder feeding issues often resolve over time.
Contractures of the ankles, fingers, hips, elbows, and knees occur in approximately 25% of affected children. Contractures may be present at birth or occur in older individuals who have decreased mobility secondary to severe weakness. Congenital hip dislocation and talipes equinovarus may also be present.
Spinal deformities, including scoliosis, kyphoscoliosis, and lordosis, are seen in 25% or more of individuals. Spinal rigidity has also been reported.
Contractures and spinal abnormalities are not necessarily associated with increased disease severity.
Cryptorchidism has been seen in a few males with CFTD.
Dilated cardiomyopathy or other cardiac abnormalities have been identified in several individuals with CFTD:
One required cardiac transplantation at age 12 years [
A male with X-linked CFTD and dilated cardiomyopathy was medically stable during follow-up from age 3.5 years to age 5.5 years [
One individual required a pacemaker for cardiomyopathy presenting with nocturnal and exertional dyspnea at age 28 years [
A nine-month-old with CFTD had atrial fibrillation and an atrial septal defect [
Dental crowding and high-arched palate, seen in other congenital myopathies, may be observed in CFTD.
Some genotype-phenotype correlations have been established. See
In affected individuals with the recurrent
In a single large family with CFTD caused by a frameshift variant in exon 39, weakness was primarily proximal [
The five individuals reported with homozygous or compound heterozygous
Delayed motor milestones, respiratory weakness, ophthalmoplegia, ptosis, and facial weakness were all reported in multiple affected individuals; however, none were present in all five cases.
Unlike other cases of CFTD associated with mutation of other genes, one mother and son had two populations of type 1 fibers: one population that was hypotrophic and a second population that was relatively normal in size [
Individuals with CFTD caused by heterozygous pathogenic missense variants in
Respiratory difficulties during sleep were common and sometimes insidious, presenting in childhood or early adulthood, making respiratory monitoring particularly important for this subset of individuals [
Extraocular muscle weakness was not reported in this group of affected individuals [
The single person with CFTD caused by homozygous
CFTD is rare; prevalence is unknown. Studies suggest that CFTD is less common than nemaline myopathy [
• One required cardiac transplantation at age 12 years [
• A male with X-linked CFTD and dilated cardiomyopathy was medically stable during follow-up from age 3.5 years to age 5.5 years [
• One individual required a pacemaker for cardiomyopathy presenting with nocturnal and exertional dyspnea at age 28 years [
• A nine-month-old with CFTD had atrial fibrillation and an atrial septal defect [
• In affected individuals with the recurrent
• In a single large family with CFTD caused by a frameshift variant in exon 39, weakness was primarily proximal [
• The five individuals reported with homozygous or compound heterozygous
• Delayed motor milestones, respiratory weakness, ophthalmoplegia, ptosis, and facial weakness were all reported in multiple affected individuals; however, none were present in all five cases.
• Unlike other cases of CFTD associated with mutation of other genes, one mother and son had two populations of type 1 fibers: one population that was hypotrophic and a second population that was relatively normal in size [
• Individuals with CFTD caused by heterozygous pathogenic missense variants in
• Respiratory difficulties during sleep were common and sometimes insidious, presenting in childhood or early adulthood, making respiratory monitoring particularly important for this subset of individuals [
• Extraocular muscle weakness was not reported in this group of affected individuals [
• The single person with CFTD caused by homozygous
## Clinical Description
Most children present with hypotonia, mild-to-severe generalized muscle weakness, and/or delayed motor milestones at birth or within the first year of life. Poor head control is also common. Limb weakness may be greatest in the limb girdle and proximal limb muscles, but weakness is not usually solely distal. Facial weakness is often present, resulting in a long face, high-arched palate, and tented upper lip. Ptosis, ophthalmoplegia, and bulbar weakness can be seen. Tendon reflexes are often decreased or absent.
Motor milestones are often delayed. Although some individuals remain non-ambulatory throughout life, many eventually develop the ability to walk. In more than 90% of affected individuals, muscle weakness becomes static or shows improvement, and in 9% it is slowly progressive [
Clinical Features Seen in CFTD Based on Frequency of Occurrence
At least 30% of individuals with CFTD have mild-to-severe respiratory involvement, which may not develop until adulthood. The majority of severely affected children develop significant respiratory weakness; however, the severity of respiratory muscle weakness and limb muscle weakness do not always correlate. Respiratory failure may occur at any age with some affected children succumbing to respiratory failure during infancy or childhood. Respiratory failure can occur without evidence of respiratory distress. In more mildly affected individuals, respiratory insufficiency may manifest as nocturnal hypoxia, potentially resulting in frequent chest infections, morning headaches, daytime fatigue, decreased appetite, reduced weight gain, and/or sleep disturbances. Severe respiratory involvement in infancy does not always predict poor prognosis.
Approximately 25% of individuals with CFTD show a more severe clinical course with significant and persistent weakness of limb or respiratory muscles at birth. The association in particular of ophthalmoplegia, ptosis, and facial and/or bulbar weakness with severe limb and respiratory weakness has previously been suggested to predict a poor prognosis.
Mild-to-severe feeding difficulties occur in almost 30% of children with CFTD. Bulbar weakness may result in chewing and swallowing problems and aspiration of secretions. Infants with severe facial and bulbar weakness may have significant feeding issues and may require intervention (gavage feeding, and/or gastrostomy with or without fundoplication) if symptoms continue beyond the first few months of life. Milder feeding issues often resolve over time.
Contractures of the ankles, fingers, hips, elbows, and knees occur in approximately 25% of affected children. Contractures may be present at birth or occur in older individuals who have decreased mobility secondary to severe weakness. Congenital hip dislocation and talipes equinovarus may also be present.
Spinal deformities, including scoliosis, kyphoscoliosis, and lordosis, are seen in 25% or more of individuals. Spinal rigidity has also been reported.
Contractures and spinal abnormalities are not necessarily associated with increased disease severity.
Cryptorchidism has been seen in a few males with CFTD.
Dilated cardiomyopathy or other cardiac abnormalities have been identified in several individuals with CFTD:
One required cardiac transplantation at age 12 years [
A male with X-linked CFTD and dilated cardiomyopathy was medically stable during follow-up from age 3.5 years to age 5.5 years [
One individual required a pacemaker for cardiomyopathy presenting with nocturnal and exertional dyspnea at age 28 years [
A nine-month-old with CFTD had atrial fibrillation and an atrial septal defect [
Dental crowding and high-arched palate, seen in other congenital myopathies, may be observed in CFTD.
• One required cardiac transplantation at age 12 years [
• A male with X-linked CFTD and dilated cardiomyopathy was medically stable during follow-up from age 3.5 years to age 5.5 years [
• One individual required a pacemaker for cardiomyopathy presenting with nocturnal and exertional dyspnea at age 28 years [
• A nine-month-old with CFTD had atrial fibrillation and an atrial septal defect [
## Genotype-Phenotype Correlations
Some genotype-phenotype correlations have been established. See
In affected individuals with the recurrent
In a single large family with CFTD caused by a frameshift variant in exon 39, weakness was primarily proximal [
The five individuals reported with homozygous or compound heterozygous
Delayed motor milestones, respiratory weakness, ophthalmoplegia, ptosis, and facial weakness were all reported in multiple affected individuals; however, none were present in all five cases.
Unlike other cases of CFTD associated with mutation of other genes, one mother and son had two populations of type 1 fibers: one population that was hypotrophic and a second population that was relatively normal in size [
Individuals with CFTD caused by heterozygous pathogenic missense variants in
Respiratory difficulties during sleep were common and sometimes insidious, presenting in childhood or early adulthood, making respiratory monitoring particularly important for this subset of individuals [
Extraocular muscle weakness was not reported in this group of affected individuals [
The single person with CFTD caused by homozygous
• In affected individuals with the recurrent
• In a single large family with CFTD caused by a frameshift variant in exon 39, weakness was primarily proximal [
• The five individuals reported with homozygous or compound heterozygous
• Delayed motor milestones, respiratory weakness, ophthalmoplegia, ptosis, and facial weakness were all reported in multiple affected individuals; however, none were present in all five cases.
• Unlike other cases of CFTD associated with mutation of other genes, one mother and son had two populations of type 1 fibers: one population that was hypotrophic and a second population that was relatively normal in size [
• Individuals with CFTD caused by heterozygous pathogenic missense variants in
• Respiratory difficulties during sleep were common and sometimes insidious, presenting in childhood or early adulthood, making respiratory monitoring particularly important for this subset of individuals [
• Extraocular muscle weakness was not reported in this group of affected individuals [
• The single person with CFTD caused by homozygous
## Prevalence
CFTD is rare; prevalence is unknown. Studies suggest that CFTD is less common than nemaline myopathy [
## Genetically Related (Allelic) Disorders
Nemaline myopathy is characterized by rod-like structures on muscle biopsy with clinical features similar to those seen in CFTD.
Less frequently,
Cardiac abnormalities have been reported in individuals with
Laing early-onset distal myopathy generally presents with distal weakness, starting with weakness of the ankle dorsiflexors in childhood through early adulthood, and later progresses to include proximal limb muscle weakness. Muscle biopsy shows nonspecific findings, including type 1 predominance and hypotrophy [
Myosin storage myopathy presents with variable proximal, distal, or scapuloperoneal weakness during early childhood to mid-to-late adulthood (4th-6th decade) [
Rare recessive
Homozygous or compound heterozygous alterations in
There has been one reported case of a heterozygous
MmD is diagnosed based on the presence of multiple minicores on muscle biopsy. Clinical features generally include the onset of axial and proximal weakness and hypotonia at birth or in infancy. Scoliosis and respiratory involvement are also common. Most individuals with classic MmD develop spinal rigidity, and thus the classic form is believed to be synonymous with RSMD [
Desmin-related myopathy with Mallory body-like inclusions is defined histologically by the presence of hyaline plaques in approximately 10% of muscle fibers. Clinical features are similar to MmD/RSMD [
Alterations in
Recessive
A heterozygous
• Nemaline myopathy is characterized by rod-like structures on muscle biopsy with clinical features similar to those seen in CFTD.
• Less frequently,
• Cardiac abnormalities have been reported in individuals with
• Laing early-onset distal myopathy generally presents with distal weakness, starting with weakness of the ankle dorsiflexors in childhood through early adulthood, and later progresses to include proximal limb muscle weakness. Muscle biopsy shows nonspecific findings, including type 1 predominance and hypotrophy [
• Myosin storage myopathy presents with variable proximal, distal, or scapuloperoneal weakness during early childhood to mid-to-late adulthood (4th-6th decade) [
• Rare recessive
• Homozygous or compound heterozygous alterations in
• There has been one reported case of a heterozygous
• MmD is diagnosed based on the presence of multiple minicores on muscle biopsy. Clinical features generally include the onset of axial and proximal weakness and hypotonia at birth or in infancy. Scoliosis and respiratory involvement are also common. Most individuals with classic MmD develop spinal rigidity, and thus the classic form is believed to be synonymous with RSMD [
• Desmin-related myopathy with Mallory body-like inclusions is defined histologically by the presence of hyaline plaques in approximately 10% of muscle fibers. Clinical features are similar to MmD/RSMD [
• Alterations in
• Recessive
• A heterozygous
## Differential Diagnosis
Since congenital myopathies often present similarly, congenital fiber-type disproportion (CFTD) cannot be distinguished from other congenital myopathies solely on clinical findings. Muscle biopsy can often help establish the appropriate diagnosis, since other congenital myopathies have specific associated histologic features, such as increased central nuclei, multiminicores, and nemaline bodies.
Type 1
Congenital muscular dystrophy, including
Becker muscular dystrophy, and rarely, Duchenne muscular dystrophy (see
These dystrophies can be distinguished from CFTD based on physical examination, serum CK concentrations (often significantly increased), and muscle biopsy findings, including dystrophic changes (fiber degeneration and regeneration with necrosis and infiltration of fatty and connective tissue) and immunohistochemistry staining indicative of decreased protein expression [
Congenital myotonic dystrophy (DM1), and congenital muscular dystrophies in particular, may present very similarly to CFTD and appear indistinguishable on muscle biopsy. Furthermore, sensitive molecular genetic testing is not possible for all congenital muscular dystrophies.
Molecular genetic testing detects a CTG expansion of
Brain MRI and ophthalmologic examination may help to differentiate between CFTD and other types of congenital muscular dystrophy.
Ullrich muscular dystrophy may be differentiated from CFTD based on the unique pattern of hyperlaxity of distal joints with contractures of more proximal joints, as well as immunohistochemical studies identifying abnormal amounts and/or localization of collagen VI.
Spinal muscular atrophy (SMA) can often be differentiated from CFTD by physical examination, abnormal brain MRI, neurogenic EMG, and neurogenic muscle pathology displaying reinnervation and fiber type grouping. Molecular genetic testing using targeted analysis for pathogenic variants and sequence analysis identifies two
Fiber size disproportion has also been seen in healthy individuals, including healthy infants younger than age two months [
• Type 1
• Congenital muscular dystrophy, including
•
• Becker muscular dystrophy, and rarely, Duchenne muscular dystrophy (see
• Molecular genetic testing detects a CTG expansion of
• Brain MRI and ophthalmologic examination may help to differentiate between CFTD and other types of congenital muscular dystrophy.
• Ullrich muscular dystrophy may be differentiated from CFTD based on the unique pattern of hyperlaxity of distal joints with contractures of more proximal joints, as well as immunohistochemical studies identifying abnormal amounts and/or localization of collagen VI.
• Spinal muscular atrophy (SMA) can often be differentiated from CFTD by physical examination, abnormal brain MRI, neurogenic EMG, and neurogenic muscle pathology displaying reinnervation and fiber type grouping. Molecular genetic testing using targeted analysis for pathogenic variants and sequence analysis identifies two
## Management
To establish the extent of disease and needs in an individual diagnosed with congenital fiber-type disproportion, the following evaluations are recommended:
Medical history and physical examination with particular attention to the following:
Weakness
Hypotonia
Failure to thrive
Scoliosis
Contractures
Comprehensive respiratory evaluation in individuals with and without respiratory symptoms including the following:
Respiratory rate
Signs of respiratory distress
History of recurrent chest infections
Ability to maintain oxygen saturation
Pulmonary function studies
Sleep study to evaluate for nocturnal hypoxia and assess the need for ventilator support
Note: Some individuals with CFTD who have nocturnal hypoxia without symptoms can develop respiratory failure without warning.
Feeding evaluation including assessment of suck and swallow and gastroesophageal reflux
Speech therapy assessment, particularly if dysarthria and/or hypernasal speech are present
Cardiac evaluation for heart disease, including
Physical therapy and occupational therapy assessment
Screening for skeletal and orthopedic issues, including skeletal examination for scoliosis (after the child starts sitting), joint contractures, congenital hip dislocations, and foot deformities
Examination by a general dentist with referral for orthodontic evaluation if dental crowding becomes apparent
Consultation with a clinical geneticist and/or genetic counselor
It is recommended that care be provided by a multidisciplinary team coordinated by a clinician familiar with treatment of neuromuscular conditions [
Hypotonia, weakness, and joint contractures may benefit from physical therapy, occupational therapy, and/or orthopedic intervention. Interventions may include exercise and stretching programs, orthotics or splinting, serial casting, or walking supports/wheelchairs [
Respiratory issues may benefit from breathing exercises, chest physiotherapy for handling secretions, seating assessment, immunization against influenza and other respiratory infections, antibiotics for chest infections, tracheostomy, or ventilatory support [
Feeding and swallowing difficulties may benefit from speech therapy, diet supplementation, and feeding by gavage or gastrostomy. Gastrostomy and fundoplication should be considered if feeding issues continue beyond a few months of age [
Referral to an orthopedist for evaluation of scoliosis and joint contractures is recommended. If scoliosis is present, serial x-rays can be used to define and monitor the degree of curve. The need for bracing or corrective (spinal fusion) surgery is based on the progression of the curve, the effect on pulmonary function, and the likelihood that surgery could affect motor function [
Foot deformities may benefit from physical therapy, splinting/casting, or corrective surgery by an orthopedic surgeon [
Cardiac involvement should be monitored by a cardiologist and treated as necessary [
Orthodontic evaluation and appropriate intervention may be necessary.
Although malignant hyperthermia has not been described in CFTD, it has been seen in other congenital myopathies, particularly
Preoperative assessment of pulmonary and cardiac function is recommended to avoid complications.
Prevention of scoliosis, respiratory and feeding issues, and cardiac disease may be possible with comprehensive early screening and regular monitoring as described in
Contractures may be avoided by consistent joint movement or therapy.
The following are appropriate:
Regular monitoring for scoliosis [
Regular pulmonary monitoring including assessment for evidence of decreased nocturnal ventilation, such as morning headaches, daytime drowsiness, and decreased appetite or school performance; sleep studies; and lung function tests, including FEV1 and FVC
After an initial cardiac evaluation, consideration of ongoing cardiac monitoring on a case-by-case basis. Monitoring is advisable in those who have been found to have pathogenic variants in
Regular assessment of motor abilities to determine need for physical therapy, occupational therapy, and physical support, such as walkers or wheelchairs
Extended immobilization following surgery can exacerbate muscle weakness and thus should be avoided [
See
Pregnancy has not been specifically studied in women or fetuses with CFTD. Women with congenital myopathies generally do not experience significant complications during pregnancy or delivery; however, gestation may lead to an increase in symptoms in some women with CFTD and other congenital myopathies, including exacerbation of fatigue and muscle weakness [
The pregnancy of a fetus with a congenital myopathy is at an increased risk for complications such as polyhydramnios and reduced fetal movements and the delivery is at an increased risk for breech presentation, fetal distress, failure to progress, and/or prematurity [
Search
• Medical history and physical examination with particular attention to the following:
• Weakness
• Hypotonia
• Failure to thrive
• Scoliosis
• Contractures
• Weakness
• Hypotonia
• Failure to thrive
• Scoliosis
• Contractures
• Comprehensive respiratory evaluation in individuals with and without respiratory symptoms including the following:
• Respiratory rate
• Signs of respiratory distress
• History of recurrent chest infections
• Ability to maintain oxygen saturation
• Pulmonary function studies
• Sleep study to evaluate for nocturnal hypoxia and assess the need for ventilator support
• Note: Some individuals with CFTD who have nocturnal hypoxia without symptoms can develop respiratory failure without warning.
• Respiratory rate
• Signs of respiratory distress
• History of recurrent chest infections
• Ability to maintain oxygen saturation
• Pulmonary function studies
• Sleep study to evaluate for nocturnal hypoxia and assess the need for ventilator support
• Note: Some individuals with CFTD who have nocturnal hypoxia without symptoms can develop respiratory failure without warning.
• Feeding evaluation including assessment of suck and swallow and gastroesophageal reflux
• Speech therapy assessment, particularly if dysarthria and/or hypernasal speech are present
• Cardiac evaluation for heart disease, including
• Physical therapy and occupational therapy assessment
• Screening for skeletal and orthopedic issues, including skeletal examination for scoliosis (after the child starts sitting), joint contractures, congenital hip dislocations, and foot deformities
• Examination by a general dentist with referral for orthodontic evaluation if dental crowding becomes apparent
• Consultation with a clinical geneticist and/or genetic counselor
• Weakness
• Hypotonia
• Failure to thrive
• Scoliosis
• Contractures
• Respiratory rate
• Signs of respiratory distress
• History of recurrent chest infections
• Ability to maintain oxygen saturation
• Pulmonary function studies
• Sleep study to evaluate for nocturnal hypoxia and assess the need for ventilator support
• Note: Some individuals with CFTD who have nocturnal hypoxia without symptoms can develop respiratory failure without warning.
• Regular monitoring for scoliosis [
• Regular pulmonary monitoring including assessment for evidence of decreased nocturnal ventilation, such as morning headaches, daytime drowsiness, and decreased appetite or school performance; sleep studies; and lung function tests, including FEV1 and FVC
• After an initial cardiac evaluation, consideration of ongoing cardiac monitoring on a case-by-case basis. Monitoring is advisable in those who have been found to have pathogenic variants in
• Regular assessment of motor abilities to determine need for physical therapy, occupational therapy, and physical support, such as walkers or wheelchairs
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with congenital fiber-type disproportion, the following evaluations are recommended:
Medical history and physical examination with particular attention to the following:
Weakness
Hypotonia
Failure to thrive
Scoliosis
Contractures
Comprehensive respiratory evaluation in individuals with and without respiratory symptoms including the following:
Respiratory rate
Signs of respiratory distress
History of recurrent chest infections
Ability to maintain oxygen saturation
Pulmonary function studies
Sleep study to evaluate for nocturnal hypoxia and assess the need for ventilator support
Note: Some individuals with CFTD who have nocturnal hypoxia without symptoms can develop respiratory failure without warning.
Feeding evaluation including assessment of suck and swallow and gastroesophageal reflux
Speech therapy assessment, particularly if dysarthria and/or hypernasal speech are present
Cardiac evaluation for heart disease, including
Physical therapy and occupational therapy assessment
Screening for skeletal and orthopedic issues, including skeletal examination for scoliosis (after the child starts sitting), joint contractures, congenital hip dislocations, and foot deformities
Examination by a general dentist with referral for orthodontic evaluation if dental crowding becomes apparent
Consultation with a clinical geneticist and/or genetic counselor
• Medical history and physical examination with particular attention to the following:
• Weakness
• Hypotonia
• Failure to thrive
• Scoliosis
• Contractures
• Weakness
• Hypotonia
• Failure to thrive
• Scoliosis
• Contractures
• Comprehensive respiratory evaluation in individuals with and without respiratory symptoms including the following:
• Respiratory rate
• Signs of respiratory distress
• History of recurrent chest infections
• Ability to maintain oxygen saturation
• Pulmonary function studies
• Sleep study to evaluate for nocturnal hypoxia and assess the need for ventilator support
• Note: Some individuals with CFTD who have nocturnal hypoxia without symptoms can develop respiratory failure without warning.
• Respiratory rate
• Signs of respiratory distress
• History of recurrent chest infections
• Ability to maintain oxygen saturation
• Pulmonary function studies
• Sleep study to evaluate for nocturnal hypoxia and assess the need for ventilator support
• Note: Some individuals with CFTD who have nocturnal hypoxia without symptoms can develop respiratory failure without warning.
• Feeding evaluation including assessment of suck and swallow and gastroesophageal reflux
• Speech therapy assessment, particularly if dysarthria and/or hypernasal speech are present
• Cardiac evaluation for heart disease, including
• Physical therapy and occupational therapy assessment
• Screening for skeletal and orthopedic issues, including skeletal examination for scoliosis (after the child starts sitting), joint contractures, congenital hip dislocations, and foot deformities
• Examination by a general dentist with referral for orthodontic evaluation if dental crowding becomes apparent
• Consultation with a clinical geneticist and/or genetic counselor
• Weakness
• Hypotonia
• Failure to thrive
• Scoliosis
• Contractures
• Respiratory rate
• Signs of respiratory distress
• History of recurrent chest infections
• Ability to maintain oxygen saturation
• Pulmonary function studies
• Sleep study to evaluate for nocturnal hypoxia and assess the need for ventilator support
• Note: Some individuals with CFTD who have nocturnal hypoxia without symptoms can develop respiratory failure without warning.
## Treatment of Manifestations
It is recommended that care be provided by a multidisciplinary team coordinated by a clinician familiar with treatment of neuromuscular conditions [
Hypotonia, weakness, and joint contractures may benefit from physical therapy, occupational therapy, and/or orthopedic intervention. Interventions may include exercise and stretching programs, orthotics or splinting, serial casting, or walking supports/wheelchairs [
Respiratory issues may benefit from breathing exercises, chest physiotherapy for handling secretions, seating assessment, immunization against influenza and other respiratory infections, antibiotics for chest infections, tracheostomy, or ventilatory support [
Feeding and swallowing difficulties may benefit from speech therapy, diet supplementation, and feeding by gavage or gastrostomy. Gastrostomy and fundoplication should be considered if feeding issues continue beyond a few months of age [
Referral to an orthopedist for evaluation of scoliosis and joint contractures is recommended. If scoliosis is present, serial x-rays can be used to define and monitor the degree of curve. The need for bracing or corrective (spinal fusion) surgery is based on the progression of the curve, the effect on pulmonary function, and the likelihood that surgery could affect motor function [
Foot deformities may benefit from physical therapy, splinting/casting, or corrective surgery by an orthopedic surgeon [
Cardiac involvement should be monitored by a cardiologist and treated as necessary [
Orthodontic evaluation and appropriate intervention may be necessary.
## Prevention of Secondary Complications
Although malignant hyperthermia has not been described in CFTD, it has been seen in other congenital myopathies, particularly
Preoperative assessment of pulmonary and cardiac function is recommended to avoid complications.
Prevention of scoliosis, respiratory and feeding issues, and cardiac disease may be possible with comprehensive early screening and regular monitoring as described in
Contractures may be avoided by consistent joint movement or therapy.
## Surveillance
The following are appropriate:
Regular monitoring for scoliosis [
Regular pulmonary monitoring including assessment for evidence of decreased nocturnal ventilation, such as morning headaches, daytime drowsiness, and decreased appetite or school performance; sleep studies; and lung function tests, including FEV1 and FVC
After an initial cardiac evaluation, consideration of ongoing cardiac monitoring on a case-by-case basis. Monitoring is advisable in those who have been found to have pathogenic variants in
Regular assessment of motor abilities to determine need for physical therapy, occupational therapy, and physical support, such as walkers or wheelchairs
• Regular monitoring for scoliosis [
• Regular pulmonary monitoring including assessment for evidence of decreased nocturnal ventilation, such as morning headaches, daytime drowsiness, and decreased appetite or school performance; sleep studies; and lung function tests, including FEV1 and FVC
• After an initial cardiac evaluation, consideration of ongoing cardiac monitoring on a case-by-case basis. Monitoring is advisable in those who have been found to have pathogenic variants in
• Regular assessment of motor abilities to determine need for physical therapy, occupational therapy, and physical support, such as walkers or wheelchairs
## Agents/Circumstances to Avoid
Extended immobilization following surgery can exacerbate muscle weakness and thus should be avoided [
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Pregnancy has not been specifically studied in women or fetuses with CFTD. Women with congenital myopathies generally do not experience significant complications during pregnancy or delivery; however, gestation may lead to an increase in symptoms in some women with CFTD and other congenital myopathies, including exacerbation of fatigue and muscle weakness [
The pregnancy of a fetus with a congenital myopathy is at an increased risk for complications such as polyhydramnios and reduced fetal movements and the delivery is at an increased risk for breech presentation, fetal distress, failure to progress, and/or prematurity [
## Therapies Under Investigation
Search
## Genetic Counseling
Congenital fiber-type disproportion (CFTD) is a genetically heterogeneous condition that can be inherited in an autosomal recessive, autosomal dominant, or X-linked manner.
To date, the majority of known cases of
Some individuals diagnosed with CFTD have an affected parent.
A proband with CFTD may have the disorder as the result of a
Although some individuals diagnosed with CFTD have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or decreased penetrance. In addition, if the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.
For probands with no apparent family history, parental disease status may be clarified through medical evaluation; i.e., physical examination and follow-up with appropriate studies (e.g., EMG, muscle biopsy) for any positive findings. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
The risk to sibs of the proband depends on the genetic status of the proband's parents.
If a parent of the proband is affected and/or has a pathogenic variant in a gene associated with autosomal dominant CFTD, the risk to sibs is 50%.
If both parents are clinically unaffected, the risk to sibs, while low, is greater than that in the general population because:
Although the incidence of germline mosaicism is unknown, it remains a possibility;
Autosomal dominant inheritance with significant variable expressivity has been suggested in multiple families [
The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
Heterozygotes (carriers) are generally asymptomatic. Because parents of children with other congenital myopathies have had subtle clinical and pathologic findings when examined closely [
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are generally asymptomatic. Because parents of children with other congenital myopathies have had subtle clinical and pathologic findings when examined closely [
Carrier testing for at-risk family members is possible if the pathogenic variants have been identified in the proband.
The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
If X-linked inheritance is established through pedigree analysis, the mother of an affected male is an obligate carrier. If X-linked inheritance cannot be established through pedigree analysis, a mother of more than one affected male may be a carrier or may have germline mosaicism. Although germline mosaicism has not been reported in X-linked CFTD, it has been reported in other X-linked congenital myopathies [
Female carriers of X-linked CFTD may have mild muscle weakness [
When an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:
He has a
His mother has a
His mother has a pathogenic variant that she inherited from a maternal female ancestor.
If the mother of the proband is a carrier, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Male sibs who inherit the variant will be affected; female sibs who inherit the variant will be carriers and will usually not be affected. Female carriers of X-linked CFTD may have mild muscle weakness [
If the mother of the only affected male in the family is not a carrier, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
Carrier testing for X-linked CFTD is not possible as the gene in which mutation is causative has not been identified.
A large proportion of individuals with CFTD represent simplex cases (i.e., a single occurrence in a family), most likely attributed to autosomal recessive inheritance, X-linked recessive inheritance, or a heterozygous
It can be difficult to determine an inheritance pattern in the family of an individual representing a simplex case (i.e., a single occurrence in a family). Detailed family history, medical history, and physical examination, EMG, and muscle biopsies of parents may or may not be helpful in differentiating among the various possibilities. For example, autosomal dominant inheritance with significant variable expressivity has been suggested in at least one family, in which the mother was clinically healthy but had subtle EMG and pathology findings suggestive of myopathy. The daughter had biopsy findings consistent with CFTD and muscle weakness, hypotonia, and joint contractures [
In some families with a simplex case, both parents have subtle myopathic findings clinically and/or on biopsy, indicating that heterozygotes of a recessive neuromuscular condition may have mild clinical or pathologic manifestations [
If one parent is clinically healthy and has a normal muscle biopsy and the second parent has clinical signs of myopathy and/or myopathic findings on biopsy, inheritance is most likely autosomal dominant or X-linked (if no male-to-male transmission has occurred).
If both parents are healthy without clinical or muscle biopsy findings suggestive of myopathy, inheritance may be autosomal recessive,
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CFTD are possible.
• Some individuals diagnosed with CFTD have an affected parent.
• A proband with CFTD may have the disorder as the result of a
• Although some individuals diagnosed with CFTD have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or decreased penetrance. In addition, if the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.
• For probands with no apparent family history, parental disease status may be clarified through medical evaluation; i.e., physical examination and follow-up with appropriate studies (e.g., EMG, muscle biopsy) for any positive findings. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
• The risk to sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected and/or has a pathogenic variant in a gene associated with autosomal dominant CFTD, the risk to sibs is 50%.
• If both parents are clinically unaffected, the risk to sibs, while low, is greater than that in the general population because:
• Although the incidence of germline mosaicism is unknown, it remains a possibility;
• Autosomal dominant inheritance with significant variable expressivity has been suggested in multiple families [
• Although the incidence of germline mosaicism is unknown, it remains a possibility;
• Autosomal dominant inheritance with significant variable expressivity has been suggested in multiple families [
• Although the incidence of germline mosaicism is unknown, it remains a possibility;
• Autosomal dominant inheritance with significant variable expressivity has been suggested in multiple families [
• The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
• Heterozygotes (carriers) are generally asymptomatic. Because parents of children with other congenital myopathies have had subtle clinical and pathologic findings when examined closely [
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are generally asymptomatic. Because parents of children with other congenital myopathies have had subtle clinical and pathologic findings when examined closely [
• The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
• If X-linked inheritance is established through pedigree analysis, the mother of an affected male is an obligate carrier. If X-linked inheritance cannot be established through pedigree analysis, a mother of more than one affected male may be a carrier or may have germline mosaicism. Although germline mosaicism has not been reported in X-linked CFTD, it has been reported in other X-linked congenital myopathies [
• Female carriers of X-linked CFTD may have mild muscle weakness [
• When an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:
• He has a
• His mother has a
• His mother has a pathogenic variant that she inherited from a maternal female ancestor.
• He has a
• His mother has a
• His mother has a pathogenic variant that she inherited from a maternal female ancestor.
• He has a
• His mother has a
• His mother has a pathogenic variant that she inherited from a maternal female ancestor.
• If the mother of the proband is a carrier, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Male sibs who inherit the variant will be affected; female sibs who inherit the variant will be carriers and will usually not be affected. Female carriers of X-linked CFTD may have mild muscle weakness [
• If the mother of the only affected male in the family is not a carrier, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
• A large proportion of individuals with CFTD represent simplex cases (i.e., a single occurrence in a family), most likely attributed to autosomal recessive inheritance, X-linked recessive inheritance, or a heterozygous
• It can be difficult to determine an inheritance pattern in the family of an individual representing a simplex case (i.e., a single occurrence in a family). Detailed family history, medical history, and physical examination, EMG, and muscle biopsies of parents may or may not be helpful in differentiating among the various possibilities. For example, autosomal dominant inheritance with significant variable expressivity has been suggested in at least one family, in which the mother was clinically healthy but had subtle EMG and pathology findings suggestive of myopathy. The daughter had biopsy findings consistent with CFTD and muscle weakness, hypotonia, and joint contractures [
• In some families with a simplex case, both parents have subtle myopathic findings clinically and/or on biopsy, indicating that heterozygotes of a recessive neuromuscular condition may have mild clinical or pathologic manifestations [
• If one parent is clinically healthy and has a normal muscle biopsy and the second parent has clinical signs of myopathy and/or myopathic findings on biopsy, inheritance is most likely autosomal dominant or X-linked (if no male-to-male transmission has occurred).
• If both parents are healthy without clinical or muscle biopsy findings suggestive of myopathy, inheritance may be autosomal recessive,
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Congenital fiber-type disproportion (CFTD) is a genetically heterogeneous condition that can be inherited in an autosomal recessive, autosomal dominant, or X-linked manner.
To date, the majority of known cases of
## Autosomal Dominant Inheritance – Risk to Family Members
Some individuals diagnosed with CFTD have an affected parent.
A proband with CFTD may have the disorder as the result of a
Although some individuals diagnosed with CFTD have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or decreased penetrance. In addition, if the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.
For probands with no apparent family history, parental disease status may be clarified through medical evaluation; i.e., physical examination and follow-up with appropriate studies (e.g., EMG, muscle biopsy) for any positive findings. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
The risk to sibs of the proband depends on the genetic status of the proband's parents.
If a parent of the proband is affected and/or has a pathogenic variant in a gene associated with autosomal dominant CFTD, the risk to sibs is 50%.
If both parents are clinically unaffected, the risk to sibs, while low, is greater than that in the general population because:
Although the incidence of germline mosaicism is unknown, it remains a possibility;
Autosomal dominant inheritance with significant variable expressivity has been suggested in multiple families [
• Some individuals diagnosed with CFTD have an affected parent.
• A proband with CFTD may have the disorder as the result of a
• Although some individuals diagnosed with CFTD have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or decreased penetrance. In addition, if the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.
• For probands with no apparent family history, parental disease status may be clarified through medical evaluation; i.e., physical examination and follow-up with appropriate studies (e.g., EMG, muscle biopsy) for any positive findings. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
• The risk to sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected and/or has a pathogenic variant in a gene associated with autosomal dominant CFTD, the risk to sibs is 50%.
• If both parents are clinically unaffected, the risk to sibs, while low, is greater than that in the general population because:
• Although the incidence of germline mosaicism is unknown, it remains a possibility;
• Autosomal dominant inheritance with significant variable expressivity has been suggested in multiple families [
• Although the incidence of germline mosaicism is unknown, it remains a possibility;
• Autosomal dominant inheritance with significant variable expressivity has been suggested in multiple families [
• Although the incidence of germline mosaicism is unknown, it remains a possibility;
• Autosomal dominant inheritance with significant variable expressivity has been suggested in multiple families [
## Autosomal Recessive Inheritance
The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
Heterozygotes (carriers) are generally asymptomatic. Because parents of children with other congenital myopathies have had subtle clinical and pathologic findings when examined closely [
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are generally asymptomatic. Because parents of children with other congenital myopathies have had subtle clinical and pathologic findings when examined closely [
Carrier testing for at-risk family members is possible if the pathogenic variants have been identified in the proband.
• The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
• Heterozygotes (carriers) are generally asymptomatic. Because parents of children with other congenital myopathies have had subtle clinical and pathologic findings when examined closely [
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are generally asymptomatic. Because parents of children with other congenital myopathies have had subtle clinical and pathologic findings when examined closely [
## Risk to Family Members
The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
Heterozygotes (carriers) are generally asymptomatic. Because parents of children with other congenital myopathies have had subtle clinical and pathologic findings when examined closely [
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are generally asymptomatic. Because parents of children with other congenital myopathies have had subtle clinical and pathologic findings when examined closely [
• The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
• Heterozygotes (carriers) are generally asymptomatic. Because parents of children with other congenital myopathies have had subtle clinical and pathologic findings when examined closely [
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are generally asymptomatic. Because parents of children with other congenital myopathies have had subtle clinical and pathologic findings when examined closely [
## Carrier (Heterozygote) Detection
Carrier testing for at-risk family members is possible if the pathogenic variants have been identified in the proband.
## X-Linked Inheritance
The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
If X-linked inheritance is established through pedigree analysis, the mother of an affected male is an obligate carrier. If X-linked inheritance cannot be established through pedigree analysis, a mother of more than one affected male may be a carrier or may have germline mosaicism. Although germline mosaicism has not been reported in X-linked CFTD, it has been reported in other X-linked congenital myopathies [
Female carriers of X-linked CFTD may have mild muscle weakness [
When an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:
He has a
His mother has a
His mother has a pathogenic variant that she inherited from a maternal female ancestor.
If the mother of the proband is a carrier, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Male sibs who inherit the variant will be affected; female sibs who inherit the variant will be carriers and will usually not be affected. Female carriers of X-linked CFTD may have mild muscle weakness [
If the mother of the only affected male in the family is not a carrier, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
Carrier testing for X-linked CFTD is not possible as the gene in which mutation is causative has not been identified.
• The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
• If X-linked inheritance is established through pedigree analysis, the mother of an affected male is an obligate carrier. If X-linked inheritance cannot be established through pedigree analysis, a mother of more than one affected male may be a carrier or may have germline mosaicism. Although germline mosaicism has not been reported in X-linked CFTD, it has been reported in other X-linked congenital myopathies [
• Female carriers of X-linked CFTD may have mild muscle weakness [
• When an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:
• He has a
• His mother has a
• His mother has a pathogenic variant that she inherited from a maternal female ancestor.
• He has a
• His mother has a
• His mother has a pathogenic variant that she inherited from a maternal female ancestor.
• He has a
• His mother has a
• His mother has a pathogenic variant that she inherited from a maternal female ancestor.
• If the mother of the proband is a carrier, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Male sibs who inherit the variant will be affected; female sibs who inherit the variant will be carriers and will usually not be affected. Female carriers of X-linked CFTD may have mild muscle weakness [
• If the mother of the only affected male in the family is not a carrier, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
## Risk to Family Members
The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
If X-linked inheritance is established through pedigree analysis, the mother of an affected male is an obligate carrier. If X-linked inheritance cannot be established through pedigree analysis, a mother of more than one affected male may be a carrier or may have germline mosaicism. Although germline mosaicism has not been reported in X-linked CFTD, it has been reported in other X-linked congenital myopathies [
Female carriers of X-linked CFTD may have mild muscle weakness [
When an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:
He has a
His mother has a
His mother has a pathogenic variant that she inherited from a maternal female ancestor.
If the mother of the proband is a carrier, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Male sibs who inherit the variant will be affected; female sibs who inherit the variant will be carriers and will usually not be affected. Female carriers of X-linked CFTD may have mild muscle weakness [
If the mother of the only affected male in the family is not a carrier, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
• The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
• If X-linked inheritance is established through pedigree analysis, the mother of an affected male is an obligate carrier. If X-linked inheritance cannot be established through pedigree analysis, a mother of more than one affected male may be a carrier or may have germline mosaicism. Although germline mosaicism has not been reported in X-linked CFTD, it has been reported in other X-linked congenital myopathies [
• Female carriers of X-linked CFTD may have mild muscle weakness [
• When an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:
• He has a
• His mother has a
• His mother has a pathogenic variant that she inherited from a maternal female ancestor.
• He has a
• His mother has a
• His mother has a pathogenic variant that she inherited from a maternal female ancestor.
• He has a
• His mother has a
• His mother has a pathogenic variant that she inherited from a maternal female ancestor.
• If the mother of the proband is a carrier, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Male sibs who inherit the variant will be affected; female sibs who inherit the variant will be carriers and will usually not be affected. Female carriers of X-linked CFTD may have mild muscle weakness [
• If the mother of the only affected male in the family is not a carrier, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
## Carrier Detection
Carrier testing for X-linked CFTD is not possible as the gene in which mutation is causative has not been identified.
## Related Genetic Counseling Issues
A large proportion of individuals with CFTD represent simplex cases (i.e., a single occurrence in a family), most likely attributed to autosomal recessive inheritance, X-linked recessive inheritance, or a heterozygous
It can be difficult to determine an inheritance pattern in the family of an individual representing a simplex case (i.e., a single occurrence in a family). Detailed family history, medical history, and physical examination, EMG, and muscle biopsies of parents may or may not be helpful in differentiating among the various possibilities. For example, autosomal dominant inheritance with significant variable expressivity has been suggested in at least one family, in which the mother was clinically healthy but had subtle EMG and pathology findings suggestive of myopathy. The daughter had biopsy findings consistent with CFTD and muscle weakness, hypotonia, and joint contractures [
In some families with a simplex case, both parents have subtle myopathic findings clinically and/or on biopsy, indicating that heterozygotes of a recessive neuromuscular condition may have mild clinical or pathologic manifestations [
If one parent is clinically healthy and has a normal muscle biopsy and the second parent has clinical signs of myopathy and/or myopathic findings on biopsy, inheritance is most likely autosomal dominant or X-linked (if no male-to-male transmission has occurred).
If both parents are healthy without clinical or muscle biopsy findings suggestive of myopathy, inheritance may be autosomal recessive,
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• A large proportion of individuals with CFTD represent simplex cases (i.e., a single occurrence in a family), most likely attributed to autosomal recessive inheritance, X-linked recessive inheritance, or a heterozygous
• It can be difficult to determine an inheritance pattern in the family of an individual representing a simplex case (i.e., a single occurrence in a family). Detailed family history, medical history, and physical examination, EMG, and muscle biopsies of parents may or may not be helpful in differentiating among the various possibilities. For example, autosomal dominant inheritance with significant variable expressivity has been suggested in at least one family, in which the mother was clinically healthy but had subtle EMG and pathology findings suggestive of myopathy. The daughter had biopsy findings consistent with CFTD and muscle weakness, hypotonia, and joint contractures [
• In some families with a simplex case, both parents have subtle myopathic findings clinically and/or on biopsy, indicating that heterozygotes of a recessive neuromuscular condition may have mild clinical or pathologic manifestations [
• If one parent is clinically healthy and has a normal muscle biopsy and the second parent has clinical signs of myopathy and/or myopathic findings on biopsy, inheritance is most likely autosomal dominant or X-linked (if no male-to-male transmission has occurred).
• If both parents are healthy without clinical or muscle biopsy findings suggestive of myopathy, inheritance may be autosomal recessive,
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CFTD are possible.
## Resources
2345 Yonge Street
Suite 900
Toronto Ontario M4P 2E5
Canada
222 South Riverside Plaza
Suite 1500
Chicago IL 60606
61A Great Suffolk Street
London SE1 0BU
United Kingdom
•
• 2345 Yonge Street
• Suite 900
• Toronto Ontario M4P 2E5
• Canada
•
•
• 222 South Riverside Plaza
• Suite 1500
• Chicago IL 60606
•
•
• 61A Great Suffolk Street
• London SE1 0BU
• United Kingdom
•
## Molecular Genetics
Congenital Fiber-Type Disproportion: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Congenital Fiber-Type Disproportion (
Variants listed in the table have been provided by the authors.
Variants listed in the table have been provided by the authors.
Ter indicates nucleotide(s) are 3' of the translation stop codon; "extTer#" is used to indicate the extension of a protein sequence until a new stop codon is reached at "#" amino acids downstream as a consequence of a variant changing the natural stop codon into an amino acid.
Variants listed in the table have been provided by the authors.
Variants listed in the table have been provided by the authors.
Variants listed in the table have been provided by the authors.
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Ter indicates nucleotide(s) are 3' of the translation stop codon; "extTer#" is used to indicate the extension of a protein sequence until a new stop codon is reached at "#" amino acids downstream as a consequence of a variant changing the natural stop codon into an amino acid.
## References
## Literature Cited
## Chapter Notes
Dr Beggs'
We would like to acknowledge and thank all of those who aided in the writing of this review, including Pankaj Agrawal, MD, MMSc; Jessie Hastings, MS, CGC; Michael Lawlor, MD, PhD; and Christopher R Pierson, MD, PhD. In addition, the authors gratefully acknowledge the Lee and Penny Anderson Family Foundation, the Joshua Frase Foundation, the Muscular Dystrophy Association (USA), and the National Institutes of Health for their funding of our studies on congenital myopathies.
18 April 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
11 April 2013 (me) Comprehensive update posted live
23 October 2008 (cd) Revision: prenatal diagnosis for
13 August 2008 (cd) Revision: sequence analysis and prenatal testing for
12 January 2007 (me) Review posted live
12 April 2006 (et) Original submission
• 18 April 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
• 11 April 2013 (me) Comprehensive update posted live
• 23 October 2008 (cd) Revision: prenatal diagnosis for
• 13 August 2008 (cd) Revision: sequence analysis and prenatal testing for
• 12 January 2007 (me) Review posted live
• 12 April 2006 (et) Original submission
## Author Notes
Dr Beggs'
## Acknowledgments
We would like to acknowledge and thank all of those who aided in the writing of this review, including Pankaj Agrawal, MD, MMSc; Jessie Hastings, MS, CGC; Michael Lawlor, MD, PhD; and Christopher R Pierson, MD, PhD. In addition, the authors gratefully acknowledge the Lee and Penny Anderson Family Foundation, the Joshua Frase Foundation, the Muscular Dystrophy Association (USA), and the National Institutes of Health for their funding of our studies on congenital myopathies.
## Revision History
18 April 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
11 April 2013 (me) Comprehensive update posted live
23 October 2008 (cd) Revision: prenatal diagnosis for
13 August 2008 (cd) Revision: sequence analysis and prenatal testing for
12 January 2007 (me) Review posted live
12 April 2006 (et) Original submission
• 18 April 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
• 11 April 2013 (me) Comprehensive update posted live
• 23 October 2008 (cd) Revision: prenatal diagnosis for
• 13 August 2008 (cd) Revision: sequence analysis and prenatal testing for
• 12 January 2007 (me) Review posted live
• 12 April 2006 (et) Original submission
(A) H and E, (B) NADH, and (C) ATPase (pH 9.4) histochemical stains of a biopsy taken from the vastus lateralis of a six-month-old female with CFTD caused by a heterozygous
|
[
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"B Moghadaszadeh, N Petit, C Jaillard, M Brockington, SQ Roy, L Merlini, N Romero, B Estournet, I Desguerre, D Chaigne, F Muntoni, H Topaloglu, P Guicheney. Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome.. Nat Genet 2001;29:17-8",
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"S Ortolano, R Tarrío, P Blanco-Arias, S Teijeira, F Rodríguez-Trelles, M García-Murias, V Delague, N Lévy, JM Fernández, B Quintáns, BS Millán, A Carracedo, C Navarro, MJ Sobrido. A novel MYH7 mutation links congenital fiber type disproportion and myosin storage myopathy.. Neuromuscul Disord. 2011;21:254-62",
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"RS Staron, FC Hagerman, RS Hikida, TF Murray, DP Hostler, MT Crill, KE Ragg, K Toma. Fiber type composition of the vastus lateralis muscle of young men and women.. J Histochem Cytochem 2000;48:623-9",
"H Tajsharghi, M Ohlsson, L Palm, A Oldfors. Myopathies associated with β-tropomyosin mutations.. Neuromuscul Disord. 2012;22:923-33",
"H Tajsharghi, A Oldfors. Myosinopathies: pathology and mechanisms.. Acta Neuropathol 2013;125:3-18",
"S Treves, AA Anderson, S Ducreux, A Divet, C Bleunven, C Grasso, S Paesante, F Zorzato. Ryanodine receptor 1 mutations, dysregulation of calcium homeostasis and neuromuscular disorders.. Neuromuscul Disord. 2005;15:577-87",
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"P Vorwerk, CT Christoffersen, J Muller, H Vestergaard, O Pedersen, P De Meyts. Alternative splicing of exon 17 and a missense mutation in exon 20 of the insulin receptor gene in two brothers with a novel syndrome of insulin resistance (congenital fiber-type disproportion myopathy).. Horm Res 1999;52:211-20",
"C Wallgren-Pettersson, H Kääriäinen, J Rapola, T Salmi, J Jääskeläinen, M Donner. Genetics of congenital nemaline myopathy: a study of 10 families.. J Med Genet. 1990;27:480-7",
"CL Wang, LM Coluccio. New insights into the regulation of the actin cytoskeleton by tropomyosin.. Int Rev Cell Mol Biol. 2010;281:91-128",
"JM Wilmshurst, S Lillis, H Zhou, K Pillay, H Henderson, W Kress, CR Müller, A Ndondo, V Cloke, T Cullup, E Bertini, C Boennemann, V Straub, R Quinlivan, JJ Dowling, S Al-Sarraj, S Treves, S Abbs, AY Manzur, CA Sewry, F Muntoni, H Jungbluth. RYR1 mutations are a common cause of congenital myopathies with central nuclei.. Ann Neurol. 2010;68:717-26"
] |
12/1/2007
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11/4/2013
|
23/10/2008
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cgd
|
cgd
|
[
"CGD",
"CGD",
"Cytochrome b-245 chaperone 1",
"Cytochrome b-245 light chain",
"NADPH oxidase 2",
"Neutrophil cytosol factor 1",
"Neutrophil cytosol factor 2",
"Neutrophil cytosol factor 4",
"CYBA",
"CYBB",
"CYBC1",
"NCF1",
"NCF2",
"NCF4",
"Chronic Granulomatous Disease"
] |
Chronic Granulomatous Disease
|
Jennifer W Leiding, Steven M Holland
|
Summary Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder of phagocytes (neutrophils, monocytes, macrophages, and eosinophils) resulting from impaired killing of bacteria and fungi. CGD is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory responses resulting in granuloma formation and other inflammatory disorders such as colitis. Infections typically involve the lung (pneumonia), lymph nodes (lymphadenitis), liver (abscess), bone (osteomyelitis), and skin (abscesses or cellulitis). Granulomas typically involve the genitourinary system (bladder) and gastrointestinal tract (often the pylorus initially, and later the esophagus, jejunum, ileum, cecum, rectum, and perirectal area). Some males with X-linked CGD have McLeod neuroacanthocytosis syndrome as the result of a contiguous gene deletion. While CGD may present anytime from infancy to late adulthood, the vast majority of affected individuals are diagnosed before age five years. Use of antimicrobial prophylaxis and therapy has greatly improved overall survival. The diagnosis of CGD is established in a proband with suggestive findings by identification of pathogenic variant(s) in one of six genes that encode or permit assembly of the subunits of phagocyte NADPH oxidase: biallelic pathogenic variants in Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known cure for CGD and is associated with excellent overall and event-free survival, especially when performed with matched donors at a younger age. CGD associated with a pathogenic variant in Once the CGD-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. (Other prenatal testing options may be available if the pathogenic variant[s] in the family are not known.)
|
## Diagnosis
Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder of phagocytes (neutrophils, monocytes, macrophages, and eosinophils) resulting from impaired killing of bacteria and fungi. CGD is caused by pathogenic variants in one of six genes that encode or permit assembly of the subunits of phagocyte NADPH oxidase.
Chronic granulomatous disease (CGD)
Growth restriction in childhood
Infections of lung (pneumonia), lymph nodes (lymphadenitis), liver (abscess), bone (osteomyelitis), and skin (abscesses or cellulitis), especially spontaneously occurring severe or recurrent bacterial infections. Microbiologic confirmation of the cause of infection helps confirm the likelihood of CGD, since the spectrum of infection in CGD is distinct and narrow (see
Granuloma formation, especially genitourinary (bladder) and gastrointestinal (often pyloric initially, and later esophageal, jejunal, ileal, cecal, rectal, and perirectal)
Colitis, manifesting as frequent stooling and fistulae or fissures. This may be the sole finding in some individuals.
Abnormal wound healing caused by excessive granulation, which may cause the wound to dehisce and gape, leading to healing by secondary intention
Clinical tests that rely on direct measurement of neutrophil superoxide production via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex to establish the diagnosis of CGD include the following.
The DHR test can distinguish the following forms of CGD:
Complete forms (i.e., those with absent-to-greatly diminished production of superoxide) commonly observed in males with X-linked CGD
Hypomorphic (variant) forms of CGD characterized by reduced protein expression/function and residual superoxide production (observed in some autosomal recessive CGD and protein-positive X-linked CGD)
Mosaic forms (i.e., those with two discrete populations of phagocytes: some oxidase-positive and some oxidase-negative) commonly observed in females who are heterozygous for X-linked CGD
Note: Although the pattern of oxidase-positive and oxidase-negative phagocytes can suggest X-linked inheritance of CGD or autosomal recessive inheritance of CGD, the results are not definitive in establishing the molecular cause or mode of inheritance.
The DHR is superior to other tests for CGD, and is widely available to ordering clinicians.
Note: Because the NBT test is semi-quantitative and evaluates only a limited number of cells, it may be falsely interpreted as normal in: (1) females who are heterozygous for X-linked CGD, especially those with skewed (non-random) X-chromosome inactivation (see
Family history is consistent with
The diagnosis of CGD
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Large deletions in Xp21.1 have been reported in some with X-CGD, which may affect genes lying in close proximity to
Molecular Genetic Testing Used in Chronic Granulomatous Disease (CGD)
AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (see
If a contiguous gene deletion involving multiple genes at Xp21.1 is suspected based on clinical findings, or if a large deletion is found within
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Growth restriction in childhood
• Infections of lung (pneumonia), lymph nodes (lymphadenitis), liver (abscess), bone (osteomyelitis), and skin (abscesses or cellulitis), especially spontaneously occurring severe or recurrent bacterial infections. Microbiologic confirmation of the cause of infection helps confirm the likelihood of CGD, since the spectrum of infection in CGD is distinct and narrow (see
• Granuloma formation, especially genitourinary (bladder) and gastrointestinal (often pyloric initially, and later esophageal, jejunal, ileal, cecal, rectal, and perirectal)
• Colitis, manifesting as frequent stooling and fistulae or fissures. This may be the sole finding in some individuals.
• Abnormal wound healing caused by excessive granulation, which may cause the wound to dehisce and gape, leading to healing by secondary intention
• Complete forms (i.e., those with absent-to-greatly diminished production of superoxide) commonly observed in males with X-linked CGD
• Hypomorphic (variant) forms of CGD characterized by reduced protein expression/function and residual superoxide production (observed in some autosomal recessive CGD and protein-positive X-linked CGD)
• Mosaic forms (i.e., those with two discrete populations of phagocytes: some oxidase-positive and some oxidase-negative) commonly observed in females who are heterozygous for X-linked CGD
• Note: Although the pattern of oxidase-positive and oxidase-negative phagocytes can suggest X-linked inheritance of CGD or autosomal recessive inheritance of CGD, the results are not definitive in establishing the molecular cause or mode of inheritance.
## Suggestive Findings
Chronic granulomatous disease (CGD)
Growth restriction in childhood
Infections of lung (pneumonia), lymph nodes (lymphadenitis), liver (abscess), bone (osteomyelitis), and skin (abscesses or cellulitis), especially spontaneously occurring severe or recurrent bacterial infections. Microbiologic confirmation of the cause of infection helps confirm the likelihood of CGD, since the spectrum of infection in CGD is distinct and narrow (see
Granuloma formation, especially genitourinary (bladder) and gastrointestinal (often pyloric initially, and later esophageal, jejunal, ileal, cecal, rectal, and perirectal)
Colitis, manifesting as frequent stooling and fistulae or fissures. This may be the sole finding in some individuals.
Abnormal wound healing caused by excessive granulation, which may cause the wound to dehisce and gape, leading to healing by secondary intention
Clinical tests that rely on direct measurement of neutrophil superoxide production via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex to establish the diagnosis of CGD include the following.
The DHR test can distinguish the following forms of CGD:
Complete forms (i.e., those with absent-to-greatly diminished production of superoxide) commonly observed in males with X-linked CGD
Hypomorphic (variant) forms of CGD characterized by reduced protein expression/function and residual superoxide production (observed in some autosomal recessive CGD and protein-positive X-linked CGD)
Mosaic forms (i.e., those with two discrete populations of phagocytes: some oxidase-positive and some oxidase-negative) commonly observed in females who are heterozygous for X-linked CGD
Note: Although the pattern of oxidase-positive and oxidase-negative phagocytes can suggest X-linked inheritance of CGD or autosomal recessive inheritance of CGD, the results are not definitive in establishing the molecular cause or mode of inheritance.
The DHR is superior to other tests for CGD, and is widely available to ordering clinicians.
Note: Because the NBT test is semi-quantitative and evaluates only a limited number of cells, it may be falsely interpreted as normal in: (1) females who are heterozygous for X-linked CGD, especially those with skewed (non-random) X-chromosome inactivation (see
Family history is consistent with
• Growth restriction in childhood
• Infections of lung (pneumonia), lymph nodes (lymphadenitis), liver (abscess), bone (osteomyelitis), and skin (abscesses or cellulitis), especially spontaneously occurring severe or recurrent bacterial infections. Microbiologic confirmation of the cause of infection helps confirm the likelihood of CGD, since the spectrum of infection in CGD is distinct and narrow (see
• Granuloma formation, especially genitourinary (bladder) and gastrointestinal (often pyloric initially, and later esophageal, jejunal, ileal, cecal, rectal, and perirectal)
• Colitis, manifesting as frequent stooling and fistulae or fissures. This may be the sole finding in some individuals.
• Abnormal wound healing caused by excessive granulation, which may cause the wound to dehisce and gape, leading to healing by secondary intention
• Complete forms (i.e., those with absent-to-greatly diminished production of superoxide) commonly observed in males with X-linked CGD
• Hypomorphic (variant) forms of CGD characterized by reduced protein expression/function and residual superoxide production (observed in some autosomal recessive CGD and protein-positive X-linked CGD)
• Mosaic forms (i.e., those with two discrete populations of phagocytes: some oxidase-positive and some oxidase-negative) commonly observed in females who are heterozygous for X-linked CGD
• Note: Although the pattern of oxidase-positive and oxidase-negative phagocytes can suggest X-linked inheritance of CGD or autosomal recessive inheritance of CGD, the results are not definitive in establishing the molecular cause or mode of inheritance.
## Clinical Features
Growth restriction in childhood
Infections of lung (pneumonia), lymph nodes (lymphadenitis), liver (abscess), bone (osteomyelitis), and skin (abscesses or cellulitis), especially spontaneously occurring severe or recurrent bacterial infections. Microbiologic confirmation of the cause of infection helps confirm the likelihood of CGD, since the spectrum of infection in CGD is distinct and narrow (see
Granuloma formation, especially genitourinary (bladder) and gastrointestinal (often pyloric initially, and later esophageal, jejunal, ileal, cecal, rectal, and perirectal)
Colitis, manifesting as frequent stooling and fistulae or fissures. This may be the sole finding in some individuals.
Abnormal wound healing caused by excessive granulation, which may cause the wound to dehisce and gape, leading to healing by secondary intention
• Growth restriction in childhood
• Infections of lung (pneumonia), lymph nodes (lymphadenitis), liver (abscess), bone (osteomyelitis), and skin (abscesses or cellulitis), especially spontaneously occurring severe or recurrent bacterial infections. Microbiologic confirmation of the cause of infection helps confirm the likelihood of CGD, since the spectrum of infection in CGD is distinct and narrow (see
• Granuloma formation, especially genitourinary (bladder) and gastrointestinal (often pyloric initially, and later esophageal, jejunal, ileal, cecal, rectal, and perirectal)
• Colitis, manifesting as frequent stooling and fistulae or fissures. This may be the sole finding in some individuals.
• Abnormal wound healing caused by excessive granulation, which may cause the wound to dehisce and gape, leading to healing by secondary intention
## Laboratory Findings
Clinical tests that rely on direct measurement of neutrophil superoxide production via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex to establish the diagnosis of CGD include the following.
The DHR test can distinguish the following forms of CGD:
Complete forms (i.e., those with absent-to-greatly diminished production of superoxide) commonly observed in males with X-linked CGD
Hypomorphic (variant) forms of CGD characterized by reduced protein expression/function and residual superoxide production (observed in some autosomal recessive CGD and protein-positive X-linked CGD)
Mosaic forms (i.e., those with two discrete populations of phagocytes: some oxidase-positive and some oxidase-negative) commonly observed in females who are heterozygous for X-linked CGD
Note: Although the pattern of oxidase-positive and oxidase-negative phagocytes can suggest X-linked inheritance of CGD or autosomal recessive inheritance of CGD, the results are not definitive in establishing the molecular cause or mode of inheritance.
The DHR is superior to other tests for CGD, and is widely available to ordering clinicians.
Note: Because the NBT test is semi-quantitative and evaluates only a limited number of cells, it may be falsely interpreted as normal in: (1) females who are heterozygous for X-linked CGD, especially those with skewed (non-random) X-chromosome inactivation (see
• Complete forms (i.e., those with absent-to-greatly diminished production of superoxide) commonly observed in males with X-linked CGD
• Hypomorphic (variant) forms of CGD characterized by reduced protein expression/function and residual superoxide production (observed in some autosomal recessive CGD and protein-positive X-linked CGD)
• Mosaic forms (i.e., those with two discrete populations of phagocytes: some oxidase-positive and some oxidase-negative) commonly observed in females who are heterozygous for X-linked CGD
• Note: Although the pattern of oxidase-positive and oxidase-negative phagocytes can suggest X-linked inheritance of CGD or autosomal recessive inheritance of CGD, the results are not definitive in establishing the molecular cause or mode of inheritance.
## Family History
Family history is consistent with
## Establishing the Diagnosis
The diagnosis of CGD
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Large deletions in Xp21.1 have been reported in some with X-CGD, which may affect genes lying in close proximity to
Molecular Genetic Testing Used in Chronic Granulomatous Disease (CGD)
AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (see
If a contiguous gene deletion involving multiple genes at Xp21.1 is suspected based on clinical findings, or if a large deletion is found within
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
## Special Consideration in a Male with Suspected CGD and Other Medical Issues
Large deletions in Xp21.1 have been reported in some with X-CGD, which may affect genes lying in close proximity to
Molecular Genetic Testing Used in Chronic Granulomatous Disease (CGD)
AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (see
If a contiguous gene deletion involving multiple genes at Xp21.1 is suspected based on clinical findings, or if a large deletion is found within
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Clinical Characteristics
Chronic granulomatous disease (CGD) is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory responses resulting in granuloma formation and other inflammatory disorders such as colitis.
Effective treatment of CGD-related infections with antimicrobials not available in the past
Recognition of milder cases of autosomal recessive CGD that may have gone undiagnosed without currently available tests and/or awareness of milder disease manifestations
Overall improvement in food handling and sanitation
Although the frequency of infections in persons with CGD has decreased with the routine administration of antibacterial and antifungal prophylaxis, infections still occur at a frequency of 0.3/year.
In North America, the majority of infections in CGD are caused by
Infections in CGD: Common Pathogens and Sites of Involvement
Osteomyelitis
Soft-tissue infection
Pneumonia
Sepsis
Outside of CGD,
Widespread prophylaxis has limited staphylococcal infections primarily to the skin, lymph nodes, liver, and (rarely) lung [
Outside of CGD,
Mycobacterial diseases in CGD are mostly limited to regional and disseminated BCG infections and tuberculosis. Persons with CGD are less susceptible to nontuberculous infections than persons with defects in T-cell or interferon gamma/IL-12 pathways: in persons with CGD, BCG infection may cause severe localized disease such as draining skin lesions at sites of BCG vaccination [
Uncommon bacterial infections that are virtually pathognomonic for CGD include the following:
Bacteremia is relatively uncommon except with certain gram-negative organisms.
Invasive fungal infections, which have the highest prevalence in CGD among all primary immunodeficiencies, remain the leading cause of mortality in CGD. They occur most commonly in the first two decades of life and can be the first presentation of disease [
Fungal infections are typically acquired through inhalation of spores or hyphae resulting in pneumonia that can spread locally to the ribs and spine or metastatically to the brain. Presentation may be insidious or manifest as failure to thrive and malaise. Other common presenting signs and symptoms include cough, fever, and chest pain.
Mucormycosis has been reported in CGD but appears to occur only in the setting of significant immunosuppression [
The overall frequency and mortality of invasive fungal infections have been significantly reduced with the use of itraconazole as antifungal prophylaxis and the use of other azoles (voriconazole and posaconazole) as therapy. However, when they occur, fungal infections develop at an older age and may require longer duration of therapy. Fungal infections cause more mortality than other infections in CGD [
Yeast infections are not nearly as common as bacterial and fungal infections in persons with CGD; mucocutaneous candidiasis is not encountered.
Note: The endemic dimorphic mold infections histoplasmosis, blastomycosis, and coccidioidomycosis do not occur in CGD [
Formation of granulomata and dysregulated inflammation in CGD contribute to morbidity and can cause multiple symptoms. The genitourinary and gastrointestinal tracts are most commonly affected.
Pyloric edema leads to functional gastric outlet obstruction and can be an initial presentation of CGD.
Esophageal, jejunal, ileal, cecal, rectal, and perirectal granulomata similar to those in Crohn disease have also been described. Symptomatic inflammatory bowel disease affects up to 50% of individuals and can be the presenting finding [
Other gastrointestinal symptoms indicative of CGD colitis include abdominal pain, diarrhea, strictures, and fistulae. Significant colitis leading to bowel obstruction, fistulae, and strictures can be an important cause of growth restriction [
Other common liver abnormalities include liver enzyme elevation, persistent elevations in alkaline phosphatase, and drug-induced hepatitis.
High rates of portal venopathy are associated with splenomegaly and nodular regenerative hyperplasia. Portal hypertension and thrombocytopenia are associated with intrahepatic disease and important risk factors for mortality [
Fungi elicit an exuberant inflammatory response regardless of whether the fungi are alive or dead [
Prolonged and dysregulated inflammation in CGD can overlap clinically with the syndrome of
The histopathologic patterns of malignancy have significant overlap with certain chronic inflammatory conditions. However, the largest series of affected individuals to date reported no malignancies [
Survival in CGD has improved greatly, and is now approximately 90% at age ten years [
Persons with
Persons with
88%-97% at age 10 years
73%-87% at age 20 years
46%-55% at age 30 years
Note: Individuals diagnosed and treated before the use of azoles usually did not survive past age 30-40 years.
Note: Inflammatory bowel disease does not influence mortality: overall survival rates of persons with CGD with and without colitis are similar [
Females who are heterozygous for a
Neutrophils from heterozygous females express two populations that dihydrorhodamine (DHR) testing can detect: an abnormal DHR(-) population expressing the pathogenic variant and a brightly staining DHR (+) population expressing the normal allele. Skewed (non-random) X-chromosome inactivation can result in low %DHR+ neutrophil population because the
When %DHR+ falls below 20%, heterozygous females are at risk for CGD-specific infections. The %DHR+ population can predict susceptibility to infections with CGD-specific pathogens but does not predict autoimmune symptoms of heterozygous females [
Careful longitudinal evaluation of heterozygous females is recommended in order to detect inflammatory or infectious conditions if they occur over time.
Clinical evidence of CGD in heterozygous females:
Cutaneous lesions resembling discoid lupus and recurrent aphthous stomatitis [
Photosensitive skin rashes, alopecia, Raynaud's phenomenon, mouth ulcers, and joint pain [
Chorioretinal lesions and granulomata with pigment clumping that are usually asymptomatic [
Crohn-like disease (colitis) [
Systemic lupus erythematosus
Infections
Hypomorphic (variant) CGD is characterized by partial protein expression/function and residual superoxide production (observed in AR-CGD and protein-positive X-linked CGD). Individuals with hypomorphic variants typically have a milder course and come to clinical attention later in life than those with absent protein expression [
All nonsense variants or deletions of
The phenotype caused by pathogenic variants in
Pathogenic missense variants that occur in the
No additional specific genotype-phenotype correlations have been identified for
When first characterized, chronic granulomatous disease was called "fatal granulomatous disease of childhood" [
The retrospectively and voluntarily reported prevalence of CGD is approximately 1:200,000 live births in the United States [
Prevalence rates in other countries vary somewhat based on frequency of consanguinity [
In regions with high rates of consanguineous marriages, the prevalence of recessive forms of CGD exceeds that of X-linked CGD.
• Effective treatment of CGD-related infections with antimicrobials not available in the past
• Recognition of milder cases of autosomal recessive CGD that may have gone undiagnosed without currently available tests and/or awareness of milder disease manifestations
• Overall improvement in food handling and sanitation
• Osteomyelitis
• Soft-tissue infection
• Pneumonia
• Sepsis
• Pyloric edema leads to functional gastric outlet obstruction and can be an initial presentation of CGD.
• Esophageal, jejunal, ileal, cecal, rectal, and perirectal granulomata similar to those in Crohn disease have also been described. Symptomatic inflammatory bowel disease affects up to 50% of individuals and can be the presenting finding [
• Other gastrointestinal symptoms indicative of CGD colitis include abdominal pain, diarrhea, strictures, and fistulae. Significant colitis leading to bowel obstruction, fistulae, and strictures can be an important cause of growth restriction [
• Persons with
• Persons with
• Persons with
• Persons with
• 88%-97% at age 10 years
• 73%-87% at age 20 years
• 46%-55% at age 30 years
• Note: Individuals diagnosed and treated before the use of azoles usually did not survive past age 30-40 years.
• 88%-97% at age 10 years
• 73%-87% at age 20 years
• 46%-55% at age 30 years
•
• Persons with
• Persons with
• 88%-97% at age 10 years
• 73%-87% at age 20 years
• 46%-55% at age 30 years
• Cutaneous lesions resembling discoid lupus and recurrent aphthous stomatitis [
• Photosensitive skin rashes, alopecia, Raynaud's phenomenon, mouth ulcers, and joint pain [
• Chorioretinal lesions and granulomata with pigment clumping that are usually asymptomatic [
• Crohn-like disease (colitis) [
• Systemic lupus erythematosus
• Infections
• All nonsense variants or deletions of
• The phenotype caused by pathogenic variants in
• Pathogenic missense variants that occur in the
• Pathogenic missense variants that occur in the
• Pathogenic missense variants that occur in the
## Clinical Description
Chronic granulomatous disease (CGD) is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory responses resulting in granuloma formation and other inflammatory disorders such as colitis.
Effective treatment of CGD-related infections with antimicrobials not available in the past
Recognition of milder cases of autosomal recessive CGD that may have gone undiagnosed without currently available tests and/or awareness of milder disease manifestations
Overall improvement in food handling and sanitation
Although the frequency of infections in persons with CGD has decreased with the routine administration of antibacterial and antifungal prophylaxis, infections still occur at a frequency of 0.3/year.
In North America, the majority of infections in CGD are caused by
Infections in CGD: Common Pathogens and Sites of Involvement
Osteomyelitis
Soft-tissue infection
Pneumonia
Sepsis
Outside of CGD,
Widespread prophylaxis has limited staphylococcal infections primarily to the skin, lymph nodes, liver, and (rarely) lung [
Outside of CGD,
Mycobacterial diseases in CGD are mostly limited to regional and disseminated BCG infections and tuberculosis. Persons with CGD are less susceptible to nontuberculous infections than persons with defects in T-cell or interferon gamma/IL-12 pathways: in persons with CGD, BCG infection may cause severe localized disease such as draining skin lesions at sites of BCG vaccination [
Uncommon bacterial infections that are virtually pathognomonic for CGD include the following:
Bacteremia is relatively uncommon except with certain gram-negative organisms.
Invasive fungal infections, which have the highest prevalence in CGD among all primary immunodeficiencies, remain the leading cause of mortality in CGD. They occur most commonly in the first two decades of life and can be the first presentation of disease [
Fungal infections are typically acquired through inhalation of spores or hyphae resulting in pneumonia that can spread locally to the ribs and spine or metastatically to the brain. Presentation may be insidious or manifest as failure to thrive and malaise. Other common presenting signs and symptoms include cough, fever, and chest pain.
Mucormycosis has been reported in CGD but appears to occur only in the setting of significant immunosuppression [
The overall frequency and mortality of invasive fungal infections have been significantly reduced with the use of itraconazole as antifungal prophylaxis and the use of other azoles (voriconazole and posaconazole) as therapy. However, when they occur, fungal infections develop at an older age and may require longer duration of therapy. Fungal infections cause more mortality than other infections in CGD [
Yeast infections are not nearly as common as bacterial and fungal infections in persons with CGD; mucocutaneous candidiasis is not encountered.
Note: The endemic dimorphic mold infections histoplasmosis, blastomycosis, and coccidioidomycosis do not occur in CGD [
Formation of granulomata and dysregulated inflammation in CGD contribute to morbidity and can cause multiple symptoms. The genitourinary and gastrointestinal tracts are most commonly affected.
Pyloric edema leads to functional gastric outlet obstruction and can be an initial presentation of CGD.
Esophageal, jejunal, ileal, cecal, rectal, and perirectal granulomata similar to those in Crohn disease have also been described. Symptomatic inflammatory bowel disease affects up to 50% of individuals and can be the presenting finding [
Other gastrointestinal symptoms indicative of CGD colitis include abdominal pain, diarrhea, strictures, and fistulae. Significant colitis leading to bowel obstruction, fistulae, and strictures can be an important cause of growth restriction [
Other common liver abnormalities include liver enzyme elevation, persistent elevations in alkaline phosphatase, and drug-induced hepatitis.
High rates of portal venopathy are associated with splenomegaly and nodular regenerative hyperplasia. Portal hypertension and thrombocytopenia are associated with intrahepatic disease and important risk factors for mortality [
Fungi elicit an exuberant inflammatory response regardless of whether the fungi are alive or dead [
Prolonged and dysregulated inflammation in CGD can overlap clinically with the syndrome of
The histopathologic patterns of malignancy have significant overlap with certain chronic inflammatory conditions. However, the largest series of affected individuals to date reported no malignancies [
Survival in CGD has improved greatly, and is now approximately 90% at age ten years [
Persons with
Persons with
88%-97% at age 10 years
73%-87% at age 20 years
46%-55% at age 30 years
Note: Individuals diagnosed and treated before the use of azoles usually did not survive past age 30-40 years.
Note: Inflammatory bowel disease does not influence mortality: overall survival rates of persons with CGD with and without colitis are similar [
Females who are heterozygous for a
Neutrophils from heterozygous females express two populations that dihydrorhodamine (DHR) testing can detect: an abnormal DHR(-) population expressing the pathogenic variant and a brightly staining DHR (+) population expressing the normal allele. Skewed (non-random) X-chromosome inactivation can result in low %DHR+ neutrophil population because the
When %DHR+ falls below 20%, heterozygous females are at risk for CGD-specific infections. The %DHR+ population can predict susceptibility to infections with CGD-specific pathogens but does not predict autoimmune symptoms of heterozygous females [
Careful longitudinal evaluation of heterozygous females is recommended in order to detect inflammatory or infectious conditions if they occur over time.
Clinical evidence of CGD in heterozygous females:
Cutaneous lesions resembling discoid lupus and recurrent aphthous stomatitis [
Photosensitive skin rashes, alopecia, Raynaud's phenomenon, mouth ulcers, and joint pain [
Chorioretinal lesions and granulomata with pigment clumping that are usually asymptomatic [
Crohn-like disease (colitis) [
Systemic lupus erythematosus
Infections
• Effective treatment of CGD-related infections with antimicrobials not available in the past
• Recognition of milder cases of autosomal recessive CGD that may have gone undiagnosed without currently available tests and/or awareness of milder disease manifestations
• Overall improvement in food handling and sanitation
• Osteomyelitis
• Soft-tissue infection
• Pneumonia
• Sepsis
• Pyloric edema leads to functional gastric outlet obstruction and can be an initial presentation of CGD.
• Esophageal, jejunal, ileal, cecal, rectal, and perirectal granulomata similar to those in Crohn disease have also been described. Symptomatic inflammatory bowel disease affects up to 50% of individuals and can be the presenting finding [
• Other gastrointestinal symptoms indicative of CGD colitis include abdominal pain, diarrhea, strictures, and fistulae. Significant colitis leading to bowel obstruction, fistulae, and strictures can be an important cause of growth restriction [
• Persons with
• Persons with
• Persons with
• Persons with
• 88%-97% at age 10 years
• 73%-87% at age 20 years
• 46%-55% at age 30 years
• Note: Individuals diagnosed and treated before the use of azoles usually did not survive past age 30-40 years.
• 88%-97% at age 10 years
• 73%-87% at age 20 years
• 46%-55% at age 30 years
•
• Persons with
• Persons with
• 88%-97% at age 10 years
• 73%-87% at age 20 years
• 46%-55% at age 30 years
• Cutaneous lesions resembling discoid lupus and recurrent aphthous stomatitis [
• Photosensitive skin rashes, alopecia, Raynaud's phenomenon, mouth ulcers, and joint pain [
• Chorioretinal lesions and granulomata with pigment clumping that are usually asymptomatic [
• Crohn-like disease (colitis) [
• Systemic lupus erythematosus
• Infections
## Bacterial Infections
Widespread prophylaxis has limited staphylococcal infections primarily to the skin, lymph nodes, liver, and (rarely) lung [
Outside of CGD,
Mycobacterial diseases in CGD are mostly limited to regional and disseminated BCG infections and tuberculosis. Persons with CGD are less susceptible to nontuberculous infections than persons with defects in T-cell or interferon gamma/IL-12 pathways: in persons with CGD, BCG infection may cause severe localized disease such as draining skin lesions at sites of BCG vaccination [
Uncommon bacterial infections that are virtually pathognomonic for CGD include the following:
Bacteremia is relatively uncommon except with certain gram-negative organisms.
## Fungal Infections
Invasive fungal infections, which have the highest prevalence in CGD among all primary immunodeficiencies, remain the leading cause of mortality in CGD. They occur most commonly in the first two decades of life and can be the first presentation of disease [
Fungal infections are typically acquired through inhalation of spores or hyphae resulting in pneumonia that can spread locally to the ribs and spine or metastatically to the brain. Presentation may be insidious or manifest as failure to thrive and malaise. Other common presenting signs and symptoms include cough, fever, and chest pain.
Mucormycosis has been reported in CGD but appears to occur only in the setting of significant immunosuppression [
The overall frequency and mortality of invasive fungal infections have been significantly reduced with the use of itraconazole as antifungal prophylaxis and the use of other azoles (voriconazole and posaconazole) as therapy. However, when they occur, fungal infections develop at an older age and may require longer duration of therapy. Fungal infections cause more mortality than other infections in CGD [
Yeast infections are not nearly as common as bacterial and fungal infections in persons with CGD; mucocutaneous candidiasis is not encountered.
Note: The endemic dimorphic mold infections histoplasmosis, blastomycosis, and coccidioidomycosis do not occur in CGD [
## Inflammatory and Other Manifestations
Formation of granulomata and dysregulated inflammation in CGD contribute to morbidity and can cause multiple symptoms. The genitourinary and gastrointestinal tracts are most commonly affected.
Pyloric edema leads to functional gastric outlet obstruction and can be an initial presentation of CGD.
Esophageal, jejunal, ileal, cecal, rectal, and perirectal granulomata similar to those in Crohn disease have also been described. Symptomatic inflammatory bowel disease affects up to 50% of individuals and can be the presenting finding [
Other gastrointestinal symptoms indicative of CGD colitis include abdominal pain, diarrhea, strictures, and fistulae. Significant colitis leading to bowel obstruction, fistulae, and strictures can be an important cause of growth restriction [
Other common liver abnormalities include liver enzyme elevation, persistent elevations in alkaline phosphatase, and drug-induced hepatitis.
High rates of portal venopathy are associated with splenomegaly and nodular regenerative hyperplasia. Portal hypertension and thrombocytopenia are associated with intrahepatic disease and important risk factors for mortality [
Fungi elicit an exuberant inflammatory response regardless of whether the fungi are alive or dead [
Prolonged and dysregulated inflammation in CGD can overlap clinically with the syndrome of
The histopathologic patterns of malignancy have significant overlap with certain chronic inflammatory conditions. However, the largest series of affected individuals to date reported no malignancies [
• Pyloric edema leads to functional gastric outlet obstruction and can be an initial presentation of CGD.
• Esophageal, jejunal, ileal, cecal, rectal, and perirectal granulomata similar to those in Crohn disease have also been described. Symptomatic inflammatory bowel disease affects up to 50% of individuals and can be the presenting finding [
• Other gastrointestinal symptoms indicative of CGD colitis include abdominal pain, diarrhea, strictures, and fistulae. Significant colitis leading to bowel obstruction, fistulae, and strictures can be an important cause of growth restriction [
## Survival in CGD
Survival in CGD has improved greatly, and is now approximately 90% at age ten years [
Persons with
Persons with
88%-97% at age 10 years
73%-87% at age 20 years
46%-55% at age 30 years
Note: Individuals diagnosed and treated before the use of azoles usually did not survive past age 30-40 years.
Note: Inflammatory bowel disease does not influence mortality: overall survival rates of persons with CGD with and without colitis are similar [
• Persons with
• Persons with
• Persons with
• Persons with
• 88%-97% at age 10 years
• 73%-87% at age 20 years
• 46%-55% at age 30 years
• Note: Individuals diagnosed and treated before the use of azoles usually did not survive past age 30-40 years.
• 88%-97% at age 10 years
• 73%-87% at age 20 years
• 46%-55% at age 30 years
•
• Persons with
• Persons with
• 88%-97% at age 10 years
• 73%-87% at age 20 years
• 46%-55% at age 30 years
## X-Linked CGD: Heterozygous Females
Females who are heterozygous for a
Neutrophils from heterozygous females express two populations that dihydrorhodamine (DHR) testing can detect: an abnormal DHR(-) population expressing the pathogenic variant and a brightly staining DHR (+) population expressing the normal allele. Skewed (non-random) X-chromosome inactivation can result in low %DHR+ neutrophil population because the
When %DHR+ falls below 20%, heterozygous females are at risk for CGD-specific infections. The %DHR+ population can predict susceptibility to infections with CGD-specific pathogens but does not predict autoimmune symptoms of heterozygous females [
Careful longitudinal evaluation of heterozygous females is recommended in order to detect inflammatory or infectious conditions if they occur over time.
Clinical evidence of CGD in heterozygous females:
Cutaneous lesions resembling discoid lupus and recurrent aphthous stomatitis [
Photosensitive skin rashes, alopecia, Raynaud's phenomenon, mouth ulcers, and joint pain [
Chorioretinal lesions and granulomata with pigment clumping that are usually asymptomatic [
Crohn-like disease (colitis) [
Systemic lupus erythematosus
Infections
• Cutaneous lesions resembling discoid lupus and recurrent aphthous stomatitis [
• Photosensitive skin rashes, alopecia, Raynaud's phenomenon, mouth ulcers, and joint pain [
• Chorioretinal lesions and granulomata with pigment clumping that are usually asymptomatic [
• Crohn-like disease (colitis) [
• Systemic lupus erythematosus
• Infections
## Phenotype Correlations by Gene
## Genotype-Phenotype Correlations
Hypomorphic (variant) CGD is characterized by partial protein expression/function and residual superoxide production (observed in AR-CGD and protein-positive X-linked CGD). Individuals with hypomorphic variants typically have a milder course and come to clinical attention later in life than those with absent protein expression [
All nonsense variants or deletions of
The phenotype caused by pathogenic variants in
Pathogenic missense variants that occur in the
No additional specific genotype-phenotype correlations have been identified for
• All nonsense variants or deletions of
• The phenotype caused by pathogenic variants in
• Pathogenic missense variants that occur in the
• Pathogenic missense variants that occur in the
• Pathogenic missense variants that occur in the
## Nomenclature
When first characterized, chronic granulomatous disease was called "fatal granulomatous disease of childhood" [
## Prevalence
The retrospectively and voluntarily reported prevalence of CGD is approximately 1:200,000 live births in the United States [
Prevalence rates in other countries vary somewhat based on frequency of consanguinity [
In regions with high rates of consanguineous marriages, the prevalence of recessive forms of CGD exceeds that of X-linked CGD.
## Genetically Related (Allelic) Disorders
Note: Concurrent deletion of
## Differential Diagnosis
The differential diagnosis of chronic granulomatous disease (CGD) mainly involves disorders with recurrent or unusual infections or disorders associated with granuloma formation and hyperinflammation (see
Disorders of Known Genetic Cause in the Differential Diagnosis of Chronic Granulomatous Disease
AD = autosomal dominant; AR = autosomal recessive; CGD = chronic granulomatous disease; MOI = mode of inheritance; XL = X-linked
Other Conditions in the Differential Diagnosis of Chronic Granulomatous Disease
CGD = chronic granulomatous disease
Recently, acetominophen administration has been shown to affect the DHR assay and should be considered in the differential of a low DHR response [
## Management
No clinical practice guidelines for chronic granulomatous disease (CGD) have been published.
To establish the extent of disease and needs in an individual diagnosed with chronic granulomatous disease (CGD), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Chronic Granulomatous Disease (CGD)
C-reactive protein;
Erythrocyte sedimentation rate.
CT scan is often used due to relative ease & sensitivity.
US & MRI can be used instead in many instances.
PET using fluorine-18-fluoro-2-deoxy-D-glucose (FDG) uptake can help discriminate active from resolved infection.
Persons w/McLeod neuroacanthocytosis syndrome do not express the erythrocyte blood group Kell antigen (i.e., they are Kell negative).
If they require transfusion of blood products, Kell-positive blood products must be avoided to prevent a transfusion reaction.
Kell-negative blood products are rarely available.
Community or
Social work involvement for parental support;
Home nursing referral.
CBC = complete blood count; MOI = mode of inheritance; PET = positron emission tomography; US = ultrasound
High FDG uptake is consistent with active inflammation [
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Consolidation, ground-glass opacity, tree-in-bud opacity, centrilobular or random nodules, septal thickening, air trapping, scarring
Empyema or abscess
Mediastinal or hilar adenopathy, honeycomb lung, pleural thickening in chronic cases
Contiguous spread to chest wall, associated osteomyelitis of ribs and vertebral bodies
Swirling debris, thickened septa, and increased color Doppler flow
Calcifications if granuloma present
Single to multiple small or large abscesses, sharply defined; variable enhancement but usually with small central area with poor enhancement
Calcifications
Esophagus: strictures, diverticula, dysmotility
Thickening of bowel wall, fistulae
Upper GI: gastric outlet obstruction with gastric dilatation, delayed gastric emptying, circumferential antral narrowing, thickened gastric folds
Gastric wall thickening on US, CT, or MRI
Treatment of Manifestations in Individuals with Chronic Granulomatous Disease
The principle is that a small number of normal phagocytes complement the oxidative defect in CGD phagocytes by supplying diffusible hydrogen peroxide.
Adverse effects may incl fever, development of leukoagglutinins, & (rarely) pulmonary leukostasis.
Alloimmunization is a major concern, as many w/history of severe infections may also be considered for HSCT [
The possibility of CMV transmission is also a cause for caution.
Chronic colitis [
Granulomatous cystitis [
Pulmonary infections w/
Staphylococcal liver abscesses [
Mulch pneumonitis (the exuberant inflammatory response to inhalation of mulch or other organic matter) [
Because the HLH-like syndrome in CGD represents a reaction to bacterial or fungal infection, such infections must be aggressively treated in affected persons on immunosuppressants for HLH.
While the merit of immunosuppression in the setting of infection-triggered HLH in CGD is unclear, treatment of infection is essential.
BMT = bone marrow transplantation; CMV = cytomegalovirus; HLH = hemophagocytic lymphohistiocytosis; HSCT = hematopoietic stem cell transplantation
Alternatives to TMP-SMX for individuals allergic to sulfonamides include trimethoprim as a single agent, dicloxacillin, cephalosporins, and fluroquinolones.
For those unable to tolerate itraconazole, posaconazole has been studied in the oncology setting and is likely to be effective in CGD as well [
Of note, the primary prophylaxis used to prevent bacterial and fungal infections also has good activity against yeasts.
Some practitioners use IFN-gamma only in the setting of acute infection, rather than as primary prophylaxis. The data for this are anecdotal and unimpressive. The authors typically discontinue IFN-gamma during acute infection, as its utility is unclear and the exacerbation of malaise and fever can confuse the clinical picture and alter decision making [
Administration by injection, cost, and lack of familiarity with cytokine therapy all affect the use of IFN-gamma in CGD. The authors use IFN-gamma in addition to antimicrobials as prophylaxis [
The issue of which individuals with CGD should undergo HSCT remains complex. While transplant-related mortality rates have fallen dramatically and successful cure has risen, issues of long-term risk, sterility, graft-versus-host disease, donor matching, expense, center experience, availability, and insurance coverage all strongly influence family and physician choices regarding transplantation. Levels of residual superoxide production have correlated well with overall survival [
Individuals with CGD may experience behavioral, emotional, and learning difficulties as a consequence of chronic disease, recurrent hospitalization, and limitations of activity. Older children and adolescents are especially likely to be noncompliant with respect to prophylaxis and risk avoidance, increasing their risk for CGD-related complications. The inflammatory bowel disease present in up to 50% of persons with X-linked CGD may result in discomfort and growth impairment, and may require colostomy or colectomy. Overall quality of life is reduced in children with CGD, whereas those with CGD who have undergone transplant report quality of life comparable to healthy children [
As HSCT has become safer, more reliable, and more available it is offered earlier [
The European Bone Marrow Transplantation (EBMT) / European Society of Immunodeficiencies Inborn Errors Working Party [
Regular follow-up visits can aid in early detection and treatment of asymptomatic or minimally symptomatic infections and noninfectious complications such as colitis, pulmonary granulomas, and pulmonary fibrosis [
Recommended Surveillance for Individuals with Chronic Granulomatous Disease
CRP & ESR; significant ↑s should prompt eval for infection.
CBC & albumin; presence of microcytic anemia & hypoalbuminemia may indicate development of colitis.
Liver chemistries; transaminase & alkaline phosphatase ↑ may indicate drug-related hepatotoxicity.
Annual eval by a health care professional w/an eye toward concerns of invasive infection or for auto-inflammatory manifestations
To follow (as needed): referral to appropriate specialist & lab &/or radiologic eval per individual findings
CRP = C-reactive protein; ESR = erythrocyte sedimentation rate
Exposure to mulch
Potting of plants or gardening
Raking leaves or mowing lawns
Swimming in stagnant water, brackish water, or ponds
All other vaccines including live viral vaccines are recommended in individuals with CGD.
Molecular genetic testing if the CGD-related pathogenic variant(s) in the family are known
Routine dihydrorhodamine (DHR) testing of peripheral blood, which will detect the CGD disease state (except for
See
The major concern during the pregnancy of a woman known to have CGD is continued use of prophylactic antimicrobials:
Data regarding teratogenicity of
The authors' practice for women with CGD who are or are planning to become pregnant is to use antibacterial prophylaxis (e.g., penicillin- or cephalosporin-based therapies) for which more data on safety during pregnancy exist [Author, personal communication]. Although no antifungal prophylactic medications known to be completely safe during pregnancy are currently available, the risks and benefits of antifungal treatment must be weighed case by case. Interferon gamma is held during pregnancy and restarted after breastfeeding has ceased.
See
Search
• C-reactive protein;
• Erythrocyte sedimentation rate.
• CT scan is often used due to relative ease & sensitivity.
• US & MRI can be used instead in many instances.
• PET using fluorine-18-fluoro-2-deoxy-D-glucose (FDG) uptake can help discriminate active from resolved infection.
• Persons w/McLeod neuroacanthocytosis syndrome do not express the erythrocyte blood group Kell antigen (i.e., they are Kell negative).
• If they require transfusion of blood products, Kell-positive blood products must be avoided to prevent a transfusion reaction.
• Kell-negative blood products are rarely available.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
•
• Consolidation, ground-glass opacity, tree-in-bud opacity, centrilobular or random nodules, septal thickening, air trapping, scarring
• Empyema or abscess
• Mediastinal or hilar adenopathy, honeycomb lung, pleural thickening in chronic cases
• Contiguous spread to chest wall, associated osteomyelitis of ribs and vertebral bodies
• Consolidation, ground-glass opacity, tree-in-bud opacity, centrilobular or random nodules, septal thickening, air trapping, scarring
• Empyema or abscess
• Mediastinal or hilar adenopathy, honeycomb lung, pleural thickening in chronic cases
• Contiguous spread to chest wall, associated osteomyelitis of ribs and vertebral bodies
• Consolidation, ground-glass opacity, tree-in-bud opacity, centrilobular or random nodules, septal thickening, air trapping, scarring
• Empyema or abscess
• Mediastinal or hilar adenopathy, honeycomb lung, pleural thickening in chronic cases
• Contiguous spread to chest wall, associated osteomyelitis of ribs and vertebral bodies
•
• Swirling debris, thickened septa, and increased color Doppler flow
• Calcifications if granuloma present
• Swirling debris, thickened septa, and increased color Doppler flow
• Calcifications if granuloma present
• Swirling debris, thickened septa, and increased color Doppler flow
• Calcifications if granuloma present
• Single to multiple small or large abscesses, sharply defined; variable enhancement but usually with small central area with poor enhancement
• Calcifications
•
• Esophagus: strictures, diverticula, dysmotility
• Thickening of bowel wall, fistulae
• Upper GI: gastric outlet obstruction with gastric dilatation, delayed gastric emptying, circumferential antral narrowing, thickened gastric folds
• Gastric wall thickening on US, CT, or MRI
• Esophagus: strictures, diverticula, dysmotility
• Thickening of bowel wall, fistulae
• Upper GI: gastric outlet obstruction with gastric dilatation, delayed gastric emptying, circumferential antral narrowing, thickened gastric folds
• Gastric wall thickening on US, CT, or MRI
• Esophagus: strictures, diverticula, dysmotility
• Thickening of bowel wall, fistulae
• Upper GI: gastric outlet obstruction with gastric dilatation, delayed gastric emptying, circumferential antral narrowing, thickened gastric folds
• Gastric wall thickening on US, CT, or MRI
• The principle is that a small number of normal phagocytes complement the oxidative defect in CGD phagocytes by supplying diffusible hydrogen peroxide.
• Adverse effects may incl fever, development of leukoagglutinins, & (rarely) pulmonary leukostasis.
• Alloimmunization is a major concern, as many w/history of severe infections may also be considered for HSCT [
• The possibility of CMV transmission is also a cause for caution.
• Chronic colitis [
• Granulomatous cystitis [
• Pulmonary infections w/
• Staphylococcal liver abscesses [
• Mulch pneumonitis (the exuberant inflammatory response to inhalation of mulch or other organic matter) [
• Because the HLH-like syndrome in CGD represents a reaction to bacterial or fungal infection, such infections must be aggressively treated in affected persons on immunosuppressants for HLH.
• While the merit of immunosuppression in the setting of infection-triggered HLH in CGD is unclear, treatment of infection is essential.
• CRP & ESR; significant ↑s should prompt eval for infection.
• CBC & albumin; presence of microcytic anemia & hypoalbuminemia may indicate development of colitis.
• Liver chemistries; transaminase & alkaline phosphatase ↑ may indicate drug-related hepatotoxicity.
• Annual eval by a health care professional w/an eye toward concerns of invasive infection or for auto-inflammatory manifestations
• To follow (as needed): referral to appropriate specialist & lab &/or radiologic eval per individual findings
• Exposure to mulch
• Potting of plants or gardening
• Raking leaves or mowing lawns
• Swimming in stagnant water, brackish water, or ponds
• All other vaccines including live viral vaccines are recommended in individuals with CGD.
• Molecular genetic testing if the CGD-related pathogenic variant(s) in the family are known
• Routine dihydrorhodamine (DHR) testing of peripheral blood, which will detect the CGD disease state (except for
• Data regarding teratogenicity of
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with chronic granulomatous disease (CGD), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Chronic Granulomatous Disease (CGD)
C-reactive protein;
Erythrocyte sedimentation rate.
CT scan is often used due to relative ease & sensitivity.
US & MRI can be used instead in many instances.
PET using fluorine-18-fluoro-2-deoxy-D-glucose (FDG) uptake can help discriminate active from resolved infection.
Persons w/McLeod neuroacanthocytosis syndrome do not express the erythrocyte blood group Kell antigen (i.e., they are Kell negative).
If they require transfusion of blood products, Kell-positive blood products must be avoided to prevent a transfusion reaction.
Kell-negative blood products are rarely available.
Community or
Social work involvement for parental support;
Home nursing referral.
CBC = complete blood count; MOI = mode of inheritance; PET = positron emission tomography; US = ultrasound
High FDG uptake is consistent with active inflammation [
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Consolidation, ground-glass opacity, tree-in-bud opacity, centrilobular or random nodules, septal thickening, air trapping, scarring
Empyema or abscess
Mediastinal or hilar adenopathy, honeycomb lung, pleural thickening in chronic cases
Contiguous spread to chest wall, associated osteomyelitis of ribs and vertebral bodies
Swirling debris, thickened septa, and increased color Doppler flow
Calcifications if granuloma present
Single to multiple small or large abscesses, sharply defined; variable enhancement but usually with small central area with poor enhancement
Calcifications
Esophagus: strictures, diverticula, dysmotility
Thickening of bowel wall, fistulae
Upper GI: gastric outlet obstruction with gastric dilatation, delayed gastric emptying, circumferential antral narrowing, thickened gastric folds
Gastric wall thickening on US, CT, or MRI
• C-reactive protein;
• Erythrocyte sedimentation rate.
• CT scan is often used due to relative ease & sensitivity.
• US & MRI can be used instead in many instances.
• PET using fluorine-18-fluoro-2-deoxy-D-glucose (FDG) uptake can help discriminate active from resolved infection.
• Persons w/McLeod neuroacanthocytosis syndrome do not express the erythrocyte blood group Kell antigen (i.e., they are Kell negative).
• If they require transfusion of blood products, Kell-positive blood products must be avoided to prevent a transfusion reaction.
• Kell-negative blood products are rarely available.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
•
• Consolidation, ground-glass opacity, tree-in-bud opacity, centrilobular or random nodules, septal thickening, air trapping, scarring
• Empyema or abscess
• Mediastinal or hilar adenopathy, honeycomb lung, pleural thickening in chronic cases
• Contiguous spread to chest wall, associated osteomyelitis of ribs and vertebral bodies
• Consolidation, ground-glass opacity, tree-in-bud opacity, centrilobular or random nodules, septal thickening, air trapping, scarring
• Empyema or abscess
• Mediastinal or hilar adenopathy, honeycomb lung, pleural thickening in chronic cases
• Contiguous spread to chest wall, associated osteomyelitis of ribs and vertebral bodies
• Consolidation, ground-glass opacity, tree-in-bud opacity, centrilobular or random nodules, septal thickening, air trapping, scarring
• Empyema or abscess
• Mediastinal or hilar adenopathy, honeycomb lung, pleural thickening in chronic cases
• Contiguous spread to chest wall, associated osteomyelitis of ribs and vertebral bodies
•
• Swirling debris, thickened septa, and increased color Doppler flow
• Calcifications if granuloma present
• Swirling debris, thickened septa, and increased color Doppler flow
• Calcifications if granuloma present
• Swirling debris, thickened septa, and increased color Doppler flow
• Calcifications if granuloma present
• Single to multiple small or large abscesses, sharply defined; variable enhancement but usually with small central area with poor enhancement
• Calcifications
•
• Esophagus: strictures, diverticula, dysmotility
• Thickening of bowel wall, fistulae
• Upper GI: gastric outlet obstruction with gastric dilatation, delayed gastric emptying, circumferential antral narrowing, thickened gastric folds
• Gastric wall thickening on US, CT, or MRI
• Esophagus: strictures, diverticula, dysmotility
• Thickening of bowel wall, fistulae
• Upper GI: gastric outlet obstruction with gastric dilatation, delayed gastric emptying, circumferential antral narrowing, thickened gastric folds
• Gastric wall thickening on US, CT, or MRI
• Esophagus: strictures, diverticula, dysmotility
• Thickening of bowel wall, fistulae
• Upper GI: gastric outlet obstruction with gastric dilatation, delayed gastric emptying, circumferential antral narrowing, thickened gastric folds
• Gastric wall thickening on US, CT, or MRI
## Affected Organs / Manifestations of CGD on Imaging
Consolidation, ground-glass opacity, tree-in-bud opacity, centrilobular or random nodules, septal thickening, air trapping, scarring
Empyema or abscess
Mediastinal or hilar adenopathy, honeycomb lung, pleural thickening in chronic cases
Contiguous spread to chest wall, associated osteomyelitis of ribs and vertebral bodies
Swirling debris, thickened septa, and increased color Doppler flow
Calcifications if granuloma present
Single to multiple small or large abscesses, sharply defined; variable enhancement but usually with small central area with poor enhancement
Calcifications
Esophagus: strictures, diverticula, dysmotility
Thickening of bowel wall, fistulae
Upper GI: gastric outlet obstruction with gastric dilatation, delayed gastric emptying, circumferential antral narrowing, thickened gastric folds
Gastric wall thickening on US, CT, or MRI
•
• Consolidation, ground-glass opacity, tree-in-bud opacity, centrilobular or random nodules, septal thickening, air trapping, scarring
• Empyema or abscess
• Mediastinal or hilar adenopathy, honeycomb lung, pleural thickening in chronic cases
• Contiguous spread to chest wall, associated osteomyelitis of ribs and vertebral bodies
• Consolidation, ground-glass opacity, tree-in-bud opacity, centrilobular or random nodules, septal thickening, air trapping, scarring
• Empyema or abscess
• Mediastinal or hilar adenopathy, honeycomb lung, pleural thickening in chronic cases
• Contiguous spread to chest wall, associated osteomyelitis of ribs and vertebral bodies
• Consolidation, ground-glass opacity, tree-in-bud opacity, centrilobular or random nodules, septal thickening, air trapping, scarring
• Empyema or abscess
• Mediastinal or hilar adenopathy, honeycomb lung, pleural thickening in chronic cases
• Contiguous spread to chest wall, associated osteomyelitis of ribs and vertebral bodies
•
• Swirling debris, thickened septa, and increased color Doppler flow
• Calcifications if granuloma present
• Swirling debris, thickened septa, and increased color Doppler flow
• Calcifications if granuloma present
• Swirling debris, thickened septa, and increased color Doppler flow
• Calcifications if granuloma present
• Single to multiple small or large abscesses, sharply defined; variable enhancement but usually with small central area with poor enhancement
• Calcifications
•
• Esophagus: strictures, diverticula, dysmotility
• Thickening of bowel wall, fistulae
• Upper GI: gastric outlet obstruction with gastric dilatation, delayed gastric emptying, circumferential antral narrowing, thickened gastric folds
• Gastric wall thickening on US, CT, or MRI
• Esophagus: strictures, diverticula, dysmotility
• Thickening of bowel wall, fistulae
• Upper GI: gastric outlet obstruction with gastric dilatation, delayed gastric emptying, circumferential antral narrowing, thickened gastric folds
• Gastric wall thickening on US, CT, or MRI
• Esophagus: strictures, diverticula, dysmotility
• Thickening of bowel wall, fistulae
• Upper GI: gastric outlet obstruction with gastric dilatation, delayed gastric emptying, circumferential antral narrowing, thickened gastric folds
• Gastric wall thickening on US, CT, or MRI
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Chronic Granulomatous Disease
The principle is that a small number of normal phagocytes complement the oxidative defect in CGD phagocytes by supplying diffusible hydrogen peroxide.
Adverse effects may incl fever, development of leukoagglutinins, & (rarely) pulmonary leukostasis.
Alloimmunization is a major concern, as many w/history of severe infections may also be considered for HSCT [
The possibility of CMV transmission is also a cause for caution.
Chronic colitis [
Granulomatous cystitis [
Pulmonary infections w/
Staphylococcal liver abscesses [
Mulch pneumonitis (the exuberant inflammatory response to inhalation of mulch or other organic matter) [
Because the HLH-like syndrome in CGD represents a reaction to bacterial or fungal infection, such infections must be aggressively treated in affected persons on immunosuppressants for HLH.
While the merit of immunosuppression in the setting of infection-triggered HLH in CGD is unclear, treatment of infection is essential.
BMT = bone marrow transplantation; CMV = cytomegalovirus; HLH = hemophagocytic lymphohistiocytosis; HSCT = hematopoietic stem cell transplantation
• The principle is that a small number of normal phagocytes complement the oxidative defect in CGD phagocytes by supplying diffusible hydrogen peroxide.
• Adverse effects may incl fever, development of leukoagglutinins, & (rarely) pulmonary leukostasis.
• Alloimmunization is a major concern, as many w/history of severe infections may also be considered for HSCT [
• The possibility of CMV transmission is also a cause for caution.
• Chronic colitis [
• Granulomatous cystitis [
• Pulmonary infections w/
• Staphylococcal liver abscesses [
• Mulch pneumonitis (the exuberant inflammatory response to inhalation of mulch or other organic matter) [
• Because the HLH-like syndrome in CGD represents a reaction to bacterial or fungal infection, such infections must be aggressively treated in affected persons on immunosuppressants for HLH.
• While the merit of immunosuppression in the setting of infection-triggered HLH in CGD is unclear, treatment of infection is essential.
## Prevention of Primary Manifestations
Alternatives to TMP-SMX for individuals allergic to sulfonamides include trimethoprim as a single agent, dicloxacillin, cephalosporins, and fluroquinolones.
For those unable to tolerate itraconazole, posaconazole has been studied in the oncology setting and is likely to be effective in CGD as well [
Of note, the primary prophylaxis used to prevent bacterial and fungal infections also has good activity against yeasts.
Some practitioners use IFN-gamma only in the setting of acute infection, rather than as primary prophylaxis. The data for this are anecdotal and unimpressive. The authors typically discontinue IFN-gamma during acute infection, as its utility is unclear and the exacerbation of malaise and fever can confuse the clinical picture and alter decision making [
Administration by injection, cost, and lack of familiarity with cytokine therapy all affect the use of IFN-gamma in CGD. The authors use IFN-gamma in addition to antimicrobials as prophylaxis [
The issue of which individuals with CGD should undergo HSCT remains complex. While transplant-related mortality rates have fallen dramatically and successful cure has risen, issues of long-term risk, sterility, graft-versus-host disease, donor matching, expense, center experience, availability, and insurance coverage all strongly influence family and physician choices regarding transplantation. Levels of residual superoxide production have correlated well with overall survival [
Individuals with CGD may experience behavioral, emotional, and learning difficulties as a consequence of chronic disease, recurrent hospitalization, and limitations of activity. Older children and adolescents are especially likely to be noncompliant with respect to prophylaxis and risk avoidance, increasing their risk for CGD-related complications. The inflammatory bowel disease present in up to 50% of persons with X-linked CGD may result in discomfort and growth impairment, and may require colostomy or colectomy. Overall quality of life is reduced in children with CGD, whereas those with CGD who have undergone transplant report quality of life comparable to healthy children [
As HSCT has become safer, more reliable, and more available it is offered earlier [
The European Bone Marrow Transplantation (EBMT) / European Society of Immunodeficiencies Inborn Errors Working Party [
## Surveillance
Regular follow-up visits can aid in early detection and treatment of asymptomatic or minimally symptomatic infections and noninfectious complications such as colitis, pulmonary granulomas, and pulmonary fibrosis [
Recommended Surveillance for Individuals with Chronic Granulomatous Disease
CRP & ESR; significant ↑s should prompt eval for infection.
CBC & albumin; presence of microcytic anemia & hypoalbuminemia may indicate development of colitis.
Liver chemistries; transaminase & alkaline phosphatase ↑ may indicate drug-related hepatotoxicity.
Annual eval by a health care professional w/an eye toward concerns of invasive infection or for auto-inflammatory manifestations
To follow (as needed): referral to appropriate specialist & lab &/or radiologic eval per individual findings
CRP = C-reactive protein; ESR = erythrocyte sedimentation rate
• CRP & ESR; significant ↑s should prompt eval for infection.
• CBC & albumin; presence of microcytic anemia & hypoalbuminemia may indicate development of colitis.
• Liver chemistries; transaminase & alkaline phosphatase ↑ may indicate drug-related hepatotoxicity.
• Annual eval by a health care professional w/an eye toward concerns of invasive infection or for auto-inflammatory manifestations
• To follow (as needed): referral to appropriate specialist & lab &/or radiologic eval per individual findings
## Agents/Circumstances to Avoid
Exposure to mulch
Potting of plants or gardening
Raking leaves or mowing lawns
Swimming in stagnant water, brackish water, or ponds
All other vaccines including live viral vaccines are recommended in individuals with CGD.
• Exposure to mulch
• Potting of plants or gardening
• Raking leaves or mowing lawns
• Swimming in stagnant water, brackish water, or ponds
• All other vaccines including live viral vaccines are recommended in individuals with CGD.
## Evaluation of Relatives at Risk
Molecular genetic testing if the CGD-related pathogenic variant(s) in the family are known
Routine dihydrorhodamine (DHR) testing of peripheral blood, which will detect the CGD disease state (except for
See
• Molecular genetic testing if the CGD-related pathogenic variant(s) in the family are known
• Routine dihydrorhodamine (DHR) testing of peripheral blood, which will detect the CGD disease state (except for
## Pregnancy Management
The major concern during the pregnancy of a woman known to have CGD is continued use of prophylactic antimicrobials:
Data regarding teratogenicity of
The authors' practice for women with CGD who are or are planning to become pregnant is to use antibacterial prophylaxis (e.g., penicillin- or cephalosporin-based therapies) for which more data on safety during pregnancy exist [Author, personal communication]. Although no antifungal prophylactic medications known to be completely safe during pregnancy are currently available, the risks and benefits of antifungal treatment must be weighed case by case. Interferon gamma is held during pregnancy and restarted after breastfeeding has ceased.
See
• Data regarding teratogenicity of
## Therapies Under Investigation
Search
## Genetic Counseling
Chronic granulomatous disease (CGD) associated with a pathogenic variant in
CGD associated with biallelic pathogenic variants in
Note: The mode of inheritance cannot be confirmed in a family unless the CGD-causing pathogenic variant(s) have been identified in an affected family member. Dihydrorhodamine (DHR) testing can suggest X-linked inheritance or autosomal recessive inheritance, but DHR results are not definitive in establishing a molecular cause or mode of inheritance.
The father of an affected male will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is presumed to be heterozygous for a
If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous, the affected male may have a
DHR testing of the mother is recommended to confirm her status, assess her risk of inflammatory or infectious conditions (see
A female proband may have the disorder as the result of a
Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
If the mother of the proband has a
Males who inherit the pathogenic variant will be affected.
Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females are typically not affected with CGD but are at substantial risk for inflammatory conditions (see
If the proband represents a simplex case and if the
If the mother of the proband has a
If the father of the proband has a
If the proband represents a simplex case and if the
Although females who are heterozygous for X-linked CGD are typically not affected with CGD (see
Note: Women who are heterozygous for X-linked CGD have circulating populations of oxidase-positive and oxidase-negative phagocytes, which can be resolved by DHR testing if the family-specific pathogenic variant has not been identified. (Note: Nitroblue tetrazolium testing is not reliable for heterozygote detection because it may be falsely interpreted as normal in females who are heterozygous for X-linked CGD).
The parents of a child with autosomal recessive CGD (AR-CGD) are typically heterozygous for a
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CGD-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
One of the pathogenic variants identified in the proband occurred as a
Note: Because
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an autosomal recessive CGD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
Heterozygotes (carriers) are usually asymptomatic and are not at risk of developing the disorder.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
Prior to pregnancy, affected women should be advised about changes in antimicrobial prophylaxis (see
PGT has also been used to identify female HLA-matched sibs of a male with X-linked CGD. After successful in vitro fertilization, embryo transfer, and pregnancy outcome, the female sib served as a hematopoietic stem cell donor for the affected child [
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is presumed to be heterozygous for a
• If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous, the affected male may have a
• DHR testing of the mother is recommended to confirm her status, assess her risk of inflammatory or infectious conditions (see
• A female proband may have the disorder as the result of a
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
• If the mother of the proband has a
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females are typically not affected with CGD but are at substantial risk for inflammatory conditions (see
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females are typically not affected with CGD but are at substantial risk for inflammatory conditions (see
• If the proband represents a simplex case and if the
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females are typically not affected with CGD but are at substantial risk for inflammatory conditions (see
• If the mother of the proband has a
• If the father of the proband has a
• If the proband represents a simplex case and if the
• The parents of a child with autosomal recessive CGD (AR-CGD) are typically heterozygous for a
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CGD-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• One of the pathogenic variants identified in the proband occurred as a
• Note: Because
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Note: Because
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Note: Because
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an autosomal recessive CGD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygotes (carriers) are usually asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
• Prior to pregnancy, affected women should be advised about changes in antimicrobial prophylaxis (see
## Mode of Inheritance
Chronic granulomatous disease (CGD) associated with a pathogenic variant in
CGD associated with biallelic pathogenic variants in
Note: The mode of inheritance cannot be confirmed in a family unless the CGD-causing pathogenic variant(s) have been identified in an affected family member. Dihydrorhodamine (DHR) testing can suggest X-linked inheritance or autosomal recessive inheritance, but DHR results are not definitive in establishing a molecular cause or mode of inheritance.
## X-Linked Inheritance – Risk to Family Members
The father of an affected male will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is presumed to be heterozygous for a
If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous, the affected male may have a
DHR testing of the mother is recommended to confirm her status, assess her risk of inflammatory or infectious conditions (see
A female proband may have the disorder as the result of a
Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
If the mother of the proband has a
Males who inherit the pathogenic variant will be affected.
Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females are typically not affected with CGD but are at substantial risk for inflammatory conditions (see
If the proband represents a simplex case and if the
If the mother of the proband has a
If the father of the proband has a
If the proband represents a simplex case and if the
Although females who are heterozygous for X-linked CGD are typically not affected with CGD (see
Note: Women who are heterozygous for X-linked CGD have circulating populations of oxidase-positive and oxidase-negative phagocytes, which can be resolved by DHR testing if the family-specific pathogenic variant has not been identified. (Note: Nitroblue tetrazolium testing is not reliable for heterozygote detection because it may be falsely interpreted as normal in females who are heterozygous for X-linked CGD).
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is presumed to be heterozygous for a
• If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous, the affected male may have a
• DHR testing of the mother is recommended to confirm her status, assess her risk of inflammatory or infectious conditions (see
• A female proband may have the disorder as the result of a
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
• If the mother of the proband has a
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females are typically not affected with CGD but are at substantial risk for inflammatory conditions (see
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females are typically not affected with CGD but are at substantial risk for inflammatory conditions (see
• If the proband represents a simplex case and if the
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females are typically not affected with CGD but are at substantial risk for inflammatory conditions (see
• If the mother of the proband has a
• If the father of the proband has a
• If the proband represents a simplex case and if the
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of a child with autosomal recessive CGD (AR-CGD) are typically heterozygous for a
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CGD-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
One of the pathogenic variants identified in the proband occurred as a
Note: Because
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an autosomal recessive CGD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
Heterozygotes (carriers) are usually asymptomatic and are not at risk of developing the disorder.
• The parents of a child with autosomal recessive CGD (AR-CGD) are typically heterozygous for a
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CGD-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• One of the pathogenic variants identified in the proband occurred as a
• Note: Because
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Note: Because
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Note: Because
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an autosomal recessive CGD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygotes (carriers) are usually asymptomatic and are not at risk of developing the disorder.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
Prior to pregnancy, affected women should be advised about changes in antimicrobial prophylaxis (see
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
• Prior to pregnancy, affected women should be advised about changes in antimicrobial prophylaxis (see
## Prenatal Testing and Preimplantation Genetic Testing
PGT has also been used to identify female HLA-matched sibs of a male with X-linked CGD. After successful in vitro fertilization, embryo transfer, and pregnancy outcome, the female sib served as a hematopoietic stem cell donor for the affected child [
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
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## Molecular Genetics
Chronic Granulomatous Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Chronic Granulomatous Disease (
Chronic granulomatous disease is a single phenotype caused by pathogenic variant(s) in of one of six genes that encode proteins of NADPH oxidase. The genes and the official names of their protein products are listed in
## Molecular Pathogenesis
Chronic granulomatous disease is a single phenotype caused by pathogenic variant(s) in of one of six genes that encode proteins of NADPH oxidase. The genes and the official names of their protein products are listed in
## Chapter Notes
21 April 2022 (ha) Comprehensive update posted live
11 February 2016 (ha) Comprehensive update posted live
9 August 2012 (me) Review posted live
7 November 2011 (jl) Original submission
• 21 April 2022 (ha) Comprehensive update posted live
• 11 February 2016 (ha) Comprehensive update posted live
• 9 August 2012 (me) Review posted live
• 7 November 2011 (jl) Original submission
## Revision History
21 April 2022 (ha) Comprehensive update posted live
11 February 2016 (ha) Comprehensive update posted live
9 August 2012 (me) Review posted live
7 November 2011 (jl) Original submission
• 21 April 2022 (ha) Comprehensive update posted live
• 11 February 2016 (ha) Comprehensive update posted live
• 9 August 2012 (me) Review posted live
• 7 November 2011 (jl) Original submission
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"J Roesler, A Koch, G Porksen, H Von Bernuth, S Brenner, G Hahn, R Fischer, N Lorenz, M Gahr, A Rosen-Wolff. Benefit assessment of preventive medical check-ups in patients suffering from chronic granulomatous disease (CGD).. J Eval Clin Pract. 2005;11:513-21",
"D Roos, K van Leeuwen, AP Hsu, DL Priel, A Begtrup, R Brandon, A Rawat, P Vignesh, M Madkaikar, MJ Stasia, FG Bakri, M de Boer, J Roesler, N Köker, MY Köker, M Jakobsen, J Bustamante, MB Garcia-Morato, JLV Shephard, D Cagdas, I Tezcan, R Sherkat, E Mortaz, A Fayezi, M Shahrooei, B Wolach, L Blancas-Galicia, H Kanegane, T Kawai, A Condino-Neto, M Vihinen, CS Zerbe, SM Holland, HL Malech, JI Gallin, DB Kuhns. Hematologically important mutations: The autosomal forms of chronic granulomatous disease (third update).. Blood Cells Mol Dis. 2021a;92",
"D Roos, K van Leeuwen, AP Hsu, DL Priel, A Begtrup, R Brandon, MJ Stasia, FG Bakri, N Köker, MY Köker, M Madkaika, M de Boer, MB Garcia-Morato, JLV Shephard, J Roesler, H Kanegane, T Kawai, G Di Matteo, M Shahrooei, J Bustamante, A Rawat, P Vignesh, E Mortaz, A Fayezi, D Cagdas, I Tezcan, M Kitcharoensakkul, MC Dinauer, I Meyts, B Wolach, A Condino-Neto, CS Zerbe, SM Holland, HL Malech, JI Gallin, DB Kuhns. Hematologically important mutations: X-linked chronic granulomatous disease (fourth update).. Blood Cells Mol Dis. 2021b;90",
"BH Segal, LA Barnhart, VL Anderson, TJ Walsh, HL Malech, SM Holland. Posaconazole as salvage therapy in patients with chronic granulomatous disease and invasive filamentous fungal infection.. Clin Infect Dis. 2005;40:1684-8",
"BH Segal, ES DeCarlo, HL Malech, JI Gallin, SM Holland. Aspergillus nidulans infection in chronic granulomatous disease.. Medicine 1998;77:345-54",
"T Shigemura, Y Nakazawa, Y Amano, A Sudo, M Watanabe, M Kobayashi, N Kobabyashi, K Koike, K Agematsu, K Nishimura. Subcutaneous abscess due to basidiomycete Phellinus mori in a patient with chronic granulomatous disease.. Infection. 2015;43:371-5",
"S Siddiqui, VL Anderson, DM Hilligoss, M Abinun, TW Kuijpers, H Masur, FG Witebsky, YR Shea, JI Gallin, HL Malech, SM Holland. Fulminant mulch pneumonitis: an emergency presentation of chronic granulomatous disease.. Clin Infect Dis. 2007;45:673-81",
"S Sirinavin, C Techasaensiri, S Benjaponpitak, R Pornkul, M. Vorachit. Invasive Chromobacterium violaceum infection in children: case report and review.. Pediatr Infect Dis J. 2005;24:559-61",
"JD Squire, SN Vazquez, A Chan, ME Smith, D Chellapandian, L Vose, B Teppa, IC Hanson, IK Chinn, L Forbes-Satter, FO Seeborg, SK Nicholas, CA Martinez, CE Allen, TJ Connors, P Satwani, M Shtessel, H Ale, LM Noroski, NL Rider, JD Milner, JW Leiding. Case Report: Secondary Hemophagocytic Lymphohistiocytosis With Disseminated Infection in Chronic Granulomatous Disease-A Serious Cause of Mortality.. Front Immunol. 2020;11",
"DM Straughan, KC McLoughlin, JE Mullinax, BE Marciano, AF Freeman, VL Anderson, G Uzel, SC Azoury, R Sorber, HS Quadri, HL Malech, SS DeRavin, N Kamal, C Koh, CS Zerbe, DB Kuhns, JI Gallin, T Heller, SM Holland, U Rudloff. The changing paradigm of management of liver abscesses in chronic granulomatous disease.. Clin Infect Dis. 2018;66:1427-34",
"DC Thomas, LM Charbonnier, A Schejtman, H Aldhekri, EL Coomber, ER Dufficy, AE Beenken, JC Lee, S Clare, AO Speak, AJ Thrasher, G Santilli, H Al-Mousa, FS Alkuraya, TA Chatila, KGC Smith. EROS/CYBC1 mutations: Decreased NADPH oxidase function and chronic granulomatous disease.. J Allergy Clin Immunol. 2019;143:782-5.e1",
"AJ Towbin, I Chaves. Chronic granulomatous disease.. Pediatr Radiol. 2010;40:657-68",
"JR Trotter, P Sriaroon, D Berman, A Petrovic, JW Leiding. Sporothrix schenckii lymphadentitis in a male with X-linked chronic granulomatous disease.. J Clin Immunol. 2014;34:49-52",
"A van de Geer, A Nieto-Patlán, DB Kuhns, AT Tool, AA Arias, M Bouaziz, M de Boer, JL Franco, RP Gazendam, JL van Hamme, M van Houdt, K van Leeuwen, PJ Verkuijlen, TK van den Berg, JF Alzate, CA Arango-Franco, V Batura, AR Bernasconi, B Boardman, C Booth, SO Burns, F Cabarcas, NC Bensussan, F Charbit-Henrion, A Corveleyn, C Deswarte, ME Azcoiti, D Foell, JI Gallin, C Garcés, M Guedes, CH Hinze, SM Holland, SM Hughes, P Ibañez, HL Malech, I Meyts, M Moncada-Velez, K Moriya, E Neves, M Oleastro, L Perez, V Rattina, C Oleaga-Quintas, N Warner, AM Muise, JS López, E Trindade, J Vasconcelos, S Vermeire, H Wittkowski, A Worth, L Abel, MC Dinauer, PD Arkwright, D Roos, JL Casanova, TW Kuijpers, J Bustamante. Inherited p40phox deficiency differs from classic chronic granulomatous disease.. J Clin Invest. 2018;128:3957-75",
"JM van den Berg, E van Koppen, A Ahlin, BH Belohradsky, E Bernatowska, L Corbeel, T Español, A Fischer, M Kurenko-Deptuch, R Mouy, T Petropoulou, J Roesler, R Seger, MJ Stasia, NH Valerius, RS Weening, B Wolach, D Roos, TW Kuijpers. Chronic granulomatous disease: the European experience.. PLoS One. 2009;4",
"DC Vinh, AF Freeman, YR Shea, HL Malech, M Abinun, GA Weinberg, SM Holland. Mucormycosis in chronic granulomatous disease: association with iatrogenic immunosuppression.. J Allergy Clin Immunol. 2009;123:1411-3",
"SJ Vowells, TA Fleisher, S Sekhsaria, DW Alling, TE Maguire, HL Malech. Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in patients with chronic granulomatous disease.. J Pediatr. 1996;128:104-7",
"MM Walther, H Malech, A Berman, P Choyke, DJ Venzon, WM Linehan, JI Gallin. The urological manifestations of chronic granulomatous disease.. J Urol. 1992;147:1314-8",
"Y Wang, BE Marciano, D Shen, RJ Bishop, S Park, SM Holland, CC Chan. Molecular identification of bacterial DNA in the chorioretinal scars of chronic granulomatous disease.. J Clin Immunol. 2013;33:917-24",
"JA Winkelstein, MC Marino, RB Johnston, J Boyle, J Curnutte, JI Gallin, HL Malech, SM Holland, H Ochs, P Quie, RH Buckley, CB Foster, SJ Chanock, H Dickler. Chronic granulomatous disease. Report on a national registry of 368 patients.. Medicine (Baltimore) 2000;79:155-69",
"B Wolach, R Gavrieli, M De Boer, G Gottesman, J Ben-Ari, M Rottem, Y Schlesinger, G Grisaru-Soen, A Etzioni, D Roos. Chronic granulomatous disease in Israel: clinical, functional and molecular studies of 38 patients.. Clin Immunol. 2008;129:103-14",
"B Wolach, R Gavrieli, M de Boer, K van Leeuwen, S Berger-Achituv, T Stauber, J Ben Ari, M Rottem, Y Schlesinger, G Grisaru-Soen, O Abuzaitoun, N Marcus, B Zion Garty, A Broides, J Levy, P Stepansky, A Etzioni, R Somech, D. Roos. Chronic granulomatous disease: Clinical, functional, molecular, and genetic studies. The Israeli experience with 84 patients.. Am J Hematol. 2017;92:28-36",
"B Wolach, Y Scharf, R Gavrieli, M de Boer, D Roos. Unusual late presentation of X-linked chronic granulomatous disease in an adult female with a somatic mosaic for a novel mutation in CYBB.. Blood. 2005;105:61-6",
"MA Yamazaki-Nakashimada, ER Stiehm, D Pietropaolo-Cienfuegos, V Hernandez-Bautista, F Espinosa-Rosales. Corticosteroid therapy for refractory infections in chronic granulomatous disease: case reports and review of the literature.. Ann Allergy Asthma Immunol. 2006;97:257-61"
] |
9/8/2012
|
21/4/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
chac
|
chac
|
[
"Chorea-Acanthocytosis (ChAc)",
"Choreoacanthocytosis",
"Choreoacanthocytosis",
"Chorea-Acanthocytosis (ChAc)",
"Intermembrane lipid transfer protein VPS13A",
"VPS13A",
"VPS13A Disease"
] |
Kevin Peikert, Carol Dobson-Stone, Luca Rampoldi, Gabriel Miltenberger-Miltenyi, Aaron Neiman, Pietro De Camilli, Andreas Hermann, Ruth H Walker, Anthony P Monaco, Adrian Danek
|
Summary The diagnosis of
|
## Diagnosis
"
Acanthocytosis is neither necessary nor sufficient to diagnose the disorder.
Suggestive clinical findings include:
Huntingtonism triad of progressive deterioration of movement, cognition, and behavior
Progressive movement disorder
Commonly chorea and dystonia in early disease stages
Sometimes a parkinsonian syndrome, especially in later disease stages
Predominant orofacial choreic and dystonic movements and tics
Orofacial chorea
Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
Habitual tongue and lip biting with self-mutilation [
Involuntary vocalizations
Bruxism
Dysarthria and dysphagia with resultant weight loss
Progressive cognitive and behavioral changes (of "frontal lobe type," i.e., executive dysfunction, impaired social cognition) [
Psychosis
Seizures, which can be the initial manifestation; sometimes suggestive of a familial temporal lobe epilepsy [
Progressive neuromuscular involvement characterized by distal muscle wasting and weakness. This can be subclinical (only creatine kinase [CK] elevation). Electromyography commonly reveals chronic denervation and, in some instances, also myopathic changes [
Peripheral neuropathy with impaired deep tendon reflexes and vibration sense contributing to muscle weakness and atrophy. Electrophysiologic tests demonstrate a sensory or sensorimotor axonopathy.
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
Increased serum concentration of muscle CK is observed in the majority of individuals.
Less commonly, serum concentrations of aspartate transaminase and alanine transaminase are increased.
Levels of haptoglobin can be reduced and levels of lactate dehydrogenase can be increased due to chronic (subclinical) hemolysis [
Note: (1) The proportion of acanthocytes does not correlate with disease severity. (2) Presence of acanthocytes is neither "specific" nor "sensitive" for the diagnosis of
A standard routine procedure is to dilute blood 1:1 with 0.9% saline containing 10 U/mL heparin, and examine it using phase-contrast microscopy after 30 minutes' incubation in a shaker and wet blood smear preparation. In control samples, fewer than 6.3% of cells are speculated [
Note: (1) Dry blood smears seem inadequate [
Scanning electron microscopy of erythrocytes fixed with glutaraldehyde is probably the most reliable method of detecting acanthocytes but is not routinely available. Distinguishing acanthocytes from erythrocytes of other shapes can be difficult, as their definitions may appear insufficient in the individual case [
Decreased erythrocyte sedimentation rate may emerge as a simpler indirect indicator of acanthocytosis [
Detection of
Cranial CT and brain MRI reveal atrophy of the caudate nuclei with dilatation of the anterior horns of the lateral ventricles. The extent of basal ganglia atrophy is best appreciated on sections in the frontal plane. MRI may show T
In addition to the caudate nucleus, the putamen also shows significant and marked reduction in volume compared with controls [
Hippocampal sclerosis and atrophy are also frequently seen [
There may be mild generalized cerebral cortical atrophy.
Although cerebellar atrophy has been reported in a few individuals, to date genetic diagnoses have not been established in these individuals [
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Deletion of exons 60-61 seems common in the Japanese population [
• Huntingtonism triad of progressive deterioration of movement, cognition, and behavior
• Progressive movement disorder
• Commonly chorea and dystonia in early disease stages
• Sometimes a parkinsonian syndrome, especially in later disease stages
• Predominant orofacial choreic and dystonic movements and tics
• Orofacial chorea
• Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
• Habitual tongue and lip biting with self-mutilation [
• Involuntary vocalizations
• Bruxism
• Commonly chorea and dystonia in early disease stages
• Sometimes a parkinsonian syndrome, especially in later disease stages
• Predominant orofacial choreic and dystonic movements and tics
• Orofacial chorea
• Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
• Habitual tongue and lip biting with self-mutilation [
• Involuntary vocalizations
• Bruxism
• Orofacial chorea
• Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
• Habitual tongue and lip biting with self-mutilation [
• Involuntary vocalizations
• Bruxism
• Dysarthria and dysphagia with resultant weight loss
• Progressive cognitive and behavioral changes (of "frontal lobe type," i.e., executive dysfunction, impaired social cognition) [
• Psychosis
• Seizures, which can be the initial manifestation; sometimes suggestive of a familial temporal lobe epilepsy [
• Progressive neuromuscular involvement characterized by distal muscle wasting and weakness. This can be subclinical (only creatine kinase [CK] elevation). Electromyography commonly reveals chronic denervation and, in some instances, also myopathic changes [
• Peripheral neuropathy with impaired deep tendon reflexes and vibration sense contributing to muscle weakness and atrophy. Electrophysiologic tests demonstrate a sensory or sensorimotor axonopathy.
• Commonly chorea and dystonia in early disease stages
• Sometimes a parkinsonian syndrome, especially in later disease stages
• Predominant orofacial choreic and dystonic movements and tics
• Orofacial chorea
• Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
• Habitual tongue and lip biting with self-mutilation [
• Involuntary vocalizations
• Bruxism
• Orofacial chorea
• Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
• Habitual tongue and lip biting with self-mutilation [
• Involuntary vocalizations
• Bruxism
• Orofacial chorea
• Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
• Habitual tongue and lip biting with self-mutilation [
• Involuntary vocalizations
• Bruxism
• Increased serum concentration of muscle CK is observed in the majority of individuals.
• Less commonly, serum concentrations of aspartate transaminase and alanine transaminase are increased.
• Levels of haptoglobin can be reduced and levels of lactate dehydrogenase can be increased due to chronic (subclinical) hemolysis [
• A standard routine procedure is to dilute blood 1:1 with 0.9% saline containing 10 U/mL heparin, and examine it using phase-contrast microscopy after 30 minutes' incubation in a shaker and wet blood smear preparation. In control samples, fewer than 6.3% of cells are speculated [
• Note: (1) Dry blood smears seem inadequate [
• Scanning electron microscopy of erythrocytes fixed with glutaraldehyde is probably the most reliable method of detecting acanthocytes but is not routinely available. Distinguishing acanthocytes from erythrocytes of other shapes can be difficult, as their definitions may appear insufficient in the individual case [
• Decreased erythrocyte sedimentation rate may emerge as a simpler indirect indicator of acanthocytosis [
## Suggestive Findings
Acanthocytosis is neither necessary nor sufficient to diagnose the disorder.
Suggestive clinical findings include:
Huntingtonism triad of progressive deterioration of movement, cognition, and behavior
Progressive movement disorder
Commonly chorea and dystonia in early disease stages
Sometimes a parkinsonian syndrome, especially in later disease stages
Predominant orofacial choreic and dystonic movements and tics
Orofacial chorea
Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
Habitual tongue and lip biting with self-mutilation [
Involuntary vocalizations
Bruxism
Dysarthria and dysphagia with resultant weight loss
Progressive cognitive and behavioral changes (of "frontal lobe type," i.e., executive dysfunction, impaired social cognition) [
Psychosis
Seizures, which can be the initial manifestation; sometimes suggestive of a familial temporal lobe epilepsy [
Progressive neuromuscular involvement characterized by distal muscle wasting and weakness. This can be subclinical (only creatine kinase [CK] elevation). Electromyography commonly reveals chronic denervation and, in some instances, also myopathic changes [
Peripheral neuropathy with impaired deep tendon reflexes and vibration sense contributing to muscle weakness and atrophy. Electrophysiologic tests demonstrate a sensory or sensorimotor axonopathy.
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
Increased serum concentration of muscle CK is observed in the majority of individuals.
Less commonly, serum concentrations of aspartate transaminase and alanine transaminase are increased.
Levels of haptoglobin can be reduced and levels of lactate dehydrogenase can be increased due to chronic (subclinical) hemolysis [
Note: (1) The proportion of acanthocytes does not correlate with disease severity. (2) Presence of acanthocytes is neither "specific" nor "sensitive" for the diagnosis of
A standard routine procedure is to dilute blood 1:1 with 0.9% saline containing 10 U/mL heparin, and examine it using phase-contrast microscopy after 30 minutes' incubation in a shaker and wet blood smear preparation. In control samples, fewer than 6.3% of cells are speculated [
Note: (1) Dry blood smears seem inadequate [
Scanning electron microscopy of erythrocytes fixed with glutaraldehyde is probably the most reliable method of detecting acanthocytes but is not routinely available. Distinguishing acanthocytes from erythrocytes of other shapes can be difficult, as their definitions may appear insufficient in the individual case [
Decreased erythrocyte sedimentation rate may emerge as a simpler indirect indicator of acanthocytosis [
Detection of
Cranial CT and brain MRI reveal atrophy of the caudate nuclei with dilatation of the anterior horns of the lateral ventricles. The extent of basal ganglia atrophy is best appreciated on sections in the frontal plane. MRI may show T
In addition to the caudate nucleus, the putamen also shows significant and marked reduction in volume compared with controls [
Hippocampal sclerosis and atrophy are also frequently seen [
There may be mild generalized cerebral cortical atrophy.
Although cerebellar atrophy has been reported in a few individuals, to date genetic diagnoses have not been established in these individuals [
• Huntingtonism triad of progressive deterioration of movement, cognition, and behavior
• Progressive movement disorder
• Commonly chorea and dystonia in early disease stages
• Sometimes a parkinsonian syndrome, especially in later disease stages
• Predominant orofacial choreic and dystonic movements and tics
• Orofacial chorea
• Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
• Habitual tongue and lip biting with self-mutilation [
• Involuntary vocalizations
• Bruxism
• Commonly chorea and dystonia in early disease stages
• Sometimes a parkinsonian syndrome, especially in later disease stages
• Predominant orofacial choreic and dystonic movements and tics
• Orofacial chorea
• Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
• Habitual tongue and lip biting with self-mutilation [
• Involuntary vocalizations
• Bruxism
• Orofacial chorea
• Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
• Habitual tongue and lip biting with self-mutilation [
• Involuntary vocalizations
• Bruxism
• Dysarthria and dysphagia with resultant weight loss
• Progressive cognitive and behavioral changes (of "frontal lobe type," i.e., executive dysfunction, impaired social cognition) [
• Psychosis
• Seizures, which can be the initial manifestation; sometimes suggestive of a familial temporal lobe epilepsy [
• Progressive neuromuscular involvement characterized by distal muscle wasting and weakness. This can be subclinical (only creatine kinase [CK] elevation). Electromyography commonly reveals chronic denervation and, in some instances, also myopathic changes [
• Peripheral neuropathy with impaired deep tendon reflexes and vibration sense contributing to muscle weakness and atrophy. Electrophysiologic tests demonstrate a sensory or sensorimotor axonopathy.
• Commonly chorea and dystonia in early disease stages
• Sometimes a parkinsonian syndrome, especially in later disease stages
• Predominant orofacial choreic and dystonic movements and tics
• Orofacial chorea
• Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
• Habitual tongue and lip biting with self-mutilation [
• Involuntary vocalizations
• Bruxism
• Orofacial chorea
• Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
• Habitual tongue and lip biting with self-mutilation [
• Involuntary vocalizations
• Bruxism
• Orofacial chorea
• Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
• Habitual tongue and lip biting with self-mutilation [
• Involuntary vocalizations
• Bruxism
• Increased serum concentration of muscle CK is observed in the majority of individuals.
• Less commonly, serum concentrations of aspartate transaminase and alanine transaminase are increased.
• Levels of haptoglobin can be reduced and levels of lactate dehydrogenase can be increased due to chronic (subclinical) hemolysis [
• A standard routine procedure is to dilute blood 1:1 with 0.9% saline containing 10 U/mL heparin, and examine it using phase-contrast microscopy after 30 minutes' incubation in a shaker and wet blood smear preparation. In control samples, fewer than 6.3% of cells are speculated [
• Note: (1) Dry blood smears seem inadequate [
• Scanning electron microscopy of erythrocytes fixed with glutaraldehyde is probably the most reliable method of detecting acanthocytes but is not routinely available. Distinguishing acanthocytes from erythrocytes of other shapes can be difficult, as their definitions may appear insufficient in the individual case [
• Decreased erythrocyte sedimentation rate may emerge as a simpler indirect indicator of acanthocytosis [
## Clinical Findings
Suggestive clinical findings include:
Huntingtonism triad of progressive deterioration of movement, cognition, and behavior
Progressive movement disorder
Commonly chorea and dystonia in early disease stages
Sometimes a parkinsonian syndrome, especially in later disease stages
Predominant orofacial choreic and dystonic movements and tics
Orofacial chorea
Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
Habitual tongue and lip biting with self-mutilation [
Involuntary vocalizations
Bruxism
Dysarthria and dysphagia with resultant weight loss
Progressive cognitive and behavioral changes (of "frontal lobe type," i.e., executive dysfunction, impaired social cognition) [
Psychosis
Seizures, which can be the initial manifestation; sometimes suggestive of a familial temporal lobe epilepsy [
Progressive neuromuscular involvement characterized by distal muscle wasting and weakness. This can be subclinical (only creatine kinase [CK] elevation). Electromyography commonly reveals chronic denervation and, in some instances, also myopathic changes [
Peripheral neuropathy with impaired deep tendon reflexes and vibration sense contributing to muscle weakness and atrophy. Electrophysiologic tests demonstrate a sensory or sensorimotor axonopathy.
• Huntingtonism triad of progressive deterioration of movement, cognition, and behavior
• Progressive movement disorder
• Commonly chorea and dystonia in early disease stages
• Sometimes a parkinsonian syndrome, especially in later disease stages
• Predominant orofacial choreic and dystonic movements and tics
• Orofacial chorea
• Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
• Habitual tongue and lip biting with self-mutilation [
• Involuntary vocalizations
• Bruxism
• Commonly chorea and dystonia in early disease stages
• Sometimes a parkinsonian syndrome, especially in later disease stages
• Predominant orofacial choreic and dystonic movements and tics
• Orofacial chorea
• Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
• Habitual tongue and lip biting with self-mutilation [
• Involuntary vocalizations
• Bruxism
• Orofacial chorea
• Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
• Habitual tongue and lip biting with self-mutilation [
• Involuntary vocalizations
• Bruxism
• Dysarthria and dysphagia with resultant weight loss
• Progressive cognitive and behavioral changes (of "frontal lobe type," i.e., executive dysfunction, impaired social cognition) [
• Psychosis
• Seizures, which can be the initial manifestation; sometimes suggestive of a familial temporal lobe epilepsy [
• Progressive neuromuscular involvement characterized by distal muscle wasting and weakness. This can be subclinical (only creatine kinase [CK] elevation). Electromyography commonly reveals chronic denervation and, in some instances, also myopathic changes [
• Peripheral neuropathy with impaired deep tendon reflexes and vibration sense contributing to muscle weakness and atrophy. Electrophysiologic tests demonstrate a sensory or sensorimotor axonopathy.
• Commonly chorea and dystonia in early disease stages
• Sometimes a parkinsonian syndrome, especially in later disease stages
• Predominant orofacial choreic and dystonic movements and tics
• Orofacial chorea
• Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
• Habitual tongue and lip biting with self-mutilation [
• Involuntary vocalizations
• Bruxism
• Orofacial chorea
• Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
• Habitual tongue and lip biting with self-mutilation [
• Involuntary vocalizations
• Bruxism
• Orofacial chorea
• Unintended tongue protrusion on attempted swallowing (i.e., feeding dystonia) [
• Habitual tongue and lip biting with self-mutilation [
• Involuntary vocalizations
• Bruxism
## Family History
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
## Supportive Laboratory Findings
Increased serum concentration of muscle CK is observed in the majority of individuals.
Less commonly, serum concentrations of aspartate transaminase and alanine transaminase are increased.
Levels of haptoglobin can be reduced and levels of lactate dehydrogenase can be increased due to chronic (subclinical) hemolysis [
Note: (1) The proportion of acanthocytes does not correlate with disease severity. (2) Presence of acanthocytes is neither "specific" nor "sensitive" for the diagnosis of
A standard routine procedure is to dilute blood 1:1 with 0.9% saline containing 10 U/mL heparin, and examine it using phase-contrast microscopy after 30 minutes' incubation in a shaker and wet blood smear preparation. In control samples, fewer than 6.3% of cells are speculated [
Note: (1) Dry blood smears seem inadequate [
Scanning electron microscopy of erythrocytes fixed with glutaraldehyde is probably the most reliable method of detecting acanthocytes but is not routinely available. Distinguishing acanthocytes from erythrocytes of other shapes can be difficult, as their definitions may appear insufficient in the individual case [
Decreased erythrocyte sedimentation rate may emerge as a simpler indirect indicator of acanthocytosis [
Detection of
• Increased serum concentration of muscle CK is observed in the majority of individuals.
• Less commonly, serum concentrations of aspartate transaminase and alanine transaminase are increased.
• Levels of haptoglobin can be reduced and levels of lactate dehydrogenase can be increased due to chronic (subclinical) hemolysis [
• A standard routine procedure is to dilute blood 1:1 with 0.9% saline containing 10 U/mL heparin, and examine it using phase-contrast microscopy after 30 minutes' incubation in a shaker and wet blood smear preparation. In control samples, fewer than 6.3% of cells are speculated [
• Note: (1) Dry blood smears seem inadequate [
• Scanning electron microscopy of erythrocytes fixed with glutaraldehyde is probably the most reliable method of detecting acanthocytes but is not routinely available. Distinguishing acanthocytes from erythrocytes of other shapes can be difficult, as their definitions may appear insufficient in the individual case [
• Decreased erythrocyte sedimentation rate may emerge as a simpler indirect indicator of acanthocytosis [
## Neuroimaging
Cranial CT and brain MRI reveal atrophy of the caudate nuclei with dilatation of the anterior horns of the lateral ventricles. The extent of basal ganglia atrophy is best appreciated on sections in the frontal plane. MRI may show T
In addition to the caudate nucleus, the putamen also shows significant and marked reduction in volume compared with controls [
Hippocampal sclerosis and atrophy are also frequently seen [
There may be mild generalized cerebral cortical atrophy.
Although cerebellar atrophy has been reported in a few individuals, to date genetic diagnoses have not been established in these individuals [
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Deletion of exons 60-61 seems common in the Japanese population [
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Deletion of exons 60-61 seems common in the Japanese population [
## Clinical Characteristics
Select Features of
+++ = very common; ++ = common; + = uncommon
A peculiar "rubber person gait" may appear due to a sudden lapse of muscle tone in the trunk or legs [
The choreic syndrome gradually evolves into predominant parkinsonism with dystonia in about one third of affected individuals. Increased rigid muscle tone, rest tremor, impaired postural reflexes, bradykinesia, facial masking, and micrographia may appear. Occasionally, parkinsonism may be the presenting manifestation.
Action-induced dystonic protrusion of the tongue while feeding is typical and causes the tongue to push the food out of the mouth. "Feeding dystonia" is the term commonly applied for this pattern of movement [
Continuous tongue and lip biting caused by behavioral compulsion or tic/chorea can lead to self-mutilation, which can result in serious and challenging infections of the oral region. Affected individuals typically try to avoid this by keeping an object such as a handkerchief between the teeth, which may function either as a sensory trick to reduce dystonia or as a mechanical obstacle.
Involuntary vocalizations (vocal tics) are present in about two thirds of affected individuals [
There may be habitual teeth grinding (bruxism), spitting, or involuntary belching [
EEG may show temporal spikes, both interictally and with seizure onset [
Dilated cardiomyopathy is rare [
Splenomegaly is occasionally noted and may be caused by erythrocyte dysfunction and hemolysis, as shown by reduced levels of hemoglobin and haptoglobin.
Hepatomegaly may be present, along with elevated liver enzymes; to date the clinical significance of this is unclear.
Autonomic nervous system dysfunction was described in one affected individual [
In a few individuals, sleep disturbance was demonstrated by polysomnography [
Chance co-occurrences with other conditions may complicate the clinical diagnostic process [
Several instances of sudden unexplained death or death during epileptic seizures have been reported [
To date, available data are inconclusive with regard to genotype-phenotype correlations involving clinical manifestations and laboratory findings for
To incorporate the genetic etiology of the disorder,
"Neuroacanthocytosis" – a nonspecific umbrella term that may refer to any disorder with neurologic abnormalities and acanthocytosis (including
The term "Levine-Critchley syndrome" is obsolete [
Other outdated terms include "chorea-amyotrophy-acanthocytosis syndrome" and "familial amyotrophic chorea with acanthocytosis."
The number of individuals with
The following observations might speak to founder effects; however, to date the overall prevalence of the following variants and
An intragenic deletion of exons 60-61 was observed in several Japanese families [
An intragenic deletion of exons 70-73 was observed in French Canadian families [
The variant c.2343delA was reported in three Jewish families from Djerba Island, Tunisia.
• Dilated cardiomyopathy is rare [
• Splenomegaly is occasionally noted and may be caused by erythrocyte dysfunction and hemolysis, as shown by reduced levels of hemoglobin and haptoglobin.
• Hepatomegaly may be present, along with elevated liver enzymes; to date the clinical significance of this is unclear.
• Autonomic nervous system dysfunction was described in one affected individual [
• In a few individuals, sleep disturbance was demonstrated by polysomnography [
• Chance co-occurrences with other conditions may complicate the clinical diagnostic process [
• An intragenic deletion of exons 60-61 was observed in several Japanese families [
• An intragenic deletion of exons 70-73 was observed in French Canadian families [
• The variant c.2343delA was reported in three Jewish families from Djerba Island, Tunisia.
## Clinical Description
Select Features of
+++ = very common; ++ = common; + = uncommon
A peculiar "rubber person gait" may appear due to a sudden lapse of muscle tone in the trunk or legs [
The choreic syndrome gradually evolves into predominant parkinsonism with dystonia in about one third of affected individuals. Increased rigid muscle tone, rest tremor, impaired postural reflexes, bradykinesia, facial masking, and micrographia may appear. Occasionally, parkinsonism may be the presenting manifestation.
Action-induced dystonic protrusion of the tongue while feeding is typical and causes the tongue to push the food out of the mouth. "Feeding dystonia" is the term commonly applied for this pattern of movement [
Continuous tongue and lip biting caused by behavioral compulsion or tic/chorea can lead to self-mutilation, which can result in serious and challenging infections of the oral region. Affected individuals typically try to avoid this by keeping an object such as a handkerchief between the teeth, which may function either as a sensory trick to reduce dystonia or as a mechanical obstacle.
Involuntary vocalizations (vocal tics) are present in about two thirds of affected individuals [
There may be habitual teeth grinding (bruxism), spitting, or involuntary belching [
EEG may show temporal spikes, both interictally and with seizure onset [
Dilated cardiomyopathy is rare [
Splenomegaly is occasionally noted and may be caused by erythrocyte dysfunction and hemolysis, as shown by reduced levels of hemoglobin and haptoglobin.
Hepatomegaly may be present, along with elevated liver enzymes; to date the clinical significance of this is unclear.
Autonomic nervous system dysfunction was described in one affected individual [
In a few individuals, sleep disturbance was demonstrated by polysomnography [
Chance co-occurrences with other conditions may complicate the clinical diagnostic process [
Several instances of sudden unexplained death or death during epileptic seizures have been reported [
• Dilated cardiomyopathy is rare [
• Splenomegaly is occasionally noted and may be caused by erythrocyte dysfunction and hemolysis, as shown by reduced levels of hemoglobin and haptoglobin.
• Hepatomegaly may be present, along with elevated liver enzymes; to date the clinical significance of this is unclear.
• Autonomic nervous system dysfunction was described in one affected individual [
• In a few individuals, sleep disturbance was demonstrated by polysomnography [
• Chance co-occurrences with other conditions may complicate the clinical diagnostic process [
## Genotype-Phenotype Correlations
To date, available data are inconclusive with regard to genotype-phenotype correlations involving clinical manifestations and laboratory findings for
## Nomenclature
To incorporate the genetic etiology of the disorder,
"Neuroacanthocytosis" – a nonspecific umbrella term that may refer to any disorder with neurologic abnormalities and acanthocytosis (including
The term "Levine-Critchley syndrome" is obsolete [
Other outdated terms include "chorea-amyotrophy-acanthocytosis syndrome" and "familial amyotrophic chorea with acanthocytosis."
## Prevalence
The number of individuals with
The following observations might speak to founder effects; however, to date the overall prevalence of the following variants and
An intragenic deletion of exons 60-61 was observed in several Japanese families [
An intragenic deletion of exons 70-73 was observed in French Canadian families [
The variant c.2343delA was reported in three Jewish families from Djerba Island, Tunisia.
• An intragenic deletion of exons 60-61 was observed in several Japanese families [
• An intragenic deletion of exons 70-73 was observed in French Canadian families [
• The variant c.2343delA was reported in three Jewish families from Djerba Island, Tunisia.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Because of the protean manifestations of
Genes of Interest in the Differential Diagnosis of
Acanthocytosis
Dysarthria, neuropathy, & areflexia
Absence of basal ganglia movement disorder
Hallmark findings of pigmentary retinopathy, vitamin E deficiency, & steatorrhea
Spinocerebellar syndrome & sensorimotor neuropathy
Choreoathetosis
Epilepsy
↑ liver enzymes
Tremor, poor coordination, loss of fine motor control, chorea, & choreoathetosis OR rigid dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement)
Psychiatric disturbance (depression, neurotic behaviors, disorganization of personality &, occasionally, intellectual deterioration)
Low serum copper & ceruloplasmin concentrations & ↑ urinary copper excretion, esp after chelator challenging
Prominent MRI abnormalities during disease progression
Cognitive & behavioral disturbances
Self-injurious behavior (biting of lips, cheeks fingers, hands; head/limb banging)
Neurologic dysfunction (dystonia, choreoathetosis, opisthotonos)
Age at manifestation (early childhood) very different from
Hyperuricemia
Chorea syndrome, changes of personality & behavior, & imaging findings in HD &
Parkinsonism is typical for juvenile HD (Westphal variant) & transition to parkinsonism is not uncommon in late-stage HD.
Seizures are much more common in
↑ serum concentrations of CK or liver enzymes & acanthocytosis are unusual for HD.
↓ ankle reflexes are more prevalent in
The neuropathology of HD is more widespread & involves the cerebral cortex.
Acanthocytes are not present in great majority of affected persons.
Serum CK is normal.
Myopathy & seizures are absent.
HDL2 has been described exclusively in persons w/African ancestry.
Acanthocytosis
Dysarthria, neuropathy, & areflexia
Hallmark findings: presence of pigmentary retinopathy, vitamin E deficiency, steatorrhea, & absence of basal ganglia movement disorder
Spinocerebellar syndrome & sensorimotor neuropathy
Early childhood onset of progressive dystonia, dysarthria, rigidity, & choreoathetosis
"Atypical" presentation: onset at age >10 yrs, prominent speech defects, psychiatric disturbances, & more gradual progression of disease
Acanthocytes often observed
"Eye of the tiger" MRI finding (identified on transverse images of globus pallidus as central region of hyperintensity surrounded by rim of hypointensity) in PKAN
Much younger age of disease onset
CNS manifestations (movement disorder, cognitive impairment, & psychiatric symptoms)
Neuromuscular manifestations (mostly subclinical sensorimotor axonopathy, muscle weakness, or atrophy)
Red blood cell acanthocytosis & compensated hemolysis
Usually later onset in MLS of some features shared w/
The McLeod blood group phenotype
Malignant arrhythmias & cardiomyopathy are common.
AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; MOI = mode of inheritance; XL = X-linked
Because the term "neuroacanthocytosis" refers to several genetically and phenotypically distinct disorders, the terms McLeod syndrome or
Hematologically, MLS is defined as a specific blood group phenotype (named after the first proband, Hugh McLeod; "McLeod blood group phenotype") that results from absent expression of the Kx erythrocyte antigen and weakened expression of Kell blood group antigens. Note: Transfusions of Kx-positive blood products should be avoided in persons w/the McLeod blood group phenotype. Kx-negative blood or, if possible, banked autologous or homologous blood should be used for transfusions.
• Acanthocytosis
• Dysarthria, neuropathy, & areflexia
• Absence of basal ganglia movement disorder
• Hallmark findings of pigmentary retinopathy, vitamin E deficiency, & steatorrhea
• Spinocerebellar syndrome & sensorimotor neuropathy
• Choreoathetosis
• Epilepsy
• ↑ liver enzymes
• Tremor, poor coordination, loss of fine motor control, chorea, & choreoathetosis OR rigid dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement)
• Psychiatric disturbance (depression, neurotic behaviors, disorganization of personality &, occasionally, intellectual deterioration)
• Low serum copper & ceruloplasmin concentrations & ↑ urinary copper excretion, esp after chelator challenging
• Prominent MRI abnormalities during disease progression
• Cognitive & behavioral disturbances
• Self-injurious behavior (biting of lips, cheeks fingers, hands; head/limb banging)
• Neurologic dysfunction (dystonia, choreoathetosis, opisthotonos)
• Age at manifestation (early childhood) very different from
• Hyperuricemia
• Chorea syndrome, changes of personality & behavior, & imaging findings in HD &
• Parkinsonism is typical for juvenile HD (Westphal variant) & transition to parkinsonism is not uncommon in late-stage HD.
• Seizures are much more common in
• ↑ serum concentrations of CK or liver enzymes & acanthocytosis are unusual for HD.
• ↓ ankle reflexes are more prevalent in
• The neuropathology of HD is more widespread & involves the cerebral cortex.
• Acanthocytes are not present in great majority of affected persons.
• Serum CK is normal.
• Myopathy & seizures are absent.
• HDL2 has been described exclusively in persons w/African ancestry.
• Acanthocytosis
• Dysarthria, neuropathy, & areflexia
• Hallmark findings: presence of pigmentary retinopathy, vitamin E deficiency, steatorrhea, & absence of basal ganglia movement disorder
• Spinocerebellar syndrome & sensorimotor neuropathy
• Early childhood onset of progressive dystonia, dysarthria, rigidity, & choreoathetosis
• "Atypical" presentation: onset at age >10 yrs, prominent speech defects, psychiatric disturbances, & more gradual progression of disease
• Acanthocytes often observed
• "Eye of the tiger" MRI finding (identified on transverse images of globus pallidus as central region of hyperintensity surrounded by rim of hypointensity) in PKAN
• Much younger age of disease onset
• CNS manifestations (movement disorder, cognitive impairment, & psychiatric symptoms)
• Neuromuscular manifestations (mostly subclinical sensorimotor axonopathy, muscle weakness, or atrophy)
• Red blood cell acanthocytosis & compensated hemolysis
• Usually later onset in MLS of some features shared w/
• The McLeod blood group phenotype
• Malignant arrhythmias & cardiomyopathy are common.
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Apply appropriate scales according to predominant movement disorder (e.g., for chorea UHDRS-TMS, for dystonia UDRS or FMDRS, for parkinsonism MDS-UPDRS Part III).
Perform structural brain imaging (if not performed previously or not available for review); MRI preferred.
Assess seizure semiology & frequency.
Perform structural brain imaging (if not performed previously or not available for review); MRI preferred to assess for hippocampal sclerosis or other epileptogenic lesions.
Perform EEG.
Assess muscle weakness or atrophy, DTRs, gross motor & fine motor skills, mobility, ADL, & need for adaptive devices.
Determine serum CK, ALT, AST, & LDH.
Perform EMG & NCV studies.
Assess need for protective devices (to counteract head banging & repeated falls).
Assess living situation (to ↓ risk of falls).
Assess need for AFOs for foot drop secondary to muscle weakness/dystonia.
Assess executive deficits & memory.
Perform formal neuropsychological eval &/or short tests such as MoCA.
Consider involving OT & neuropsychologist if needed.
Perform standardized psychiatric assessment; eval of symptom-oriented psychotherapeutic & psychopharmacologic interventions.
Consider involving psychiatry specialist, psychologist, &/or neuropsychologist if needed.
Feeding/nutritional assessment
Speech eval
Assess feeding/tongue protrusion dystonia.
Consider clinical &/or fiberoptic &/or radiologic feeding eval.
Nutrition is a significant issue; assess body weight regularly.
Assess possible dysarthria & communication skills, incl need for alternative means of communication (e.g., text-to-speech computer technology).
Perform echocardiography, EKG, & cardiac biomarker analysis (e.g., troponin T/I, pro-BNP).
If available, perform cardiac MRI.
Perform abdominal ultrasound exam.
Inform affected persons & families re nature of condition, MOI, implications of disease.
Community &/or
Support by/for family, caregiver, or others.
Patient advocacy organization contact may be beneficial.
Home nursing can be considered to ↓ burden to patient & family.
ADL = activities of daily living; AFOs = ankle-foot orthoses; ALT = alanine transaminase; AST = aspartate transaminase; BNP = B-type natriuretic peptide; CK = creatine kinase; DTRs = deep tendon reflexes; EKG = electrocardiogram; EEG = electroencephalogram; EMG = electromyography; FMDRS = Fahn-Marsden Dystonia Rating Scale; LDH = lactate dehydrogenase; MDS-UPDRS = Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale; MoCA = Montreal Cognitive Assessment; MOI = mode of inheritance; NCV = nerve conduction velocity; OCD = obsessive-compulsive disorder; OT = occupational therapist; PT = physical therapist; UDRS = Unified Dystonia Rating Scale; UHDRS-TMS = Unified Huntington Disease Rating Scale Total Motor Score
Early recognition and treatment of seizures are important, as potential complications may be severe and could cause premature death [
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for
Treatment of Manifestations in Individuals with VPS13A Disease
Dopamine depletors (i.e., VMAT2 inhibitors) or dopamine D2 receptor antagonists such as atypical neuroleptics should be offered.
Amantadine may be beneficial.
Monitor for side effects of parkinsonism & depression.
Neuroleptics can also help w/behavioral issues.
Botulinum toxin may help ↓ the orolingual dystonia that interferes w/eating.
Orofacial chorea & tics can be ↓ by dopamine depleters & dopamine D2 receptor antagonists.
Keep object (e.g., handkerchief) in mouth to ↓ damage to lips & tongue from involuntary biting.
Use of mouth guard to prevent teeth grinding can also ↓ psychiatric manifestations.
Standard medications for dystonia can be tried (e.g., benzodiazepines, anti-cholinergics).
Amantadine may be beneficial.
Physiotherapy (See
Deep brain stimulation of globus pallidus pars interna may improve chorea & dystonia.
Dopaminergic agents can be tried (w/caution due to psychotropic side effects).
Physiotherapy
Physiatry to address need for adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, ramps to accommodate motorized chairs)
PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
OT to optimize ADL
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
Speech/swallowing therapy
Gastrostomy tube placement
ADL = activities of daily living; VMAT2 = vesicular monoamine transporter-2
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended (see
Recommended Surveillance for Individuals with
Assess nutritional status & adaptation of diet to assure adequate caloric intake & prevent aspiration.
Assess need for gastrostomy tube & obtain informed consent as early as possible.
Eval of social, psychological, & financial situation
Assess family need for palliative/respite care, home nursing, & other local resources or follow-up genetic counseling if new questions arise (e.g., family planning).
ASM = anti-seizure medication; CK = creatine kinase; MoCA = Montreal Cognitive Assessment; OT = occupational therapist; PT = physical therapist
Be aware of / monitor carefully seizure-provoking effects of antipsychotics/neuroleptics
Avoid the following:
Seizure-provoking circumstances (e.g., sleep deprivation, alcohol intake)
Anticonvulsants that may worsen involuntary movements/tics (e.g., carbamazepine, lamotrigine)
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early recognition and treatment of potential manifestations of the disease such as seizures, as possible complications (e.g., status epilepticus, sudden unexpected death in epilepsy) may be severe.
See
Several studies showed pathologically elevated tyrosine kinase Lyn activity in individuals with
VPS13A loss of function was reported to impair PI3K signaling leading to reduced store-operated Ca
Search
• Apply appropriate scales according to predominant movement disorder (e.g., for chorea UHDRS-TMS, for dystonia UDRS or FMDRS, for parkinsonism MDS-UPDRS Part III).
• Perform structural brain imaging (if not performed previously or not available for review); MRI preferred.
• Assess seizure semiology & frequency.
• Perform structural brain imaging (if not performed previously or not available for review); MRI preferred to assess for hippocampal sclerosis or other epileptogenic lesions.
• Perform EEG.
• Assess muscle weakness or atrophy, DTRs, gross motor & fine motor skills, mobility, ADL, & need for adaptive devices.
• Determine serum CK, ALT, AST, & LDH.
• Perform EMG & NCV studies.
• Assess need for protective devices (to counteract head banging & repeated falls).
• Assess living situation (to ↓ risk of falls).
• Assess need for AFOs for foot drop secondary to muscle weakness/dystonia.
• Assess executive deficits & memory.
• Perform formal neuropsychological eval &/or short tests such as MoCA.
• Consider involving OT & neuropsychologist if needed.
• Perform standardized psychiatric assessment; eval of symptom-oriented psychotherapeutic & psychopharmacologic interventions.
• Consider involving psychiatry specialist, psychologist, &/or neuropsychologist if needed.
• Feeding/nutritional assessment
• Speech eval
• Assess feeding/tongue protrusion dystonia.
• Consider clinical &/or fiberoptic &/or radiologic feeding eval.
• Nutrition is a significant issue; assess body weight regularly.
• Assess possible dysarthria & communication skills, incl need for alternative means of communication (e.g., text-to-speech computer technology).
• Perform echocardiography, EKG, & cardiac biomarker analysis (e.g., troponin T/I, pro-BNP).
• If available, perform cardiac MRI.
• Perform abdominal ultrasound exam.
• Inform affected persons & families re nature of condition, MOI, implications of disease.
• Community &/or
• Support by/for family, caregiver, or others.
• Patient advocacy organization contact may be beneficial.
• Home nursing can be considered to ↓ burden to patient & family.
• Dopamine depletors (i.e., VMAT2 inhibitors) or dopamine D2 receptor antagonists such as atypical neuroleptics should be offered.
• Amantadine may be beneficial.
• Monitor for side effects of parkinsonism & depression.
• Neuroleptics can also help w/behavioral issues.
• Botulinum toxin may help ↓ the orolingual dystonia that interferes w/eating.
• Orofacial chorea & tics can be ↓ by dopamine depleters & dopamine D2 receptor antagonists.
• Keep object (e.g., handkerchief) in mouth to ↓ damage to lips & tongue from involuntary biting.
• Use of mouth guard to prevent teeth grinding can also ↓ psychiatric manifestations.
• Standard medications for dystonia can be tried (e.g., benzodiazepines, anti-cholinergics).
• Amantadine may be beneficial.
• Physiotherapy (See
• Deep brain stimulation of globus pallidus pars interna may improve chorea & dystonia.
• Dopaminergic agents can be tried (w/caution due to psychotropic side effects).
• Physiotherapy
• Physiatry to address need for adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, ramps to accommodate motorized chairs)
• PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
• OT to optimize ADL
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
• Speech/swallowing therapy
• Gastrostomy tube placement
• Assess nutritional status & adaptation of diet to assure adequate caloric intake & prevent aspiration.
• Assess need for gastrostomy tube & obtain informed consent as early as possible.
• Eval of social, psychological, & financial situation
• Assess family need for palliative/respite care, home nursing, & other local resources or follow-up genetic counseling if new questions arise (e.g., family planning).
• Seizure-provoking circumstances (e.g., sleep deprivation, alcohol intake)
• Anticonvulsants that may worsen involuntary movements/tics (e.g., carbamazepine, lamotrigine)
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Apply appropriate scales according to predominant movement disorder (e.g., for chorea UHDRS-TMS, for dystonia UDRS or FMDRS, for parkinsonism MDS-UPDRS Part III).
Perform structural brain imaging (if not performed previously or not available for review); MRI preferred.
Assess seizure semiology & frequency.
Perform structural brain imaging (if not performed previously or not available for review); MRI preferred to assess for hippocampal sclerosis or other epileptogenic lesions.
Perform EEG.
Assess muscle weakness or atrophy, DTRs, gross motor & fine motor skills, mobility, ADL, & need for adaptive devices.
Determine serum CK, ALT, AST, & LDH.
Perform EMG & NCV studies.
Assess need for protective devices (to counteract head banging & repeated falls).
Assess living situation (to ↓ risk of falls).
Assess need for AFOs for foot drop secondary to muscle weakness/dystonia.
Assess executive deficits & memory.
Perform formal neuropsychological eval &/or short tests such as MoCA.
Consider involving OT & neuropsychologist if needed.
Perform standardized psychiatric assessment; eval of symptom-oriented psychotherapeutic & psychopharmacologic interventions.
Consider involving psychiatry specialist, psychologist, &/or neuropsychologist if needed.
Feeding/nutritional assessment
Speech eval
Assess feeding/tongue protrusion dystonia.
Consider clinical &/or fiberoptic &/or radiologic feeding eval.
Nutrition is a significant issue; assess body weight regularly.
Assess possible dysarthria & communication skills, incl need for alternative means of communication (e.g., text-to-speech computer technology).
Perform echocardiography, EKG, & cardiac biomarker analysis (e.g., troponin T/I, pro-BNP).
If available, perform cardiac MRI.
Perform abdominal ultrasound exam.
Inform affected persons & families re nature of condition, MOI, implications of disease.
Community &/or
Support by/for family, caregiver, or others.
Patient advocacy organization contact may be beneficial.
Home nursing can be considered to ↓ burden to patient & family.
ADL = activities of daily living; AFOs = ankle-foot orthoses; ALT = alanine transaminase; AST = aspartate transaminase; BNP = B-type natriuretic peptide; CK = creatine kinase; DTRs = deep tendon reflexes; EKG = electrocardiogram; EEG = electroencephalogram; EMG = electromyography; FMDRS = Fahn-Marsden Dystonia Rating Scale; LDH = lactate dehydrogenase; MDS-UPDRS = Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale; MoCA = Montreal Cognitive Assessment; MOI = mode of inheritance; NCV = nerve conduction velocity; OCD = obsessive-compulsive disorder; OT = occupational therapist; PT = physical therapist; UDRS = Unified Dystonia Rating Scale; UHDRS-TMS = Unified Huntington Disease Rating Scale Total Motor Score
Early recognition and treatment of seizures are important, as potential complications may be severe and could cause premature death [
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Apply appropriate scales according to predominant movement disorder (e.g., for chorea UHDRS-TMS, for dystonia UDRS or FMDRS, for parkinsonism MDS-UPDRS Part III).
• Perform structural brain imaging (if not performed previously or not available for review); MRI preferred.
• Assess seizure semiology & frequency.
• Perform structural brain imaging (if not performed previously or not available for review); MRI preferred to assess for hippocampal sclerosis or other epileptogenic lesions.
• Perform EEG.
• Assess muscle weakness or atrophy, DTRs, gross motor & fine motor skills, mobility, ADL, & need for adaptive devices.
• Determine serum CK, ALT, AST, & LDH.
• Perform EMG & NCV studies.
• Assess need for protective devices (to counteract head banging & repeated falls).
• Assess living situation (to ↓ risk of falls).
• Assess need for AFOs for foot drop secondary to muscle weakness/dystonia.
• Assess executive deficits & memory.
• Perform formal neuropsychological eval &/or short tests such as MoCA.
• Consider involving OT & neuropsychologist if needed.
• Perform standardized psychiatric assessment; eval of symptom-oriented psychotherapeutic & psychopharmacologic interventions.
• Consider involving psychiatry specialist, psychologist, &/or neuropsychologist if needed.
• Feeding/nutritional assessment
• Speech eval
• Assess feeding/tongue protrusion dystonia.
• Consider clinical &/or fiberoptic &/or radiologic feeding eval.
• Nutrition is a significant issue; assess body weight regularly.
• Assess possible dysarthria & communication skills, incl need for alternative means of communication (e.g., text-to-speech computer technology).
• Perform echocardiography, EKG, & cardiac biomarker analysis (e.g., troponin T/I, pro-BNP).
• If available, perform cardiac MRI.
• Perform abdominal ultrasound exam.
• Inform affected persons & families re nature of condition, MOI, implications of disease.
• Community &/or
• Support by/for family, caregiver, or others.
• Patient advocacy organization contact may be beneficial.
• Home nursing can be considered to ↓ burden to patient & family.
## Treatment of Manifestations
There is no cure for
Treatment of Manifestations in Individuals with VPS13A Disease
Dopamine depletors (i.e., VMAT2 inhibitors) or dopamine D2 receptor antagonists such as atypical neuroleptics should be offered.
Amantadine may be beneficial.
Monitor for side effects of parkinsonism & depression.
Neuroleptics can also help w/behavioral issues.
Botulinum toxin may help ↓ the orolingual dystonia that interferes w/eating.
Orofacial chorea & tics can be ↓ by dopamine depleters & dopamine D2 receptor antagonists.
Keep object (e.g., handkerchief) in mouth to ↓ damage to lips & tongue from involuntary biting.
Use of mouth guard to prevent teeth grinding can also ↓ psychiatric manifestations.
Standard medications for dystonia can be tried (e.g., benzodiazepines, anti-cholinergics).
Amantadine may be beneficial.
Physiotherapy (See
Deep brain stimulation of globus pallidus pars interna may improve chorea & dystonia.
Dopaminergic agents can be tried (w/caution due to psychotropic side effects).
Physiotherapy
Physiatry to address need for adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, ramps to accommodate motorized chairs)
PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
OT to optimize ADL
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
Speech/swallowing therapy
Gastrostomy tube placement
ADL = activities of daily living; VMAT2 = vesicular monoamine transporter-2
• Dopamine depletors (i.e., VMAT2 inhibitors) or dopamine D2 receptor antagonists such as atypical neuroleptics should be offered.
• Amantadine may be beneficial.
• Monitor for side effects of parkinsonism & depression.
• Neuroleptics can also help w/behavioral issues.
• Botulinum toxin may help ↓ the orolingual dystonia that interferes w/eating.
• Orofacial chorea & tics can be ↓ by dopamine depleters & dopamine D2 receptor antagonists.
• Keep object (e.g., handkerchief) in mouth to ↓ damage to lips & tongue from involuntary biting.
• Use of mouth guard to prevent teeth grinding can also ↓ psychiatric manifestations.
• Standard medications for dystonia can be tried (e.g., benzodiazepines, anti-cholinergics).
• Amantadine may be beneficial.
• Physiotherapy (See
• Deep brain stimulation of globus pallidus pars interna may improve chorea & dystonia.
• Dopaminergic agents can be tried (w/caution due to psychotropic side effects).
• Physiotherapy
• Physiatry to address need for adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, ramps to accommodate motorized chairs)
• PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
• OT to optimize ADL
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
• Speech/swallowing therapy
• Gastrostomy tube placement
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended (see
Recommended Surveillance for Individuals with
Assess nutritional status & adaptation of diet to assure adequate caloric intake & prevent aspiration.
Assess need for gastrostomy tube & obtain informed consent as early as possible.
Eval of social, psychological, & financial situation
Assess family need for palliative/respite care, home nursing, & other local resources or follow-up genetic counseling if new questions arise (e.g., family planning).
ASM = anti-seizure medication; CK = creatine kinase; MoCA = Montreal Cognitive Assessment; OT = occupational therapist; PT = physical therapist
Be aware of / monitor carefully seizure-provoking effects of antipsychotics/neuroleptics
• Assess nutritional status & adaptation of diet to assure adequate caloric intake & prevent aspiration.
• Assess need for gastrostomy tube & obtain informed consent as early as possible.
• Eval of social, psychological, & financial situation
• Assess family need for palliative/respite care, home nursing, & other local resources or follow-up genetic counseling if new questions arise (e.g., family planning).
## Agents/Circumstances to Avoid
Avoid the following:
Seizure-provoking circumstances (e.g., sleep deprivation, alcohol intake)
Anticonvulsants that may worsen involuntary movements/tics (e.g., carbamazepine, lamotrigine)
• Seizure-provoking circumstances (e.g., sleep deprivation, alcohol intake)
• Anticonvulsants that may worsen involuntary movements/tics (e.g., carbamazepine, lamotrigine)
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early recognition and treatment of potential manifestations of the disease such as seizures, as possible complications (e.g., status epilepticus, sudden unexpected death in epilepsy) may be severe.
See
## Therapies Under Investigation
Several studies showed pathologically elevated tyrosine kinase Lyn activity in individuals with
VPS13A loss of function was reported to impair PI3K signaling leading to reduced store-operated Ca
Search
## Genetic Counseling
Note: Previous speculation as to possible autosomal dominant inheritance of
The parents of an affected child are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Based on current knowledge, heterozygotes (carriers) do not have features of
If both parents are known to be heterozygous for a
Significant phenotypic variability may be observed between affected sibs who inherit the same biallelic pathogenic variants [
Based on current knowledge, heterozygotes (carriers) do not have features of
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of individuals known to be affected with or carriers of
Consanguinity has been reported in a number of families with
Recurrent
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Based on current knowledge, heterozygotes (carriers) do not have features of
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Significant phenotypic variability may be observed between affected sibs who inherit the same biallelic pathogenic variants [
• Based on current knowledge, heterozygotes (carriers) do not have features of
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals known to be affected with or carriers of
• Consanguinity has been reported in a number of families with
• Recurrent
• Consanguinity has been reported in a number of families with
• Recurrent
• Consanguinity has been reported in a number of families with
• Recurrent
## Mode of Inheritance
Note: Previous speculation as to possible autosomal dominant inheritance of
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Based on current knowledge, heterozygotes (carriers) do not have features of
If both parents are known to be heterozygous for a
Significant phenotypic variability may be observed between affected sibs who inherit the same biallelic pathogenic variants [
Based on current knowledge, heterozygotes (carriers) do not have features of
• The parents of an affected child are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Based on current knowledge, heterozygotes (carriers) do not have features of
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Significant phenotypic variability may be observed between affected sibs who inherit the same biallelic pathogenic variants [
• Based on current knowledge, heterozygotes (carriers) do not have features of
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of individuals known to be affected with or carriers of
Consanguinity has been reported in a number of families with
Recurrent
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals known to be affected with or carriers of
• Consanguinity has been reported in a number of families with
• Recurrent
• Consanguinity has been reported in a number of families with
• Recurrent
• Consanguinity has been reported in a number of families with
• Recurrent
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
• United Kingdom
•
•
•
## Molecular Genetics
VPS13A Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for VPS13A Disease (
VPS13A is one of four very similar mammalian VPS13 paralogues that have different subcellular localizations and functions in cell and organismal physiology [
It is not yet known how lipid flow through VPS13A is regulated or at which of these contact sites the loss of lipid flow is relevant to disease causation. However, the extreme C-terminal end of VPS13A (a PH domain) has been shown to bind directly to the XK protein, loss of which is responsible for
Loss of VPS13A has been associated with increased Lyn kinase activity, disturbed autophagy, and alteration of the actin cytoskeleton [
Variants of uncertain significance (VUS) in
Negative molecular analysis of
Used as a first diagnostic indicator when DNA analysis is not affordable or generally unavailable
Individuals with reduced levels of VPS13A need further diagnostic workup by molecular genetic testing [
Notes: (1) Some pathogenic variants in
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• Variants of uncertain significance (VUS) in
• Negative molecular analysis of
• Used as a first diagnostic indicator when DNA analysis is not affordable or generally unavailable
## Molecular Pathogenesis
VPS13A is one of four very similar mammalian VPS13 paralogues that have different subcellular localizations and functions in cell and organismal physiology [
It is not yet known how lipid flow through VPS13A is regulated or at which of these contact sites the loss of lipid flow is relevant to disease causation. However, the extreme C-terminal end of VPS13A (a PH domain) has been shown to bind directly to the XK protein, loss of which is responsible for
Loss of VPS13A has been associated with increased Lyn kinase activity, disturbed autophagy, and alteration of the actin cytoskeleton [
Variants of uncertain significance (VUS) in
Negative molecular analysis of
Used as a first diagnostic indicator when DNA analysis is not affordable or generally unavailable
Individuals with reduced levels of VPS13A need further diagnostic workup by molecular genetic testing [
Notes: (1) Some pathogenic variants in
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• Variants of uncertain significance (VUS) in
• Negative molecular analysis of
• Used as a first diagnostic indicator when DNA analysis is not affordable or generally unavailable
## Chapter Notes
The following web pages provide descriptions of our clinical work, research interests, and contact information:
Kevin Peikert, MD, and Andreas Hermann, MD, PhD, Translational Neurodegeneration Section "Albrecht Kossel,"
As an international community of clinicians, scientists, and families dealing with
Drs Adrian Danek (
Drs Adrian Danek (
Contact Drs Gabriel Miltenberger-Miltenyi (
We are grateful to Glenn Irvine, who sadly passed away, and Ginger Irvine, the founders of the
We thank Antonio Velayos Baeza and Benedikt Bader, former coauthors of this
Benedikt Bader, MD; Ludwig-Maximilians-Universität (2010-2023)
Adrian Danek, MD (2002-present)
Pietro De Camilli, PhD (2023-present)
Carol Dobson-Stone, DPhil (2002-present)
Andreas Hermann, MD, PhD (2023-present)
Gabriel Miltenberger-Miltenyi, MD (2023-present)
Anthony P Monaco, MD, PhD (2002-present)
Aaron Neiman, PhD (2023-present)
Kevin Peikert, MD (2023-present)
Luca Rampoldi, PhD (2002-present)
Antonio Velayos Baeza, PhD; Wellcome Trust Centre for Human Genetics (2004-2023)
Ruth H Walker, MB, ChB, PhD (2006-present)
30 March 2023 (bp) Comprehensive update posted live
18 April 2019 (avb) Revision: New information on VPS13C and VPS13D
30 January 2014 (me) Comprehensive update posted live
18 August 2011 (cd) Revision: prenatal testing available clinically as listed in the GeneTests Laboratory Directory
6 July 2010 (me) Comprehensive update posted live
13 October 2006 (me) Comprehensive update posted live
10 January 2005 (ad) Revision: Differential Diagnosis; Testing
16 July 2004 (me) Comprehensive update posted live
14 June 2002 (me) Review posted live
7 March 2002 (lr) Original submission
•
•
• Kevin Peikert, MD, and Andreas Hermann, MD, PhD, Translational Neurodegeneration Section "Albrecht Kossel,"
• 30 March 2023 (bp) Comprehensive update posted live
• 18 April 2019 (avb) Revision: New information on VPS13C and VPS13D
• 30 January 2014 (me) Comprehensive update posted live
• 18 August 2011 (cd) Revision: prenatal testing available clinically as listed in the GeneTests Laboratory Directory
• 6 July 2010 (me) Comprehensive update posted live
• 13 October 2006 (me) Comprehensive update posted live
• 10 January 2005 (ad) Revision: Differential Diagnosis; Testing
• 16 July 2004 (me) Comprehensive update posted live
• 14 June 2002 (me) Review posted live
• 7 March 2002 (lr) Original submission
## Author Notes
The following web pages provide descriptions of our clinical work, research interests, and contact information:
Kevin Peikert, MD, and Andreas Hermann, MD, PhD, Translational Neurodegeneration Section "Albrecht Kossel,"
As an international community of clinicians, scientists, and families dealing with
Drs Adrian Danek (
Drs Adrian Danek (
Contact Drs Gabriel Miltenberger-Miltenyi (
•
•
• Kevin Peikert, MD, and Andreas Hermann, MD, PhD, Translational Neurodegeneration Section "Albrecht Kossel,"
## Acknowledgments
We are grateful to Glenn Irvine, who sadly passed away, and Ginger Irvine, the founders of the
We thank Antonio Velayos Baeza and Benedikt Bader, former coauthors of this
## Author History
Benedikt Bader, MD; Ludwig-Maximilians-Universität (2010-2023)
Adrian Danek, MD (2002-present)
Pietro De Camilli, PhD (2023-present)
Carol Dobson-Stone, DPhil (2002-present)
Andreas Hermann, MD, PhD (2023-present)
Gabriel Miltenberger-Miltenyi, MD (2023-present)
Anthony P Monaco, MD, PhD (2002-present)
Aaron Neiman, PhD (2023-present)
Kevin Peikert, MD (2023-present)
Luca Rampoldi, PhD (2002-present)
Antonio Velayos Baeza, PhD; Wellcome Trust Centre for Human Genetics (2004-2023)
Ruth H Walker, MB, ChB, PhD (2006-present)
## Revision History
30 March 2023 (bp) Comprehensive update posted live
18 April 2019 (avb) Revision: New information on VPS13C and VPS13D
30 January 2014 (me) Comprehensive update posted live
18 August 2011 (cd) Revision: prenatal testing available clinically as listed in the GeneTests Laboratory Directory
6 July 2010 (me) Comprehensive update posted live
13 October 2006 (me) Comprehensive update posted live
10 January 2005 (ad) Revision: Differential Diagnosis; Testing
16 July 2004 (me) Comprehensive update posted live
14 June 2002 (me) Review posted live
7 March 2002 (lr) Original submission
• 30 March 2023 (bp) Comprehensive update posted live
• 18 April 2019 (avb) Revision: New information on VPS13C and VPS13D
• 30 January 2014 (me) Comprehensive update posted live
• 18 August 2011 (cd) Revision: prenatal testing available clinically as listed in the GeneTests Laboratory Directory
• 6 July 2010 (me) Comprehensive update posted live
• 13 October 2006 (me) Comprehensive update posted live
• 10 January 2005 (ad) Revision: Differential Diagnosis; Testing
• 16 July 2004 (me) Comprehensive update posted live
• 14 June 2002 (me) Review posted live
• 7 March 2002 (lr) Original submission
## References
## Literature Cited
|
[] |
14/6/2002
|
30/3/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
char
|
char
|
[
"Transcription factor AP-2-beta",
"TFAP2B",
"Char Syndrome"
] |
Char Syndrome
|
Bruce D Gelb
|
Summary Char syndrome is characterized by the triad of typical facial features, patent ductus arteriosus, and aplasia or hypoplasia of the middle phalanges of the fifth fingers. Typical facial features are depressed nasal bridge and broad flat nasal tip, widely spaced eyes, downslanted palpebral fissures, mild ptosis, short philtrum with prominent philtral ridges with an upward pointing vermilion border resulting in a triangular mouth, and thickened (patulous) everted lips. Less common findings include other types of congenital heart defects, other hand and foot anomalies, hypodontia, hearing loss, myopia and/or strabismus, polythelia, parasomnia, craniosynostosis (involving either the metopic or sagittal suture), and short stature. The diagnosis of Char syndrome is established in a proband with suggestive clinical findings and/or a heterozygous pathogenic variant in Char syndrome is inherited in an autosomal dominant manner. The proportion of cases caused by a
|
## Diagnosis
Formal clinical diagnostic criteria for Char syndrome have not been published.
Char syndrome
Typical facial features with depressed nasal bridge and broad flat nasal tip, widely spaced eyes, downslanted palpebral fissures, mild ptosis, short philtrum with prominent philtral ridges with an upward pointing vermilion border resulting in a triangular mouth, and thickened (patulous) everted lips
Patent ductus arteriosus
Aplasia or hypoplasia of the middle phalanges of the fifth fingers
The diagnosis of Char syndrome
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Char syndrome is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of Char syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of Char syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Char Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Because most of the pathogenic variants identified to date result in mutated protein with dominant-negative effects, it is likely that variants will be missense defects in the coding region for critical domains, particularly the basic domain. Rare pathogenic changes altering splice sites & engendering haploinsufficiency have also been reported [
• Typical facial features with depressed nasal bridge and broad flat nasal tip, widely spaced eyes, downslanted palpebral fissures, mild ptosis, short philtrum with prominent philtral ridges with an upward pointing vermilion border resulting in a triangular mouth, and thickened (patulous) everted lips
• Patent ductus arteriosus
• Aplasia or hypoplasia of the middle phalanges of the fifth fingers
• For an introduction to multigene panels click
## Suggestive Findings
Char syndrome
Typical facial features with depressed nasal bridge and broad flat nasal tip, widely spaced eyes, downslanted palpebral fissures, mild ptosis, short philtrum with prominent philtral ridges with an upward pointing vermilion border resulting in a triangular mouth, and thickened (patulous) everted lips
Patent ductus arteriosus
Aplasia or hypoplasia of the middle phalanges of the fifth fingers
• Typical facial features with depressed nasal bridge and broad flat nasal tip, widely spaced eyes, downslanted palpebral fissures, mild ptosis, short philtrum with prominent philtral ridges with an upward pointing vermilion border resulting in a triangular mouth, and thickened (patulous) everted lips
• Patent ductus arteriosus
• Aplasia or hypoplasia of the middle phalanges of the fifth fingers
## Establishing the Diagnosis
The diagnosis of Char syndrome
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Char syndrome is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of Char syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of Char syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Char Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Because most of the pathogenic variants identified to date result in mutated protein with dominant-negative effects, it is likely that variants will be missense defects in the coding region for critical domains, particularly the basic domain. Rare pathogenic changes altering splice sites & engendering haploinsufficiency have also been reported [
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of Char syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the diagnosis of Char syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Char Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Because most of the pathogenic variants identified to date result in mutated protein with dominant-negative effects, it is likely that variants will be missense defects in the coding region for critical domains, particularly the basic domain. Rare pathogenic changes altering splice sites & engendering haploinsufficiency have also been reported [
## Clinical Characteristics
Char syndrome is characterized by the triad of typical facial features (see
Features of Char Syndrome
Other heart defects (e.g., muscular ventricular septal defects, complex congenital defects)
Other hand abnormalities including interstitial polydactyly [
Foot anomalies including interphalangeal joint fusion or clinodactyly [
Hypodontia. Lack of second and/or third molars in all four quadrants [
Visual impairment. Myopia [
Hearing abnormalities including profound bilateral hearing loss in two affected individuals [
Polythelia (supernumerary nipples) [
Parasomnia [
Craniosynostosis involving either the metopic or sagittal suture reported in four affected individuals [
Short stature (≤3 SD below the mean) reported in two affected individuals [
Among the 16 different pathogenic variants in
Individuals harboring basic domain alleles tend to have the classic form of Char syndrome (97% with facial features, 58% with PDA, and 79% with hand anomalies) [
For individuals in the one family inheriting the transactivation domain-altering variant, the facial features were prevalent (14/14) but mild, PDA was generally present (10/14), but hand anomalies were not observed in any [
The phenotypes associated with loss-of-function pathogenic variants often included PDA (32/40; 80%) but facial features of Char syndrome were less prevalent (23/39; 59%); features in these individuals not observed in those with missense variants included craniosynostosis (n = 3) and short stature (n = 2) [
The penetrance of Char syndrome has not been formally determined. Two asymptomatic individuals with
The prevalence of Char syndrome has not been determined but is thought to be quite low.
• Other heart defects (e.g., muscular ventricular septal defects, complex congenital defects)
• Other hand abnormalities including interstitial polydactyly [
• Foot anomalies including interphalangeal joint fusion or clinodactyly [
• Hypodontia. Lack of second and/or third molars in all four quadrants [
• Visual impairment. Myopia [
• Hearing abnormalities including profound bilateral hearing loss in two affected individuals [
• Polythelia (supernumerary nipples) [
• Parasomnia [
• Craniosynostosis involving either the metopic or sagittal suture reported in four affected individuals [
• Short stature (≤3 SD below the mean) reported in two affected individuals [
• Individuals harboring basic domain alleles tend to have the classic form of Char syndrome (97% with facial features, 58% with PDA, and 79% with hand anomalies) [
• For individuals in the one family inheriting the transactivation domain-altering variant, the facial features were prevalent (14/14) but mild, PDA was generally present (10/14), but hand anomalies were not observed in any [
• The phenotypes associated with loss-of-function pathogenic variants often included PDA (32/40; 80%) but facial features of Char syndrome were less prevalent (23/39; 59%); features in these individuals not observed in those with missense variants included craniosynostosis (n = 3) and short stature (n = 2) [
## Clinical Description
Char syndrome is characterized by the triad of typical facial features (see
Features of Char Syndrome
Other heart defects (e.g., muscular ventricular septal defects, complex congenital defects)
Other hand abnormalities including interstitial polydactyly [
Foot anomalies including interphalangeal joint fusion or clinodactyly [
Hypodontia. Lack of second and/or third molars in all four quadrants [
Visual impairment. Myopia [
Hearing abnormalities including profound bilateral hearing loss in two affected individuals [
Polythelia (supernumerary nipples) [
Parasomnia [
Craniosynostosis involving either the metopic or sagittal suture reported in four affected individuals [
Short stature (≤3 SD below the mean) reported in two affected individuals [
• Other heart defects (e.g., muscular ventricular septal defects, complex congenital defects)
• Other hand abnormalities including interstitial polydactyly [
• Foot anomalies including interphalangeal joint fusion or clinodactyly [
• Hypodontia. Lack of second and/or third molars in all four quadrants [
• Visual impairment. Myopia [
• Hearing abnormalities including profound bilateral hearing loss in two affected individuals [
• Polythelia (supernumerary nipples) [
• Parasomnia [
• Craniosynostosis involving either the metopic or sagittal suture reported in four affected individuals [
• Short stature (≤3 SD below the mean) reported in two affected individuals [
## Genotype-Phenotype Correlations
Among the 16 different pathogenic variants in
Individuals harboring basic domain alleles tend to have the classic form of Char syndrome (97% with facial features, 58% with PDA, and 79% with hand anomalies) [
For individuals in the one family inheriting the transactivation domain-altering variant, the facial features were prevalent (14/14) but mild, PDA was generally present (10/14), but hand anomalies were not observed in any [
The phenotypes associated with loss-of-function pathogenic variants often included PDA (32/40; 80%) but facial features of Char syndrome were less prevalent (23/39; 59%); features in these individuals not observed in those with missense variants included craniosynostosis (n = 3) and short stature (n = 2) [
• Individuals harboring basic domain alleles tend to have the classic form of Char syndrome (97% with facial features, 58% with PDA, and 79% with hand anomalies) [
• For individuals in the one family inheriting the transactivation domain-altering variant, the facial features were prevalent (14/14) but mild, PDA was generally present (10/14), but hand anomalies were not observed in any [
• The phenotypes associated with loss-of-function pathogenic variants often included PDA (32/40; 80%) but facial features of Char syndrome were less prevalent (23/39; 59%); features in these individuals not observed in those with missense variants included craniosynostosis (n = 3) and short stature (n = 2) [
## Penetrance
The penetrance of Char syndrome has not been formally determined. Two asymptomatic individuals with
## Prevalence
The prevalence of Char syndrome has not been determined but is thought to be quite low.
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Isolated PDA (in the absence of other congenital heart defects) occurs in about one in 2,000 full-term infants. PDA is considerably more common in premature infants. It is one of the cardiac lesions observed in congenital rubella syndrome and may occur in autosomal dominant and recessive disorders that are nonsyndromic [
Note: Screening of a group of individuals with isolated PDA rarely revealed the presence of
Genes Associated with Heart-Hand Syndromes in the Differential Diagnosis of Char Syndrome
CHDs variable; septal defects common
Pulmonic stenosis, CoA, transposition of the great vessels, & PDA or patent foramen ovale reported
Present in 15% of affected persons
CHDs include pulmonary valve stenosis/ atresia, ASD, VSD, CoA, tetralogy of Fallot, & tricuspid atresia
CHDs are the major cause of early death.
Phalanges & carpal bones may be fused.
Partial cutaneous syndactyly or ectrodactyly (i.e., split hand) may be seen.
AD = autosomal dominant; AR = autosomal recessive; ASD = atrial septal defect; CHD = congenital heart disease; CoA = coarctation of the aorta; ID = intellectual disability; MOI = mode of inheritance; PDA = patent ductus arteriosus; VSD = ventricular septal defect; XL = X-linked
Heart-hand disorders of unknown genetic etiology to consider:
PDA and bicuspid aortic valve with hand anomalies (fifth metacarpal hypoplasia and brachydactyly), but normal facies (OMIM
Tabatznik syndrome [
Heart-hand syndrome type III (OMIM
• CHDs variable; septal defects common
• Pulmonic stenosis, CoA, transposition of the great vessels, & PDA or patent foramen ovale reported
• Present in 15% of affected persons
• CHDs include pulmonary valve stenosis/ atresia, ASD, VSD, CoA, tetralogy of Fallot, & tricuspid atresia
• CHDs are the major cause of early death.
• Phalanges & carpal bones may be fused.
• Partial cutaneous syndactyly or ectrodactyly (i.e., split hand) may be seen.
• PDA and bicuspid aortic valve with hand anomalies (fifth metacarpal hypoplasia and brachydactyly), but normal facies (OMIM
• Tabatznik syndrome [
• Heart-hand syndrome type III (OMIM
## Management
To establish the extent of disease and needs in an individual diagnosed with Char syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Char Syndrome
PDA = patent ductus arteriosus
Evaluation in the newborn nursery may not be completely informative, as the ductus arteriosus may remain open for several days in any neonate.
The most striking external aspects of Char syndrome, namely the dysmorphia and hand anomalies, require no special care early in life. The dysmorphic features do become important as affected individuals go through childhood and adolescence because of their stigmatizing effects. No data on the success of plastic surgical intervention for the facial features in Char syndrome are available.
Treatment of Manifestations in Individuals with Char Syndrome
PDA = patent ductus arteriosus
Children with Char syndrome need pediatric attention during infancy and childhood.
Recommended Surveillance for Individuals with Char Syndrome
See
Search
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Char syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Char Syndrome
PDA = patent ductus arteriosus
Evaluation in the newborn nursery may not be completely informative, as the ductus arteriosus may remain open for several days in any neonate.
## Treatment of Manifestations
The most striking external aspects of Char syndrome, namely the dysmorphia and hand anomalies, require no special care early in life. The dysmorphic features do become important as affected individuals go through childhood and adolescence because of their stigmatizing effects. No data on the success of plastic surgical intervention for the facial features in Char syndrome are available.
Treatment of Manifestations in Individuals with Char Syndrome
PDA = patent ductus arteriosus
## Surveillance
Children with Char syndrome need pediatric attention during infancy and childhood.
Recommended Surveillance for Individuals with Char Syndrome
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Char syndrome is inherited in an autosomal dominant manner.
Some individuals diagnosed with Char syndrome have an affected parent.
A proband with Char syndrome may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent negative family history include molecular genetic testing (if a
If the proband has a known
* Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history of some individuals diagnosed with Char syndrome may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation and/or molecular genetic testing (if the causative variant in the proband is known) to establish that neither parent is heterozygous for the causative pathogenic variant.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known
If the parents are clinically unaffected but have not undergone molecular genetic testing (and/or a pathogenic variant has not been identified in the proband), the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for Char syndrome because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
The prenatal finding of complex congenital heart disease could alter the management of the infant at birth as well as suggest a need to change the delivery site to a center able to provide urgent interventions for complex heart defects.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Some individuals diagnosed with Char syndrome have an affected parent.
• A proband with Char syndrome may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent negative family history include molecular genetic testing (if a
• If the proband has a known
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history of some individuals diagnosed with Char syndrome may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation and/or molecular genetic testing (if the causative variant in the proband is known) to establish that neither parent is heterozygous for the causative pathogenic variant.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known
• If the parents are clinically unaffected but have not undergone molecular genetic testing (and/or a pathogenic variant has not been identified in the proband), the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for Char syndrome because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Char syndrome is inherited in an autosomal dominant manner.
## Risk to Family Members
Some individuals diagnosed with Char syndrome have an affected parent.
A proband with Char syndrome may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent negative family history include molecular genetic testing (if a
If the proband has a known
* Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history of some individuals diagnosed with Char syndrome may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation and/or molecular genetic testing (if the causative variant in the proband is known) to establish that neither parent is heterozygous for the causative pathogenic variant.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known
If the parents are clinically unaffected but have not undergone molecular genetic testing (and/or a pathogenic variant has not been identified in the proband), the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for Char syndrome because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
• Some individuals diagnosed with Char syndrome have an affected parent.
• A proband with Char syndrome may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent negative family history include molecular genetic testing (if a
• If the proband has a known
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history of some individuals diagnosed with Char syndrome may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation and/or molecular genetic testing (if the causative variant in the proband is known) to establish that neither parent is heterozygous for the causative pathogenic variant.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known
• If the parents are clinically unaffected but have not undergone molecular genetic testing (and/or a pathogenic variant has not been identified in the proband), the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for Char syndrome because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
The prenatal finding of complex congenital heart disease could alter the management of the infant at birth as well as suggest a need to change the delivery site to a center able to provide urgent interventions for complex heart defects.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
Char Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Char Syndrome (
## Molecular Pathogenesis
## Chapter Notes
This work was supported in part by a grant from the National Institutes of Health (HL098123) to BDG.
21 May 2020 (ma) Comprehensive update posted live
24 January 2013 (me) Comprehensive update posted live
19 March 2008 (me) Comprehensive update posted live
17 June 2005 (me) Comprehensive update posted live
15 August 2003 (ca) Review posted live
18 April 2003 (bg) Original submission
• 21 May 2020 (ma) Comprehensive update posted live
• 24 January 2013 (me) Comprehensive update posted live
• 19 March 2008 (me) Comprehensive update posted live
• 17 June 2005 (me) Comprehensive update posted live
• 15 August 2003 (ca) Review posted live
• 18 April 2003 (bg) Original submission
## Acknowledgments
This work was supported in part by a grant from the National Institutes of Health (HL098123) to BDG.
## Revision History
21 May 2020 (ma) Comprehensive update posted live
24 January 2013 (me) Comprehensive update posted live
19 March 2008 (me) Comprehensive update posted live
17 June 2005 (me) Comprehensive update posted live
15 August 2003 (ca) Review posted live
18 April 2003 (bg) Original submission
• 21 May 2020 (ma) Comprehensive update posted live
• 24 January 2013 (me) Comprehensive update posted live
• 19 March 2008 (me) Comprehensive update posted live
• 17 June 2005 (me) Comprehensive update posted live
• 15 August 2003 (ca) Review posted live
• 18 April 2003 (bg) Original submission
## References
## Literature Cited
Typical facial features in a woman with Char syndrome
Reprinted with permission from
|
[] |
15/8/2003
|
21/5/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
charge
|
charge
|
[
"CHD7-Related CHARGE Syndrome",
"Chromodomain-helicase-DNA-binding protein 7",
"CHD7",
"CHD7 Disorder"
] |
Conny M van Ravenswaaij-Arts, Meg Hefner, Kim Blake, Donna M Martin
|
Summary The diagnosis of
|
With the current widespread use of multigene panels and comprehensive genomic testing, it has become apparent that the phenotypic spectrum of heterozygous
## Diagnosis
Coloboma of the iris, retina, choroid, and/or disc, and/or anophthalmos or microphthalmos
Choanal atresia or stenosis: unilateral or bilateral, bony or membranous, confirmed by axial sections of non-enhanced axial CT scan
Cleft palate with or without cleft lip (Note: Choanal atresia is rare in the presence of a cleft palate.)
Cranial nerve dysfunction or anomaly
Cranial nerve I. Hyposmia or anosmia
Cranial nerve VII. Facial palsy (unilateral or bilateral)
Cranial nerve VIII. Sensorineural hearing loss and/or balance problems, hypoplasia or aplasia on imaging
Cranial nerve IX/X. Difficulty with sucking/swallowing and aspiration, gut motility problems
Ear malformations (most characteristic of
Auricle. Short, wide ear with little or no lobe, "snipped-off" helix, prominent antihelix that is often discontinuous with tragus, triangular concha, decreased cartilage; often protruding and usually asymmetric (See
Middle ear. Ossicular malformations (resulting in a typical wedge-shaped audiogram due to mixed sensorineural and conductive hearing loss)
Temporal bone abnormalities (most commonly determined by temporal bone CT scan). Mondini defect of the cochlea (cochlear hypoplasia), absent or hypoplastic semicircular canals
Tracheoesophageal fistula or esophageal atresia
Cardiovascular malformation, including conotruncal defects (e.g., tetralogy of Fallot), AV canal defects, and aortic arch anomalies [
Hypogonadotropic hypogonadism
Males at birth. Micropenis and cryptorchidism
Females at birth. Hypoplastic labia, abnormal or (rarely) absent uterus
Males and females. Delayed or absent puberty, often in combination with anosmia [
Developmental delay / intellectual disability, delayed motor milestones, often secondary to sensory and balance deficits
Growth deficiency. Short stature, usually postnatal with or without growth hormone deficiency
Other clinical features
Face. Square-shaped with broad forehead, broad nasal bridge, prominent nasal columella, flattened malar area, facial palsy or other asymmetry, cleft lip, and small chin (gets larger and broader with age) (See
Neck. Short and wide with sloping shoulders [
Hands. Typically, short, wide palm with hockey-stick crease, short fingers, and finger-like thumb (see
Brain MRI. Clivus hypoplasia [
The diagnosis of
Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determines which gene(s) are likely involved, whereas genomic testing does not. Individuals with
For an introduction to multigene panels click
Because
Alternatively, if exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Percentages based on information from the locus-specific database
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Most deletions detected to date are whole-gene deletions that can be detected with gene-targeted deletion/duplication analysis; however, this method will not provide the size of a larger deletion that may include
• Coloboma of the iris, retina, choroid, and/or disc, and/or anophthalmos or microphthalmos
• Choanal atresia or stenosis: unilateral or bilateral, bony or membranous, confirmed by axial sections of non-enhanced axial CT scan
• Cleft palate with or without cleft lip (Note: Choanal atresia is rare in the presence of a cleft palate.)
• Cranial nerve dysfunction or anomaly
• Cranial nerve I. Hyposmia or anosmia
• Cranial nerve VII. Facial palsy (unilateral or bilateral)
• Cranial nerve VIII. Sensorineural hearing loss and/or balance problems, hypoplasia or aplasia on imaging
• Cranial nerve IX/X. Difficulty with sucking/swallowing and aspiration, gut motility problems
• Cranial nerve I. Hyposmia or anosmia
• Cranial nerve VII. Facial palsy (unilateral or bilateral)
• Cranial nerve VIII. Sensorineural hearing loss and/or balance problems, hypoplasia or aplasia on imaging
• Cranial nerve IX/X. Difficulty with sucking/swallowing and aspiration, gut motility problems
• Ear malformations (most characteristic of
• Auricle. Short, wide ear with little or no lobe, "snipped-off" helix, prominent antihelix that is often discontinuous with tragus, triangular concha, decreased cartilage; often protruding and usually asymmetric (See
• Middle ear. Ossicular malformations (resulting in a typical wedge-shaped audiogram due to mixed sensorineural and conductive hearing loss)
• Temporal bone abnormalities (most commonly determined by temporal bone CT scan). Mondini defect of the cochlea (cochlear hypoplasia), absent or hypoplastic semicircular canals
• Auricle. Short, wide ear with little or no lobe, "snipped-off" helix, prominent antihelix that is often discontinuous with tragus, triangular concha, decreased cartilage; often protruding and usually asymmetric (See
• Middle ear. Ossicular malformations (resulting in a typical wedge-shaped audiogram due to mixed sensorineural and conductive hearing loss)
• Temporal bone abnormalities (most commonly determined by temporal bone CT scan). Mondini defect of the cochlea (cochlear hypoplasia), absent or hypoplastic semicircular canals
• Tracheoesophageal fistula or esophageal atresia
• Cardiovascular malformation, including conotruncal defects (e.g., tetralogy of Fallot), AV canal defects, and aortic arch anomalies [
• Hypogonadotropic hypogonadism
• Males at birth. Micropenis and cryptorchidism
• Females at birth. Hypoplastic labia, abnormal or (rarely) absent uterus
• Males and females. Delayed or absent puberty, often in combination with anosmia [
• Males at birth. Micropenis and cryptorchidism
• Females at birth. Hypoplastic labia, abnormal or (rarely) absent uterus
• Males and females. Delayed or absent puberty, often in combination with anosmia [
• Developmental delay / intellectual disability, delayed motor milestones, often secondary to sensory and balance deficits
• Growth deficiency. Short stature, usually postnatal with or without growth hormone deficiency
• Other clinical features
• Face. Square-shaped with broad forehead, broad nasal bridge, prominent nasal columella, flattened malar area, facial palsy or other asymmetry, cleft lip, and small chin (gets larger and broader with age) (See
• Neck. Short and wide with sloping shoulders [
• Hands. Typically, short, wide palm with hockey-stick crease, short fingers, and finger-like thumb (see
• Face. Square-shaped with broad forehead, broad nasal bridge, prominent nasal columella, flattened malar area, facial palsy or other asymmetry, cleft lip, and small chin (gets larger and broader with age) (See
• Neck. Short and wide with sloping shoulders [
• Hands. Typically, short, wide palm with hockey-stick crease, short fingers, and finger-like thumb (see
• Brain MRI. Clivus hypoplasia [
• Cranial nerve I. Hyposmia or anosmia
• Cranial nerve VII. Facial palsy (unilateral or bilateral)
• Cranial nerve VIII. Sensorineural hearing loss and/or balance problems, hypoplasia or aplasia on imaging
• Cranial nerve IX/X. Difficulty with sucking/swallowing and aspiration, gut motility problems
• Auricle. Short, wide ear with little or no lobe, "snipped-off" helix, prominent antihelix that is often discontinuous with tragus, triangular concha, decreased cartilage; often protruding and usually asymmetric (See
• Middle ear. Ossicular malformations (resulting in a typical wedge-shaped audiogram due to mixed sensorineural and conductive hearing loss)
• Temporal bone abnormalities (most commonly determined by temporal bone CT scan). Mondini defect of the cochlea (cochlear hypoplasia), absent or hypoplastic semicircular canals
• Males at birth. Micropenis and cryptorchidism
• Females at birth. Hypoplastic labia, abnormal or (rarely) absent uterus
• Males and females. Delayed or absent puberty, often in combination with anosmia [
• Face. Square-shaped with broad forehead, broad nasal bridge, prominent nasal columella, flattened malar area, facial palsy or other asymmetry, cleft lip, and small chin (gets larger and broader with age) (See
• Neck. Short and wide with sloping shoulders [
• Hands. Typically, short, wide palm with hockey-stick crease, short fingers, and finger-like thumb (see
## Suggestive Findings
Coloboma of the iris, retina, choroid, and/or disc, and/or anophthalmos or microphthalmos
Choanal atresia or stenosis: unilateral or bilateral, bony or membranous, confirmed by axial sections of non-enhanced axial CT scan
Cleft palate with or without cleft lip (Note: Choanal atresia is rare in the presence of a cleft palate.)
Cranial nerve dysfunction or anomaly
Cranial nerve I. Hyposmia or anosmia
Cranial nerve VII. Facial palsy (unilateral or bilateral)
Cranial nerve VIII. Sensorineural hearing loss and/or balance problems, hypoplasia or aplasia on imaging
Cranial nerve IX/X. Difficulty with sucking/swallowing and aspiration, gut motility problems
Ear malformations (most characteristic of
Auricle. Short, wide ear with little or no lobe, "snipped-off" helix, prominent antihelix that is often discontinuous with tragus, triangular concha, decreased cartilage; often protruding and usually asymmetric (See
Middle ear. Ossicular malformations (resulting in a typical wedge-shaped audiogram due to mixed sensorineural and conductive hearing loss)
Temporal bone abnormalities (most commonly determined by temporal bone CT scan). Mondini defect of the cochlea (cochlear hypoplasia), absent or hypoplastic semicircular canals
Tracheoesophageal fistula or esophageal atresia
Cardiovascular malformation, including conotruncal defects (e.g., tetralogy of Fallot), AV canal defects, and aortic arch anomalies [
Hypogonadotropic hypogonadism
Males at birth. Micropenis and cryptorchidism
Females at birth. Hypoplastic labia, abnormal or (rarely) absent uterus
Males and females. Delayed or absent puberty, often in combination with anosmia [
Developmental delay / intellectual disability, delayed motor milestones, often secondary to sensory and balance deficits
Growth deficiency. Short stature, usually postnatal with or without growth hormone deficiency
Other clinical features
Face. Square-shaped with broad forehead, broad nasal bridge, prominent nasal columella, flattened malar area, facial palsy or other asymmetry, cleft lip, and small chin (gets larger and broader with age) (See
Neck. Short and wide with sloping shoulders [
Hands. Typically, short, wide palm with hockey-stick crease, short fingers, and finger-like thumb (see
Brain MRI. Clivus hypoplasia [
• Coloboma of the iris, retina, choroid, and/or disc, and/or anophthalmos or microphthalmos
• Choanal atresia or stenosis: unilateral or bilateral, bony or membranous, confirmed by axial sections of non-enhanced axial CT scan
• Cleft palate with or without cleft lip (Note: Choanal atresia is rare in the presence of a cleft palate.)
• Cranial nerve dysfunction or anomaly
• Cranial nerve I. Hyposmia or anosmia
• Cranial nerve VII. Facial palsy (unilateral or bilateral)
• Cranial nerve VIII. Sensorineural hearing loss and/or balance problems, hypoplasia or aplasia on imaging
• Cranial nerve IX/X. Difficulty with sucking/swallowing and aspiration, gut motility problems
• Cranial nerve I. Hyposmia or anosmia
• Cranial nerve VII. Facial palsy (unilateral or bilateral)
• Cranial nerve VIII. Sensorineural hearing loss and/or balance problems, hypoplasia or aplasia on imaging
• Cranial nerve IX/X. Difficulty with sucking/swallowing and aspiration, gut motility problems
• Ear malformations (most characteristic of
• Auricle. Short, wide ear with little or no lobe, "snipped-off" helix, prominent antihelix that is often discontinuous with tragus, triangular concha, decreased cartilage; often protruding and usually asymmetric (See
• Middle ear. Ossicular malformations (resulting in a typical wedge-shaped audiogram due to mixed sensorineural and conductive hearing loss)
• Temporal bone abnormalities (most commonly determined by temporal bone CT scan). Mondini defect of the cochlea (cochlear hypoplasia), absent or hypoplastic semicircular canals
• Auricle. Short, wide ear with little or no lobe, "snipped-off" helix, prominent antihelix that is often discontinuous with tragus, triangular concha, decreased cartilage; often protruding and usually asymmetric (See
• Middle ear. Ossicular malformations (resulting in a typical wedge-shaped audiogram due to mixed sensorineural and conductive hearing loss)
• Temporal bone abnormalities (most commonly determined by temporal bone CT scan). Mondini defect of the cochlea (cochlear hypoplasia), absent or hypoplastic semicircular canals
• Tracheoesophageal fistula or esophageal atresia
• Cardiovascular malformation, including conotruncal defects (e.g., tetralogy of Fallot), AV canal defects, and aortic arch anomalies [
• Hypogonadotropic hypogonadism
• Males at birth. Micropenis and cryptorchidism
• Females at birth. Hypoplastic labia, abnormal or (rarely) absent uterus
• Males and females. Delayed or absent puberty, often in combination with anosmia [
• Males at birth. Micropenis and cryptorchidism
• Females at birth. Hypoplastic labia, abnormal or (rarely) absent uterus
• Males and females. Delayed or absent puberty, often in combination with anosmia [
• Developmental delay / intellectual disability, delayed motor milestones, often secondary to sensory and balance deficits
• Growth deficiency. Short stature, usually postnatal with or without growth hormone deficiency
• Other clinical features
• Face. Square-shaped with broad forehead, broad nasal bridge, prominent nasal columella, flattened malar area, facial palsy or other asymmetry, cleft lip, and small chin (gets larger and broader with age) (See
• Neck. Short and wide with sloping shoulders [
• Hands. Typically, short, wide palm with hockey-stick crease, short fingers, and finger-like thumb (see
• Face. Square-shaped with broad forehead, broad nasal bridge, prominent nasal columella, flattened malar area, facial palsy or other asymmetry, cleft lip, and small chin (gets larger and broader with age) (See
• Neck. Short and wide with sloping shoulders [
• Hands. Typically, short, wide palm with hockey-stick crease, short fingers, and finger-like thumb (see
• Brain MRI. Clivus hypoplasia [
• Cranial nerve I. Hyposmia or anosmia
• Cranial nerve VII. Facial palsy (unilateral or bilateral)
• Cranial nerve VIII. Sensorineural hearing loss and/or balance problems, hypoplasia or aplasia on imaging
• Cranial nerve IX/X. Difficulty with sucking/swallowing and aspiration, gut motility problems
• Auricle. Short, wide ear with little or no lobe, "snipped-off" helix, prominent antihelix that is often discontinuous with tragus, triangular concha, decreased cartilage; often protruding and usually asymmetric (See
• Middle ear. Ossicular malformations (resulting in a typical wedge-shaped audiogram due to mixed sensorineural and conductive hearing loss)
• Temporal bone abnormalities (most commonly determined by temporal bone CT scan). Mondini defect of the cochlea (cochlear hypoplasia), absent or hypoplastic semicircular canals
• Males at birth. Micropenis and cryptorchidism
• Females at birth. Hypoplastic labia, abnormal or (rarely) absent uterus
• Males and females. Delayed or absent puberty, often in combination with anosmia [
• Face. Square-shaped with broad forehead, broad nasal bridge, prominent nasal columella, flattened malar area, facial palsy or other asymmetry, cleft lip, and small chin (gets larger and broader with age) (See
• Neck. Short and wide with sloping shoulders [
• Hands. Typically, short, wide palm with hockey-stick crease, short fingers, and finger-like thumb (see
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determines which gene(s) are likely involved, whereas genomic testing does not. Individuals with
For an introduction to multigene panels click
Because
Alternatively, if exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Percentages based on information from the locus-specific database
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Most deletions detected to date are whole-gene deletions that can be detected with gene-targeted deletion/duplication analysis; however, this method will not provide the size of a larger deletion that may include
## Option 1
For an introduction to multigene panels click
## Option 2
Because
Alternatively, if exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Percentages based on information from the locus-specific database
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Most deletions detected to date are whole-gene deletions that can be detected with gene-targeted deletion/duplication analysis; however, this method will not provide the size of a larger deletion that may include
## Clinical Characteristics
In the premolecular era, the acronym CHARGE was proposed for the combination of the clinical features
This section discusses only those reports in which a
Features of
Interferes w/breathing & feeding
May require several surgeries to remain patent
Unilateral stenosis may be easily missed.
Asymmetric face or lack of facial expression
Facial nerve often has an aberrant course, which correlates w/SNHL & can be damaged during cochlear implant surgery.
Hearing loss
Cochlear implant may not be successful.
Lack of coordination of suck & swallow, aspiration, &/or gastroesophageal reflux
Oral defensiveness
Digestive & constipation issues
See description in
SNHL, esp high frequency
Conductive hearing loss, which may fluctuate w/middle ear disease
Complex mixed hearing loss may present as a wedge-shaped audiogram.
Micropenis, cryptorchidism
Small labia, uterine abnormality
Delayed or absent puberty & infertility
Often in combination w/anosmia
Conotruncal/outflow defects are particularly common; isolated ASD, VSD, PDA, PFO also occur.
Vascular sling/aberrant aortic artery may result in choking.
Missing, hypoplastic, horseshoe, ectopic, or cystic kidney
Vesicoureteral reflux & hydronephrosis
ASD = atrial septal defect; DD = developmental delay; PDA = patent ductus arteriosus; PFO = patent foramen ovale; SNHL = sensorineural hearing loss; VSD = ventricular septal defect
Based on individuals with molecularly confirmed typical or partial CHARGE syndrome [
Because the majority of individuals with a pathogenic
Motor delay is invariably present due to vestibular anomalies and presents as poor head control, five-point crawl, delayed motor milestones, and reduced fine motor skills.
Language delay is caused by hearing loss, vision loss, vestibular anomalies, hospitalizations and illness, and/or cognitive impairment.
Assessment of cognitive abilities is difficult because of the multiple sensory deficits (vision, hearing, balance, smell), and much of the delay observed in motor and speech/language abilities is secondary to these deficits. Nonetheless, intellectual outcome is within the normal range in 50% of the individuals with clinical features consistent with CHARGE syndrome [
Children with better walking skills and fewer medical problems exhibit better adaptive behavior than children with less mobility and more medical problems [
Behavioral features often reported are attention-deficit/hyperactivity disorder, repetitive behavior, and obsessive-compulsive behaviors. Self-abuse is occasionally seen. An increased pain threshold may predispose children to behaviors that are incorrectly interpreted by others as aggressive [
Many adults with clinical features consistent with CHARGE syndrome live independently, including many who have college or even advanced degrees. However, the level of independence comprises a broad spectrum [
Late-onset issues can include malrotation of intestines, intussusception, and choking due to mouth overstuffing [
Hypermobility and contractures can be part of the syndrome.
Multiple complex surgeries, along with the breathing problems or difficulty with anesthesia reported in CHARGE syndrome [
After the first two or three years, mortality (and certainly morbidity and medical fragility) remains increased, with parents reporting frequent illnesses, infections, and hospitalizations [
In childhood, adolescence, and adulthood, increased mortality is likely related to a combination of residual heart defects, infections, aspiration or choking [
A number of families have reported serious (and in some instances lethal) intestinal issues such as volvulus [
Despite these complications, the life span for many individuals can be normal. Individuals with clinical features consistent with CHARGE syndrome in their 60s who are in good health have been observed.
While no clear genotype-phenotype correlations exist for
Because of the more widespread use of genomic testing, it is currently difficult to assess the prevalence of
In the past, when the diagnosis of CHARGE syndrome was based on clinical features or gene-specific molecular testing, its estimated prevalence ranged from one in 15,000 newborns in the Netherlands [
• Interferes w/breathing & feeding
• May require several surgeries to remain patent
• Unilateral stenosis may be easily missed.
• Asymmetric face or lack of facial expression
• Facial nerve often has an aberrant course, which correlates w/SNHL & can be damaged during cochlear implant surgery.
• Hearing loss
• Cochlear implant may not be successful.
• Lack of coordination of suck & swallow, aspiration, &/or gastroesophageal reflux
• Oral defensiveness
• Digestive & constipation issues
• See description in
• SNHL, esp high frequency
• Conductive hearing loss, which may fluctuate w/middle ear disease
• Complex mixed hearing loss may present as a wedge-shaped audiogram.
• Micropenis, cryptorchidism
• Small labia, uterine abnormality
• Delayed or absent puberty & infertility
• Often in combination w/anosmia
• Conotruncal/outflow defects are particularly common; isolated ASD, VSD, PDA, PFO also occur.
• Vascular sling/aberrant aortic artery may result in choking.
• Missing, hypoplastic, horseshoe, ectopic, or cystic kidney
• Vesicoureteral reflux & hydronephrosis
## Clinical Description
In the premolecular era, the acronym CHARGE was proposed for the combination of the clinical features
This section discusses only those reports in which a
Features of
Interferes w/breathing & feeding
May require several surgeries to remain patent
Unilateral stenosis may be easily missed.
Asymmetric face or lack of facial expression
Facial nerve often has an aberrant course, which correlates w/SNHL & can be damaged during cochlear implant surgery.
Hearing loss
Cochlear implant may not be successful.
Lack of coordination of suck & swallow, aspiration, &/or gastroesophageal reflux
Oral defensiveness
Digestive & constipation issues
See description in
SNHL, esp high frequency
Conductive hearing loss, which may fluctuate w/middle ear disease
Complex mixed hearing loss may present as a wedge-shaped audiogram.
Micropenis, cryptorchidism
Small labia, uterine abnormality
Delayed or absent puberty & infertility
Often in combination w/anosmia
Conotruncal/outflow defects are particularly common; isolated ASD, VSD, PDA, PFO also occur.
Vascular sling/aberrant aortic artery may result in choking.
Missing, hypoplastic, horseshoe, ectopic, or cystic kidney
Vesicoureteral reflux & hydronephrosis
ASD = atrial septal defect; DD = developmental delay; PDA = patent ductus arteriosus; PFO = patent foramen ovale; SNHL = sensorineural hearing loss; VSD = ventricular septal defect
Based on individuals with molecularly confirmed typical or partial CHARGE syndrome [
Because the majority of individuals with a pathogenic
Motor delay is invariably present due to vestibular anomalies and presents as poor head control, five-point crawl, delayed motor milestones, and reduced fine motor skills.
Language delay is caused by hearing loss, vision loss, vestibular anomalies, hospitalizations and illness, and/or cognitive impairment.
Assessment of cognitive abilities is difficult because of the multiple sensory deficits (vision, hearing, balance, smell), and much of the delay observed in motor and speech/language abilities is secondary to these deficits. Nonetheless, intellectual outcome is within the normal range in 50% of the individuals with clinical features consistent with CHARGE syndrome [
Children with better walking skills and fewer medical problems exhibit better adaptive behavior than children with less mobility and more medical problems [
Behavioral features often reported are attention-deficit/hyperactivity disorder, repetitive behavior, and obsessive-compulsive behaviors. Self-abuse is occasionally seen. An increased pain threshold may predispose children to behaviors that are incorrectly interpreted by others as aggressive [
Many adults with clinical features consistent with CHARGE syndrome live independently, including many who have college or even advanced degrees. However, the level of independence comprises a broad spectrum [
Late-onset issues can include malrotation of intestines, intussusception, and choking due to mouth overstuffing [
Hypermobility and contractures can be part of the syndrome.
Multiple complex surgeries, along with the breathing problems or difficulty with anesthesia reported in CHARGE syndrome [
After the first two or three years, mortality (and certainly morbidity and medical fragility) remains increased, with parents reporting frequent illnesses, infections, and hospitalizations [
In childhood, adolescence, and adulthood, increased mortality is likely related to a combination of residual heart defects, infections, aspiration or choking [
A number of families have reported serious (and in some instances lethal) intestinal issues such as volvulus [
Despite these complications, the life span for many individuals can be normal. Individuals with clinical features consistent with CHARGE syndrome in their 60s who are in good health have been observed.
• Interferes w/breathing & feeding
• May require several surgeries to remain patent
• Unilateral stenosis may be easily missed.
• Asymmetric face or lack of facial expression
• Facial nerve often has an aberrant course, which correlates w/SNHL & can be damaged during cochlear implant surgery.
• Hearing loss
• Cochlear implant may not be successful.
• Lack of coordination of suck & swallow, aspiration, &/or gastroesophageal reflux
• Oral defensiveness
• Digestive & constipation issues
• See description in
• SNHL, esp high frequency
• Conductive hearing loss, which may fluctuate w/middle ear disease
• Complex mixed hearing loss may present as a wedge-shaped audiogram.
• Micropenis, cryptorchidism
• Small labia, uterine abnormality
• Delayed or absent puberty & infertility
• Often in combination w/anosmia
• Conotruncal/outflow defects are particularly common; isolated ASD, VSD, PDA, PFO also occur.
• Vascular sling/aberrant aortic artery may result in choking.
• Missing, hypoplastic, horseshoe, ectopic, or cystic kidney
• Vesicoureteral reflux & hydronephrosis
## Development
Motor delay is invariably present due to vestibular anomalies and presents as poor head control, five-point crawl, delayed motor milestones, and reduced fine motor skills.
Language delay is caused by hearing loss, vision loss, vestibular anomalies, hospitalizations and illness, and/or cognitive impairment.
Assessment of cognitive abilities is difficult because of the multiple sensory deficits (vision, hearing, balance, smell), and much of the delay observed in motor and speech/language abilities is secondary to these deficits. Nonetheless, intellectual outcome is within the normal range in 50% of the individuals with clinical features consistent with CHARGE syndrome [
Children with better walking skills and fewer medical problems exhibit better adaptive behavior than children with less mobility and more medical problems [
Behavioral features often reported are attention-deficit/hyperactivity disorder, repetitive behavior, and obsessive-compulsive behaviors. Self-abuse is occasionally seen. An increased pain threshold may predispose children to behaviors that are incorrectly interpreted by others as aggressive [
Many adults with clinical features consistent with CHARGE syndrome live independently, including many who have college or even advanced degrees. However, the level of independence comprises a broad spectrum [
## Other Features
Late-onset issues can include malrotation of intestines, intussusception, and choking due to mouth overstuffing [
Hypermobility and contractures can be part of the syndrome.
Multiple complex surgeries, along with the breathing problems or difficulty with anesthesia reported in CHARGE syndrome [
After the first two or three years, mortality (and certainly morbidity and medical fragility) remains increased, with parents reporting frequent illnesses, infections, and hospitalizations [
In childhood, adolescence, and adulthood, increased mortality is likely related to a combination of residual heart defects, infections, aspiration or choking [
A number of families have reported serious (and in some instances lethal) intestinal issues such as volvulus [
Despite these complications, the life span for many individuals can be normal. Individuals with clinical features consistent with CHARGE syndrome in their 60s who are in good health have been observed.
## Genotype-Phenotype Correlations
While no clear genotype-phenotype correlations exist for
## Prevalence
Because of the more widespread use of genomic testing, it is currently difficult to assess the prevalence of
In the past, when the diagnosis of CHARGE syndrome was based on clinical features or gene-specific molecular testing, its estimated prevalence ranged from one in 15,000 newborns in the Netherlands [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genetic disorders with multiple features overlapping those associated with
Genes to Consider in the Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
Although
If hyposmia or anosmia is the presenting feature, Kallmann syndrome must be considered, especially Kallmann syndrome caused by pathogenic variants in
Chromosomal Syndromes that Significantly Overlap with
Exposure to antithyroid agents, especially methimazole, has been reported to result in a variety of congenital anomalies including choanal and esophageal atresia, iris and retinal coloboma, hearing loss, and delayed neurodevelopment. The risk of birth defects in fetuses exposed during the first trimester of pregnancy has been estimated at 2%-3% [
## Management
The management of the manifestations of
To establish the extent of disease and needs of an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in an Individual with a
Best corrected visual acuity; assess for refractive error, possible amblyopia
Assess for iris coloboma, photophobia, & possible corneal exposure due to VIIth nerve palsy.
Dilated fundus exam for chorioretinal coloboma, optic nerve coloboma, retinal detachment
Functional visual assessment incl visual fields in older individuals
Suggestive findings in neonates & infants incl apnea & unilateral nasal discharge
Referral to otolaryngologist
Aspiration pneumonia
Coughing or choking w/feeding
Infant has a full, round abdomen
Abnormal shape & # of teeth
Complications due to craniofacial abnormalities &/or bruxism
Cryptorchidism: referral to urologist
Micropenis: see
To assess for uterine & ovarian anomalies
Note that ability of US exam &/or MRI to detect uterine anomalies in prepubertal girls is limited.
Consider spine radiographs as a baseline.
Consider referral to orthopedist.
To incl assessment for swallowing dysfunction (See
If present, consider CT &/or MRI imaging
A team approach is necessary.
Incl motor, speech-language eval, general cognitive abilities, educational needs, &/or vocational opportunities.
Incl appropriate testing to assess cognitive function in those w/sensory deficits.
Abilities may be underestimated, especially in early yrs.
Evaluate for early intervention/special education, referral to deaf-blind programs when appropriate.
Adapt testing environment as needed to ↑ patient comfort.
Screen for ADHD, anxiety, obsessive-compulsive symptomatology.
Males w/micropenis: consider HCG stimulation test, ideally before age 6 mos.
Males & females w/delayed or absent puberty: eval for hypogonadotropic hypogonadism
Measure calcium & vitamin D levels.
Thyroid function tests
Consider referral to endocrinologist.
Community or
Social work involvement for parental support.
ADHD = attention-deficit/hyperactivity disorder; GERD = gastroesophageal reflux disease; GnRH = gonadotropin-releasing hormone; HCG = human chorionic gonadotropin; MOI = mode of inheritance; US = ultrasound; VFSS = video fluoroscopic swallow study
See
To assess for arrhythmias and structural heart defects including vascular anomalies [
Other issues may include malrotation, constipation, chronic abdominal pain, bloating, and late dumping syndrome [
May include measurement of serum concentration of luteinizing hormone, follicle-stimulating hormone, and sex hormones (total testosterone in males, estrogen in females). See also
In adolescents and adults
May include immunoglobulin levels (IgG, IgM, IgA) and T and B cell subsets in case of a history of recurrent infections [
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Management of children with a
Treatment of Manifestations in Individuals with a
Nutrition optimization (team approach)
If poor linear growth remains, consider growth hormone stimulation test &/or growth hormone therapy.
Start hearing habilitation (auditory & speech training, sign language) as soon as possible.
Community hearing services through early intervention or school district
Simple measures (e.g., ↑ fluid uptake) are often unsuccessful.
Referral to gastroenterologist as needed
Behavior therapy combined w/stress reduction may be helpful.
Behavior issues may be exacerbated by sensory processing issues.
ADHD = attention-deficit/hyperactivity disorder; ASM = anti-seizure medication; BAHA = bone-anchored hearing aid; CPAP = continuous positive airway pressure; DD = developmental delay; HRT = hormone replacement treatment; ID = intellectual disability; OCD = obsessive-compulsive disorder; OT = occupational therapist; PDD = pervasive developmental disorders; PET = pressure-equalizing tube; POTS = postural orthostatic tachycardia; PT = physical therapist; SNHL = sensorineural hearing loss; TEF = tracheoesophageal fistula
See
Evaluation of bony landmarks and the structure and pathways of the vestibular and facial nerves (which can be abnormal) is important in surgical planning [
In some individuals, an aberrant course of the facial nerve may be a contraindication for cochlear implant [
CT and MR Scanning in CHARGE Syndrome
Reproduced from
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
State deaf-blind services:
In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues (
State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions.
A growing body of evidence indicates that normal language development can occur if hearing habilitation is started prior to age six months for hearing-impaired children, whether or not they are visually impaired. (See
Depending on the degrees of hearing and vision loss, communication may start with touch cues, followed by object cues and proceeding to auditory/oral and/or sign language. Communication training initiated by age three years is critical to the eventual development of symbolic communication [
Recommended Surveillance for Individuals with
DXA = dual-energy x-ray absorptiometry; EKG = electrocardiogram; POTS = postural orthostatic tachycardia
Including clinical evaluation of tonsil hypertrophy in those with retained tonsils
With low threshold to perform swallowing study, even in adolescents and adults
Particularly those with hypogonadotropic hypogonadism or those undergoing routine hormone replacement therapy
See
Search
• Best corrected visual acuity; assess for refractive error, possible amblyopia
• Assess for iris coloboma, photophobia, & possible corneal exposure due to VIIth nerve palsy.
• Dilated fundus exam for chorioretinal coloboma, optic nerve coloboma, retinal detachment
• Functional visual assessment incl visual fields in older individuals
• Suggestive findings in neonates & infants incl apnea & unilateral nasal discharge
• Referral to otolaryngologist
• Aspiration pneumonia
• Coughing or choking w/feeding
• Infant has a full, round abdomen
• Abnormal shape & # of teeth
• Complications due to craniofacial abnormalities &/or bruxism
• Cryptorchidism: referral to urologist
• Micropenis: see
• To assess for uterine & ovarian anomalies
• Note that ability of US exam &/or MRI to detect uterine anomalies in prepubertal girls is limited.
• Consider spine radiographs as a baseline.
• Consider referral to orthopedist.
• To incl assessment for swallowing dysfunction (See
• If present, consider CT &/or MRI imaging
• A team approach is necessary.
• Incl motor, speech-language eval, general cognitive abilities, educational needs, &/or vocational opportunities.
• Incl appropriate testing to assess cognitive function in those w/sensory deficits.
• Abilities may be underestimated, especially in early yrs.
• Evaluate for early intervention/special education, referral to deaf-blind programs when appropriate.
• Adapt testing environment as needed to ↑ patient comfort.
• Screen for ADHD, anxiety, obsessive-compulsive symptomatology.
• Males w/micropenis: consider HCG stimulation test, ideally before age 6 mos.
• Males & females w/delayed or absent puberty: eval for hypogonadotropic hypogonadism
• Measure calcium & vitamin D levels.
• Thyroid function tests
• Consider referral to endocrinologist.
• Community or
• Social work involvement for parental support.
• Nutrition optimization (team approach)
• If poor linear growth remains, consider growth hormone stimulation test &/or growth hormone therapy.
• Start hearing habilitation (auditory & speech training, sign language) as soon as possible.
• Community hearing services through early intervention or school district
• Simple measures (e.g., ↑ fluid uptake) are often unsuccessful.
• Referral to gastroenterologist as needed
• Behavior therapy combined w/stress reduction may be helpful.
• Behavior issues may be exacerbated by sensory processing issues.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• State deaf-blind services:
• In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues (
• State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions.
• In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues (
• State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues (
• State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in an Individual with a
Best corrected visual acuity; assess for refractive error, possible amblyopia
Assess for iris coloboma, photophobia, & possible corneal exposure due to VIIth nerve palsy.
Dilated fundus exam for chorioretinal coloboma, optic nerve coloboma, retinal detachment
Functional visual assessment incl visual fields in older individuals
Suggestive findings in neonates & infants incl apnea & unilateral nasal discharge
Referral to otolaryngologist
Aspiration pneumonia
Coughing or choking w/feeding
Infant has a full, round abdomen
Abnormal shape & # of teeth
Complications due to craniofacial abnormalities &/or bruxism
Cryptorchidism: referral to urologist
Micropenis: see
To assess for uterine & ovarian anomalies
Note that ability of US exam &/or MRI to detect uterine anomalies in prepubertal girls is limited.
Consider spine radiographs as a baseline.
Consider referral to orthopedist.
To incl assessment for swallowing dysfunction (See
If present, consider CT &/or MRI imaging
A team approach is necessary.
Incl motor, speech-language eval, general cognitive abilities, educational needs, &/or vocational opportunities.
Incl appropriate testing to assess cognitive function in those w/sensory deficits.
Abilities may be underestimated, especially in early yrs.
Evaluate for early intervention/special education, referral to deaf-blind programs when appropriate.
Adapt testing environment as needed to ↑ patient comfort.
Screen for ADHD, anxiety, obsessive-compulsive symptomatology.
Males w/micropenis: consider HCG stimulation test, ideally before age 6 mos.
Males & females w/delayed or absent puberty: eval for hypogonadotropic hypogonadism
Measure calcium & vitamin D levels.
Thyroid function tests
Consider referral to endocrinologist.
Community or
Social work involvement for parental support.
ADHD = attention-deficit/hyperactivity disorder; GERD = gastroesophageal reflux disease; GnRH = gonadotropin-releasing hormone; HCG = human chorionic gonadotropin; MOI = mode of inheritance; US = ultrasound; VFSS = video fluoroscopic swallow study
See
To assess for arrhythmias and structural heart defects including vascular anomalies [
Other issues may include malrotation, constipation, chronic abdominal pain, bloating, and late dumping syndrome [
May include measurement of serum concentration of luteinizing hormone, follicle-stimulating hormone, and sex hormones (total testosterone in males, estrogen in females). See also
In adolescents and adults
May include immunoglobulin levels (IgG, IgM, IgA) and T and B cell subsets in case of a history of recurrent infections [
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Best corrected visual acuity; assess for refractive error, possible amblyopia
• Assess for iris coloboma, photophobia, & possible corneal exposure due to VIIth nerve palsy.
• Dilated fundus exam for chorioretinal coloboma, optic nerve coloboma, retinal detachment
• Functional visual assessment incl visual fields in older individuals
• Suggestive findings in neonates & infants incl apnea & unilateral nasal discharge
• Referral to otolaryngologist
• Aspiration pneumonia
• Coughing or choking w/feeding
• Infant has a full, round abdomen
• Abnormal shape & # of teeth
• Complications due to craniofacial abnormalities &/or bruxism
• Cryptorchidism: referral to urologist
• Micropenis: see
• To assess for uterine & ovarian anomalies
• Note that ability of US exam &/or MRI to detect uterine anomalies in prepubertal girls is limited.
• Consider spine radiographs as a baseline.
• Consider referral to orthopedist.
• To incl assessment for swallowing dysfunction (See
• If present, consider CT &/or MRI imaging
• A team approach is necessary.
• Incl motor, speech-language eval, general cognitive abilities, educational needs, &/or vocational opportunities.
• Incl appropriate testing to assess cognitive function in those w/sensory deficits.
• Abilities may be underestimated, especially in early yrs.
• Evaluate for early intervention/special education, referral to deaf-blind programs when appropriate.
• Adapt testing environment as needed to ↑ patient comfort.
• Screen for ADHD, anxiety, obsessive-compulsive symptomatology.
• Males w/micropenis: consider HCG stimulation test, ideally before age 6 mos.
• Males & females w/delayed or absent puberty: eval for hypogonadotropic hypogonadism
• Measure calcium & vitamin D levels.
• Thyroid function tests
• Consider referral to endocrinologist.
• Community or
• Social work involvement for parental support.
## Treatment of Manifestations
Management of children with a
Treatment of Manifestations in Individuals with a
Nutrition optimization (team approach)
If poor linear growth remains, consider growth hormone stimulation test &/or growth hormone therapy.
Start hearing habilitation (auditory & speech training, sign language) as soon as possible.
Community hearing services through early intervention or school district
Simple measures (e.g., ↑ fluid uptake) are often unsuccessful.
Referral to gastroenterologist as needed
Behavior therapy combined w/stress reduction may be helpful.
Behavior issues may be exacerbated by sensory processing issues.
ADHD = attention-deficit/hyperactivity disorder; ASM = anti-seizure medication; BAHA = bone-anchored hearing aid; CPAP = continuous positive airway pressure; DD = developmental delay; HRT = hormone replacement treatment; ID = intellectual disability; OCD = obsessive-compulsive disorder; OT = occupational therapist; PDD = pervasive developmental disorders; PET = pressure-equalizing tube; POTS = postural orthostatic tachycardia; PT = physical therapist; SNHL = sensorineural hearing loss; TEF = tracheoesophageal fistula
See
Evaluation of bony landmarks and the structure and pathways of the vestibular and facial nerves (which can be abnormal) is important in surgical planning [
In some individuals, an aberrant course of the facial nerve may be a contraindication for cochlear implant [
CT and MR Scanning in CHARGE Syndrome
Reproduced from
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
State deaf-blind services:
In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues (
State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions.
A growing body of evidence indicates that normal language development can occur if hearing habilitation is started prior to age six months for hearing-impaired children, whether or not they are visually impaired. (See
Depending on the degrees of hearing and vision loss, communication may start with touch cues, followed by object cues and proceeding to auditory/oral and/or sign language. Communication training initiated by age three years is critical to the eventual development of symbolic communication [
• Nutrition optimization (team approach)
• If poor linear growth remains, consider growth hormone stimulation test &/or growth hormone therapy.
• Start hearing habilitation (auditory & speech training, sign language) as soon as possible.
• Community hearing services through early intervention or school district
• Simple measures (e.g., ↑ fluid uptake) are often unsuccessful.
• Referral to gastroenterologist as needed
• Behavior therapy combined w/stress reduction may be helpful.
• Behavior issues may be exacerbated by sensory processing issues.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• State deaf-blind services:
• In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues (
• State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions.
• In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues (
• State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues (
• State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
State deaf-blind services:
In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues (
State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• State deaf-blind services:
• In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues (
• State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions.
• In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues (
• State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues (
• State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions.
## Communication
A growing body of evidence indicates that normal language development can occur if hearing habilitation is started prior to age six months for hearing-impaired children, whether or not they are visually impaired. (See
Depending on the degrees of hearing and vision loss, communication may start with touch cues, followed by object cues and proceeding to auditory/oral and/or sign language. Communication training initiated by age three years is critical to the eventual development of symbolic communication [
## Surveillance
Recommended Surveillance for Individuals with
DXA = dual-energy x-ray absorptiometry; EKG = electrocardiogram; POTS = postural orthostatic tachycardia
Including clinical evaluation of tonsil hypertrophy in those with retained tonsils
With low threshold to perform swallowing study, even in adolescents and adults
Particularly those with hypogonadotropic hypogonadism or those undergoing routine hormone replacement therapy
## Agents/Circumstances to Avoid
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Most individuals diagnosed with a
In rare instances, an individual with
Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the
The proband has a
The proband inherited a pathogenic variant from a parent with somatic/germline mosaicism. Somatic mosaicism for a
If a parent of the proband has a
If the
The severity of
Many individuals with
Each child of an individual with
The severity of
For a review of genetic counseling issues in families in which a child has been diagnosed with CHARGE syndrome, see
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of affected children and to young adults who are mildly affected.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals diagnosed with a
• In rare instances, an individual with
• Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the
• The proband has a
• The proband inherited a pathogenic variant from a parent with somatic/germline mosaicism. Somatic mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with somatic/germline mosaicism. Somatic mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with somatic/germline mosaicism. Somatic mosaicism for a
• If a parent of the proband has a
• If the
• The severity of
• Many individuals with
• Each child of an individual with
• The severity of
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of affected children and to young adults who are mildly affected.
## Mode of Inheritance
## Risk to Family Members
Most individuals diagnosed with a
In rare instances, an individual with
Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the
The proband has a
The proband inherited a pathogenic variant from a parent with somatic/germline mosaicism. Somatic mosaicism for a
If a parent of the proband has a
If the
The severity of
Many individuals with
Each child of an individual with
The severity of
• Most individuals diagnosed with a
• In rare instances, an individual with
• Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the
• The proband has a
• The proband inherited a pathogenic variant from a parent with somatic/germline mosaicism. Somatic mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with somatic/germline mosaicism. Somatic mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with somatic/germline mosaicism. Somatic mosaicism for a
• If a parent of the proband has a
• If the
• The severity of
• Many individuals with
• Each child of an individual with
• The severity of
## Related Genetic Counseling Issues
For a review of genetic counseling issues in families in which a child has been diagnosed with CHARGE syndrome, see
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of affected children and to young adults who are mildly affected.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of affected children and to young adults who are mildly affected.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
France
London
United Kingdom
Sense
Australia
Germany
18 Half Day Road #305
Buffalo Grove IL 60089
United Kingdom
345 North Monmouth Avenue
Monmouth OR 97361
•
• France
•
•
• London
• United Kingdom
•
•
• Sense
•
•
• Australia
•
•
• Germany
•
•
• 18 Half Day Road #305
• Buffalo Grove IL 60089
•
•
•
•
• United Kingdom
•
•
•
• 345 North Monmouth Avenue
• Monmouth OR 97361
•
## Molecular Genetics
CHD7 Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CHD7 Disorder (
CHD7 functions in a multiprotein complex and uses the energy of ATP to remodel nucleosomes. CHD7 is considered an epigenetic regulator because it modifies the degree to which chromatin is "open" or "closed," making it more or less accessible, respectively, to other proteins that activate or repress gene expression. The broad variability in phenotypes observed in individuals with
## Molecular Pathogenesis
CHD7 functions in a multiprotein complex and uses the energy of ATP to remodel nucleosomes. CHD7 is considered an epigenetic regulator because it modifies the degree to which chromatin is "open" or "closed," making it more or less accessible, respectively, to other proteins that activate or repress gene expression. The broad variability in phenotypes observed in individuals with
## Chapter Notes
John W Belmont, MD, PhD; Baylor College of Medicine (2006-2020)Kim Blake, MD, MRCP, FRCPC (2020-present)Sandra LH Davenport, MD, CM; Sensory Genetics/Neurodevelopment, Bloomington, Minnesota (2006-2020)Meg Hefner, MS (2006-present)Seema R Lalani, MD; Baylor College of Medicine (2006-2020)Donna M Martin, MD, PhD (2020-present)Conny M van Ravenswaaij-Arts, MD, PhD (2020-present)
14 August 2025 (aa) Revision:
29 September 2022 (sw) Revision: epigenetic signature analysis (Establishing the Diagnosis,
17 September 2020 (bp) Comprehensive update posted live
2 February 2012 (me) Comprehensive update posted live
22 September 2009 (me) Comprehensive update posted live
2 October 2006 (me) Review posted live
14 April 2005 (jwb) Original submission
• 14 August 2025 (aa) Revision:
• 29 September 2022 (sw) Revision: epigenetic signature analysis (Establishing the Diagnosis,
• 17 September 2020 (bp) Comprehensive update posted live
• 2 February 2012 (me) Comprehensive update posted live
• 22 September 2009 (me) Comprehensive update posted live
• 2 October 2006 (me) Review posted live
• 14 April 2005 (jwb) Original submission
## Author History
John W Belmont, MD, PhD; Baylor College of Medicine (2006-2020)Kim Blake, MD, MRCP, FRCPC (2020-present)Sandra LH Davenport, MD, CM; Sensory Genetics/Neurodevelopment, Bloomington, Minnesota (2006-2020)Meg Hefner, MS (2006-present)Seema R Lalani, MD; Baylor College of Medicine (2006-2020)Donna M Martin, MD, PhD (2020-present)Conny M van Ravenswaaij-Arts, MD, PhD (2020-present)
## Revision History
14 August 2025 (aa) Revision:
29 September 2022 (sw) Revision: epigenetic signature analysis (Establishing the Diagnosis,
17 September 2020 (bp) Comprehensive update posted live
2 February 2012 (me) Comprehensive update posted live
22 September 2009 (me) Comprehensive update posted live
2 October 2006 (me) Review posted live
14 April 2005 (jwb) Original submission
• 14 August 2025 (aa) Revision:
• 29 September 2022 (sw) Revision: epigenetic signature analysis (Establishing the Diagnosis,
• 17 September 2020 (bp) Comprehensive update posted live
• 2 February 2012 (me) Comprehensive update posted live
• 22 September 2009 (me) Comprehensive update posted live
• 2 October 2006 (me) Review posted live
• 14 April 2005 (jwb) Original submission
## References
## Literature Cited
## Suggested Reading
Ears
1a. Clipped-off helix, prominent antihelix that extends to the outer helical rim, antihelix discontinuous with the antitragus; absent lobe
1b. Antihelix discontinuous with the antitragus; very small lobe. Preauricular tag occurs occasionally.
1c. Clipped-off helix, prominent antihelix that extends to helical margin and does not connect with antitragus, triangular concha, and absent lobe
1d. Thin, unfolded helix, prominent inferior antihelix with notch between it and antitragus, rudimentary lobe
Face
2a. Female age 2.5 years; square face, round eye, straight nose with broad nasal root, unilateral facial palsy
2b. Female age five years; mild expression of CHARGE facies; relatively square face, prominent columella of the nose. Note sloping shoulders.
2c. Male age seven years; square face, somewhat broad nasal root. Note prominent ear with unfolded helix and wide neck.
2d. Female age nine years; square face, round eyes, wide neck, sloping shoulders. Note lack of facial expression as a result of bilateral facial palsy.
2e. Male age 15 years. Note longer but still somewhat square face, wide neck with sloping shoulders.
2f. Female age 18 years; square, asymmetric face, prominent ears, head tilted back, wide neck, and sloping shoulders
Hand
Typical CHARGE hand: square hand, short fingers, finger-like thumb, hockey-stick palmar crease
CHARGE syndrome checklist
Reproduced from
|
[] |
2/10/2006
|
17/9/2020
|
14/8/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
chchd10-dis
|
chchd10-dis
|
[
"Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial",
"CHCHD10",
"CHCHD10-Related Disorders"
] |
Samira Ait-El-Mkadem Saadi, Annabelle Chaussenot, Sylvie Bannwarth, Cécile Rouzier, Véronique Paquis-Flucklinger
|
Summary Mitochondrial myopathy (may also be early onset): weakness, amyotrophy, exercise intolerance Amyotrophic lateral sclerosis (ALS): progressive degeneration of upper motor neurons and lower motor neurons Frontotemporal dementia (FTD): slowly progressive behavioral changes, language disturbances, cognitive decline, extrapyramidal signs Late-onset spinal motor neuronopathy (SMA, Jokela type): weakness, cramps, and/or fasciculations; areflexia Axonal Charcot-Marie-Tooth neuropathy: slowly progressive lower-leg muscle weakness and atrophy, small hand muscle weakness, loss of tendon reflexes, sensory abnormalities Cerebellar ataxia: gait ataxia, kinetic ataxia (progressive loss of coordination of lower- and upper-limb movements), dysarthria/dysphagia, nystagmus, cerebellar oculomotor disorder Because of the recent discovery of The diagnosis is established when a heterozygous
|
With the current widespread use of multigene panels and comprehensive genomic testing, it has become apparent that heterozygous
## Diagnosis
A
Slowly progressive behavioral changes (disinhibition, loss of initiative, loss of interest in environment, psychiatric symptoms)
Language disturbances (word-finding difficulties and semantic paraphasias, perseveration, echolalia, mutism)
Cognitive decline (executive dysfunctions, attention disorders, loss of abstract reasoning ability)
Extrapyramidal signs (rigidity, bradykinesia)
Slowly progressive lower leg muscle weakness and atrophy
Small hand muscles weakness
Loss of tendon reflexes
Sensory abnormalities such as loss of sensation for vibration or cold
Electroneuromyopgraphy (ENMG) showing chronic motor neuropathy with regeneration and sometimes sensory findings
Note: The following signs of
Gait ataxia
Kinetic ataxia (progressive loss of coordination of lower- and upper-limb movements)
Dysarthria
Dysphagia
Nystagmus
Cerebellar oculomotor disorder
The diagnosis of a
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Because a
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Targeted analysis for the
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Slowly progressive behavioral changes (disinhibition, loss of initiative, loss of interest in environment, psychiatric symptoms)
• Language disturbances (word-finding difficulties and semantic paraphasias, perseveration, echolalia, mutism)
• Cognitive decline (executive dysfunctions, attention disorders, loss of abstract reasoning ability)
• Extrapyramidal signs (rigidity, bradykinesia)
• Slowly progressive lower leg muscle weakness and atrophy
• Small hand muscles weakness
• Loss of tendon reflexes
• Sensory abnormalities such as loss of sensation for vibration or cold
• Electroneuromyopgraphy (ENMG) showing chronic motor neuropathy with regeneration and sometimes sensory findings
• Gait ataxia
• Kinetic ataxia (progressive loss of coordination of lower- and upper-limb movements)
• Dysarthria
• Dysphagia
• Nystagmus
• Cerebellar oculomotor disorder
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
A
Slowly progressive behavioral changes (disinhibition, loss of initiative, loss of interest in environment, psychiatric symptoms)
Language disturbances (word-finding difficulties and semantic paraphasias, perseveration, echolalia, mutism)
Cognitive decline (executive dysfunctions, attention disorders, loss of abstract reasoning ability)
Extrapyramidal signs (rigidity, bradykinesia)
Slowly progressive lower leg muscle weakness and atrophy
Small hand muscles weakness
Loss of tendon reflexes
Sensory abnormalities such as loss of sensation for vibration or cold
Electroneuromyopgraphy (ENMG) showing chronic motor neuropathy with regeneration and sometimes sensory findings
Note: The following signs of
Gait ataxia
Kinetic ataxia (progressive loss of coordination of lower- and upper-limb movements)
Dysarthria
Dysphagia
Nystagmus
Cerebellar oculomotor disorder
• Slowly progressive behavioral changes (disinhibition, loss of initiative, loss of interest in environment, psychiatric symptoms)
• Language disturbances (word-finding difficulties and semantic paraphasias, perseveration, echolalia, mutism)
• Cognitive decline (executive dysfunctions, attention disorders, loss of abstract reasoning ability)
• Extrapyramidal signs (rigidity, bradykinesia)
• Slowly progressive lower leg muscle weakness and atrophy
• Small hand muscles weakness
• Loss of tendon reflexes
• Sensory abnormalities such as loss of sensation for vibration or cold
• Electroneuromyopgraphy (ENMG) showing chronic motor neuropathy with regeneration and sometimes sensory findings
• Gait ataxia
• Kinetic ataxia (progressive loss of coordination of lower- and upper-limb movements)
• Dysarthria
• Dysphagia
• Nystagmus
• Cerebellar oculomotor disorder
## Clinical Findings
Slowly progressive behavioral changes (disinhibition, loss of initiative, loss of interest in environment, psychiatric symptoms)
Language disturbances (word-finding difficulties and semantic paraphasias, perseveration, echolalia, mutism)
Cognitive decline (executive dysfunctions, attention disorders, loss of abstract reasoning ability)
Extrapyramidal signs (rigidity, bradykinesia)
Slowly progressive lower leg muscle weakness and atrophy
Small hand muscles weakness
Loss of tendon reflexes
Sensory abnormalities such as loss of sensation for vibration or cold
Electroneuromyopgraphy (ENMG) showing chronic motor neuropathy with regeneration and sometimes sensory findings
Note: The following signs of
Gait ataxia
Kinetic ataxia (progressive loss of coordination of lower- and upper-limb movements)
Dysarthria
Dysphagia
Nystagmus
Cerebellar oculomotor disorder
• Slowly progressive behavioral changes (disinhibition, loss of initiative, loss of interest in environment, psychiatric symptoms)
• Language disturbances (word-finding difficulties and semantic paraphasias, perseveration, echolalia, mutism)
• Cognitive decline (executive dysfunctions, attention disorders, loss of abstract reasoning ability)
• Extrapyramidal signs (rigidity, bradykinesia)
• Slowly progressive lower leg muscle weakness and atrophy
• Small hand muscles weakness
• Loss of tendon reflexes
• Sensory abnormalities such as loss of sensation for vibration or cold
• Electroneuromyopgraphy (ENMG) showing chronic motor neuropathy with regeneration and sometimes sensory findings
• Gait ataxia
• Kinetic ataxia (progressive loss of coordination of lower- and upper-limb movements)
• Dysarthria
• Dysphagia
• Nystagmus
• Cerebellar oculomotor disorder
## Establishing the Diagnosis
The diagnosis of a
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Because a
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Targeted analysis for the
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
The phenotypic spectrum of
To date, approximately 100 individuals have been identified with a pathogenic variant in
The ALS may occur by itself or in combination with FTD (referred to as FTD-ALS).
Persecutory delusions and visual or auditory hallucinations, which occur rarely in FTD in general, are not reported in individuals with
Frontal and/or temporal atrophy on brain CT or MRI
Decrease of cerebral perfusion anteriorly (single-photon emission computed tomography [SPECT])
Frontotemporal hypometabolism (positron emission tomography with
Reduced striatal uptake of
Spinal motor neuronopathy phenotype in
Mild, non-progressive dysphagia appears later in the disease course in 13% of affected individuals. About half of affected individuals develop mild reduction in sensory nerve amplitudes or reduced vibration sense in the distal lower limbs usually later in the disease course. Affected individuals remain ambulant for several decades after onset [
No signs of upper motor neuron disease, bulbar symptoms, or progressive cognitive issues have been observed.
As the ataxia worsens, other cerebellar signs such as dysmetria, dysdiadochokinesia, and hypotonia become apparent.
No genotype-phenotype correlations have been identified.
The clinical course of
Penetrance is difficult to estimate because few unaffected individuals in families with a
The prevalence of
• The ALS may occur by itself or in combination with FTD (referred to as FTD-ALS).
• Persecutory delusions and visual or auditory hallucinations, which occur rarely in FTD in general, are not reported in individuals with
• Frontal and/or temporal atrophy on brain CT or MRI
• Decrease of cerebral perfusion anteriorly (single-photon emission computed tomography [SPECT])
• Frontotemporal hypometabolism (positron emission tomography with
• Reduced striatal uptake of
• Frontal and/or temporal atrophy on brain CT or MRI
• Decrease of cerebral perfusion anteriorly (single-photon emission computed tomography [SPECT])
• Frontotemporal hypometabolism (positron emission tomography with
• Reduced striatal uptake of
• Frontal and/or temporal atrophy on brain CT or MRI
• Decrease of cerebral perfusion anteriorly (single-photon emission computed tomography [SPECT])
• Frontotemporal hypometabolism (positron emission tomography with
• Reduced striatal uptake of
• Spinal motor neuronopathy phenotype in
• Mild, non-progressive dysphagia appears later in the disease course in 13% of affected individuals. About half of affected individuals develop mild reduction in sensory nerve amplitudes or reduced vibration sense in the distal lower limbs usually later in the disease course. Affected individuals remain ambulant for several decades after onset [
• No signs of upper motor neuron disease, bulbar symptoms, or progressive cognitive issues have been observed.
• As the ataxia worsens, other cerebellar signs such as dysmetria, dysdiadochokinesia, and hypotonia become apparent.
## Clinical Description
The phenotypic spectrum of
To date, approximately 100 individuals have been identified with a pathogenic variant in
The ALS may occur by itself or in combination with FTD (referred to as FTD-ALS).
Persecutory delusions and visual or auditory hallucinations, which occur rarely in FTD in general, are not reported in individuals with
Frontal and/or temporal atrophy on brain CT or MRI
Decrease of cerebral perfusion anteriorly (single-photon emission computed tomography [SPECT])
Frontotemporal hypometabolism (positron emission tomography with
Reduced striatal uptake of
Spinal motor neuronopathy phenotype in
Mild, non-progressive dysphagia appears later in the disease course in 13% of affected individuals. About half of affected individuals develop mild reduction in sensory nerve amplitudes or reduced vibration sense in the distal lower limbs usually later in the disease course. Affected individuals remain ambulant for several decades after onset [
No signs of upper motor neuron disease, bulbar symptoms, or progressive cognitive issues have been observed.
As the ataxia worsens, other cerebellar signs such as dysmetria, dysdiadochokinesia, and hypotonia become apparent.
• The ALS may occur by itself or in combination with FTD (referred to as FTD-ALS).
• Persecutory delusions and visual or auditory hallucinations, which occur rarely in FTD in general, are not reported in individuals with
• Frontal and/or temporal atrophy on brain CT or MRI
• Decrease of cerebral perfusion anteriorly (single-photon emission computed tomography [SPECT])
• Frontotemporal hypometabolism (positron emission tomography with
• Reduced striatal uptake of
• Frontal and/or temporal atrophy on brain CT or MRI
• Decrease of cerebral perfusion anteriorly (single-photon emission computed tomography [SPECT])
• Frontotemporal hypometabolism (positron emission tomography with
• Reduced striatal uptake of
• Frontal and/or temporal atrophy on brain CT or MRI
• Decrease of cerebral perfusion anteriorly (single-photon emission computed tomography [SPECT])
• Frontotemporal hypometabolism (positron emission tomography with
• Reduced striatal uptake of
• Spinal motor neuronopathy phenotype in
• Mild, non-progressive dysphagia appears later in the disease course in 13% of affected individuals. About half of affected individuals develop mild reduction in sensory nerve amplitudes or reduced vibration sense in the distal lower limbs usually later in the disease course. Affected individuals remain ambulant for several decades after onset [
• No signs of upper motor neuron disease, bulbar symptoms, or progressive cognitive issues have been observed.
• As the ataxia worsens, other cerebellar signs such as dysmetria, dysdiadochokinesia, and hypotonia become apparent.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
The clinical course of
## Penetrance
Penetrance is difficult to estimate because few unaffected individuals in families with a
## Nomenclature
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The differential diagnosis of
Mitochondrial myopathy (See
•
•
•
• Mitochondrial myopathy (See
## Management
Consensus clinical management recommendations for
To establish the extent of disease and needs in an individual diagnosed with a
Recommended Evaluations Following Initial Diagnosis in Individuals with
UMN involvement: spasticity, Babinski signs, hyperreflexia
LMN involvement: weakness, amyotrophy, fasciculations
Muscle strength
Coordination & balance
Nutritional status;
Aspiration risk.
EMG = electromyogram; LMN = lower motor neuron; MOI = mode of inheritance; NCS = nerve conduction studies; OT = occupational therapy; PT = physical therapy; UMN = upper motor neuron
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Many individuals benefit from care by a multidisciplinary team that includes a neurologist, specially trained nurses, pulmonologist, speech therapist, physical therapist, occupational therapist, respiratory therapist, nutritionist, psychologist, social worker, and genetic counselor.
Treatment of Manifestations in Individuals with
CMT = Charcot-Marie-Tooth; SMA = spinal muscular atrophy
Recommended Surveillance for Individuals with
Mitochondrial myopathy: undefined; depends on disease progression & presenting symptoms
ALS: every 2-3 mos
FTD: undefined; depends on disease progression & presenting symptoms
SMAJ or axonal CMT: annually initially, then depending on person's progress
ALS: every 2-3 mos
FTD: undefined; depends on disease progression & presenting symptoms
Other phenotypes: NA
ALS: every 2-3 mos
Other phenotypes: NA
Mitochondrial myopathy: annually
Other phenotypes: NA
ALS = amyotrophic lateral sclerosis; FTD = frontotemporal dementia; FVC = forced vital capacity; NA = not applicable; SMAJ = spinal muscular atrophy, Jokela type
The following should be noted:
Baclofen used to treat spasticity can sometimes worsen muscle weakness.
Some drugs used to treat the behavioral manifestations of FTD may worsen dysarthria, dysphagia, and/or respiratory weakness.
See
Search
• UMN involvement: spasticity, Babinski signs, hyperreflexia
• LMN involvement: weakness, amyotrophy, fasciculations
• Muscle strength
• Coordination & balance
• Nutritional status;
• Aspiration risk.
• Mitochondrial myopathy: undefined; depends on disease progression & presenting symptoms
• ALS: every 2-3 mos
• FTD: undefined; depends on disease progression & presenting symptoms
• SMAJ or axonal CMT: annually initially, then depending on person's progress
• ALS: every 2-3 mos
• FTD: undefined; depends on disease progression & presenting symptoms
• Other phenotypes: NA
• ALS: every 2-3 mos
• Other phenotypes: NA
• Mitochondrial myopathy: annually
• Other phenotypes: NA
• Baclofen used to treat spasticity can sometimes worsen muscle weakness.
• Some drugs used to treat the behavioral manifestations of FTD may worsen dysarthria, dysphagia, and/or respiratory weakness.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a
Recommended Evaluations Following Initial Diagnosis in Individuals with
UMN involvement: spasticity, Babinski signs, hyperreflexia
LMN involvement: weakness, amyotrophy, fasciculations
Muscle strength
Coordination & balance
Nutritional status;
Aspiration risk.
EMG = electromyogram; LMN = lower motor neuron; MOI = mode of inheritance; NCS = nerve conduction studies; OT = occupational therapy; PT = physical therapy; UMN = upper motor neuron
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• UMN involvement: spasticity, Babinski signs, hyperreflexia
• LMN involvement: weakness, amyotrophy, fasciculations
• Muscle strength
• Coordination & balance
• Nutritional status;
• Aspiration risk.
## Treatment of Manifestations
Many individuals benefit from care by a multidisciplinary team that includes a neurologist, specially trained nurses, pulmonologist, speech therapist, physical therapist, occupational therapist, respiratory therapist, nutritionist, psychologist, social worker, and genetic counselor.
Treatment of Manifestations in Individuals with
CMT = Charcot-Marie-Tooth; SMA = spinal muscular atrophy
## Surveillance
Recommended Surveillance for Individuals with
Mitochondrial myopathy: undefined; depends on disease progression & presenting symptoms
ALS: every 2-3 mos
FTD: undefined; depends on disease progression & presenting symptoms
SMAJ or axonal CMT: annually initially, then depending on person's progress
ALS: every 2-3 mos
FTD: undefined; depends on disease progression & presenting symptoms
Other phenotypes: NA
ALS: every 2-3 mos
Other phenotypes: NA
Mitochondrial myopathy: annually
Other phenotypes: NA
ALS = amyotrophic lateral sclerosis; FTD = frontotemporal dementia; FVC = forced vital capacity; NA = not applicable; SMAJ = spinal muscular atrophy, Jokela type
• Mitochondrial myopathy: undefined; depends on disease progression & presenting symptoms
• ALS: every 2-3 mos
• FTD: undefined; depends on disease progression & presenting symptoms
• SMAJ or axonal CMT: annually initially, then depending on person's progress
• ALS: every 2-3 mos
• FTD: undefined; depends on disease progression & presenting symptoms
• Other phenotypes: NA
• ALS: every 2-3 mos
• Other phenotypes: NA
• Mitochondrial myopathy: annually
• Other phenotypes: NA
## Agents/Circumstances to Avoid
The following should be noted:
Baclofen used to treat spasticity can sometimes worsen muscle weakness.
Some drugs used to treat the behavioral manifestations of FTD may worsen dysarthria, dysphagia, and/or respiratory weakness.
• Baclofen used to treat spasticity can sometimes worsen muscle weakness.
• Some drugs used to treat the behavioral manifestations of FTD may worsen dysarthria, dysphagia, and/or respiratory weakness.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Many individuals diagnosed with a
A proband with a
Clinical examination and molecular genetic testing for the
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
The family history of some individuals diagnosed with a
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because significant clinical heterogeneity is observed within families, it is impossible to accurately predict the age at onset and manifestations that will develop in sibs who inherit a
If the
If the parents have not been tested for the
Predictive testing for at-risk relatives is possible once the
Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
See also the National Society of Genetic Counselors
In a family with an established diagnosis of a
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors
• Many individuals diagnosed with a
• A proband with a
• Clinical examination and molecular genetic testing for the
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The family history of some individuals diagnosed with a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because significant clinical heterogeneity is observed within families, it is impossible to accurately predict the age at onset and manifestations that will develop in sibs who inherit a
• If the
• If the parents have not been tested for the
• Predictive testing for at-risk relatives is possible once the
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• See also the National Society of Genetic Counselors
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk.
## Mode of Inheritance
## Risk to Family Members
Many individuals diagnosed with a
A proband with a
Clinical examination and molecular genetic testing for the
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
The family history of some individuals diagnosed with a
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because significant clinical heterogeneity is observed within families, it is impossible to accurately predict the age at onset and manifestations that will develop in sibs who inherit a
If the
If the parents have not been tested for the
• Many individuals diagnosed with a
• A proband with a
• Clinical examination and molecular genetic testing for the
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The family history of some individuals diagnosed with a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because significant clinical heterogeneity is observed within families, it is impossible to accurately predict the age at onset and manifestations that will develop in sibs who inherit a
• If the
• If the parents have not been tested for the
## Related Genetic Counseling Issues
Predictive testing for at-risk relatives is possible once the
Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
See also the National Society of Genetic Counselors
In a family with an established diagnosis of a
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk.
• Predictive testing for at-risk relatives is possible once the
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• See also the National Society of Genetic Counselors
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors
## Resources
Canada
Australia
•
•
•
• Canada
•
•
•
•
• Australia
•
## Molecular Genetics
CHCHD10-Related Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CHCHD10-Related Disorders (
The precise function of CHCHD10 in mitochondria is unclear. Fibroblasts of individuals with p.Ser59Leu variant in
Knock-in (KI) mice with a punctual pathogenic variant in
Notable
Variants listed in the table have been provided by the authors.
ALS = amyotrophic lateral sclerosis; CMT = Charcot-Marie-Tooth; FTD = frontotemporal dementia; SMAJ = spinal muscular atrophy, Jokela type; SMN = spinal motor neuropathy
## Molecular Pathogenesis
The precise function of CHCHD10 in mitochondria is unclear. Fibroblasts of individuals with p.Ser59Leu variant in
Knock-in (KI) mice with a punctual pathogenic variant in
Notable
Variants listed in the table have been provided by the authors.
ALS = amyotrophic lateral sclerosis; CMT = Charcot-Marie-Tooth; FTD = frontotemporal dementia; SMAJ = spinal muscular atrophy, Jokela type; SMN = spinal motor neuropathy
## Chapter Notes
Authors belong to the Department of Medical Genetics and the Reference Center for Rare Diseases on "Mitochondrial Disorders," at the Teaching Hospital of Nice (CHU de Nice) and UCA (Université Côte d'Azur). This reference center is affiliated with the
We thank the ANR (Agence Nationale de la Recherche, ANR-16-CE16-0024-01), the AFM-Téléthon (Association Française contre les Myopathies, #20947), and the Fondation Maladies Rares for financial support.
27 May 2021 (ha) Comprehensive update posted live
1 July 2015 (me) Review posted live
20 January 2015 (saem) Original submission
• 27 May 2021 (ha) Comprehensive update posted live
• 1 July 2015 (me) Review posted live
• 20 January 2015 (saem) Original submission
## Author Notes
Authors belong to the Department of Medical Genetics and the Reference Center for Rare Diseases on "Mitochondrial Disorders," at the Teaching Hospital of Nice (CHU de Nice) and UCA (Université Côte d'Azur). This reference center is affiliated with the
## Acknowledgments
We thank the ANR (Agence Nationale de la Recherche, ANR-16-CE16-0024-01), the AFM-Téléthon (Association Française contre les Myopathies, #20947), and the Fondation Maladies Rares for financial support.
## Revision History
27 May 2021 (ha) Comprehensive update posted live
1 July 2015 (me) Review posted live
20 January 2015 (saem) Original submission
• 27 May 2021 (ha) Comprehensive update posted live
• 1 July 2015 (me) Review posted live
• 20 January 2015 (saem) Original submission
## References
Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
## Published Guidelines / Consensus Statements
Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
## Literature Cited
|
[] |
1/7/2015
|
27/5/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
chd2-dis
|
chd2-dis
|
[
"Chromodomain-helicase-DNA-binding protein 2",
"CHD2",
"CHD2-Related Neurodevelopmental Disorders"
] |
Gemma L Carvill, Heather C Mefford
|
Summary The diagnosis of a
|
## Diagnosis
Early-onset developmental and epileptic encephalopathy (i.e., refractory seizures and cognitive slowing or regression associated with frequent ongoing epileptiform activity [
Seizure onset between ages six months and four years
Drop attacks and rapid onset of multiple seizure types associated with generalized spike-wave on EEG
Atonic-myoclonic-absence seizures (See
Clinical photosensitivity
Note: Photic stimulation during an EEG may be a helpful diagnostic modality (even though not all individuals with a
Intellectual disability and/or autism spectrum disorders, particularly when epilepsy is also present
The diagnosis of a
Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Because the phenotypes of many genetic epileptic encephalopathies overlap, most children with
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from author review of variants reported in the literature, large-scale cohort exome studies, and data from genetic testing companies [Author, personal communication]
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Individuals with features of
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No intragenic
• Early-onset developmental and epileptic encephalopathy (i.e., refractory seizures and cognitive slowing or regression associated with frequent ongoing epileptiform activity [
• Seizure onset between ages six months and four years
• Drop attacks and rapid onset of multiple seizure types associated with generalized spike-wave on EEG
• Atonic-myoclonic-absence seizures (See
• Clinical photosensitivity
• Note: Photic stimulation during an EEG may be a helpful diagnostic modality (even though not all individuals with a
• Seizure onset between ages six months and four years
• Drop attacks and rapid onset of multiple seizure types associated with generalized spike-wave on EEG
• Atonic-myoclonic-absence seizures (See
• Clinical photosensitivity
• Intellectual disability and/or autism spectrum disorders, particularly when epilepsy is also present
• Seizure onset between ages six months and four years
• Drop attacks and rapid onset of multiple seizure types associated with generalized spike-wave on EEG
• Atonic-myoclonic-absence seizures (See
• Clinical photosensitivity
## Suggestive Findings
Early-onset developmental and epileptic encephalopathy (i.e., refractory seizures and cognitive slowing or regression associated with frequent ongoing epileptiform activity [
Seizure onset between ages six months and four years
Drop attacks and rapid onset of multiple seizure types associated with generalized spike-wave on EEG
Atonic-myoclonic-absence seizures (See
Clinical photosensitivity
Note: Photic stimulation during an EEG may be a helpful diagnostic modality (even though not all individuals with a
Intellectual disability and/or autism spectrum disorders, particularly when epilepsy is also present
• Early-onset developmental and epileptic encephalopathy (i.e., refractory seizures and cognitive slowing or regression associated with frequent ongoing epileptiform activity [
• Seizure onset between ages six months and four years
• Drop attacks and rapid onset of multiple seizure types associated with generalized spike-wave on EEG
• Atonic-myoclonic-absence seizures (See
• Clinical photosensitivity
• Note: Photic stimulation during an EEG may be a helpful diagnostic modality (even though not all individuals with a
• Seizure onset between ages six months and four years
• Drop attacks and rapid onset of multiple seizure types associated with generalized spike-wave on EEG
• Atonic-myoclonic-absence seizures (See
• Clinical photosensitivity
• Intellectual disability and/or autism spectrum disorders, particularly when epilepsy is also present
• Seizure onset between ages six months and four years
• Drop attacks and rapid onset of multiple seizure types associated with generalized spike-wave on EEG
• Atonic-myoclonic-absence seizures (See
• Clinical photosensitivity
## Establishing the Diagnosis
The diagnosis of a
Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Because the phenotypes of many genetic epileptic encephalopathies overlap, most children with
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from author review of variants reported in the literature, large-scale cohort exome studies, and data from genetic testing companies [Author, personal communication]
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Individuals with features of
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No intragenic
## Recommended Testing
For an introduction to multigene panels click
## Testing to Consider
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from author review of variants reported in the literature, large-scale cohort exome studies, and data from genetic testing companies [Author, personal communication]
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Individuals with features of
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No intragenic
## Clinical Characteristics
To date 139 individuals with a
A systematic single study of individuals with
The most common clinical features of these individuals are described below.
Select Features of
Seizure onset, which is explosive in many children, is characterized by multiple daily myoclonic and absence seizures.
Although
A classic seizure type termed "atonic-myoclonic-absence seizure," a progressive seizure pattern comprising an abrupt head nod and atonia followed by a myoclonic absence phase and progression to a "ratchet-like" tonic abduction of the upper limbs, was observed in video footage of three children aged two to seven years. Seizures were brief (2-8 seconds) and awareness rapidly returned [
Clinical photosensitivity (i.e., seizures triggered by photic stimulation) is a distinguishing feature reported in a total of 80% (20/25) of individuals where it was specifically queried. A small number of individuals could self-induce seizures, suggesting an unusually strong degree of photosensitivity. In contrast, a photoparoxysmal response (an epileptiform EEG response to intermittent photic stimulation) has only been recorded in two affected individuals [
Seizures are often refractory to currently available anti-seizure medications (ASMs). Only 13 of 33 affected individuals have been reported to be seizure free on ASM treatment for two to five years (see
No genotype-phenotype correlation has been observed between the location/nature of the pathogenic variant and clinical outcome.
Penetrance for
The prevalence of
A
In each of four studies of exome-based sequencing of hundreds to thousands of individuals with neurodevelopmental disorders including intellectual disability and autism spectrum disorders, one to three individuals with a
## Clinical Description
To date 139 individuals with a
A systematic single study of individuals with
The most common clinical features of these individuals are described below.
Select Features of
Seizure onset, which is explosive in many children, is characterized by multiple daily myoclonic and absence seizures.
Although
A classic seizure type termed "atonic-myoclonic-absence seizure," a progressive seizure pattern comprising an abrupt head nod and atonia followed by a myoclonic absence phase and progression to a "ratchet-like" tonic abduction of the upper limbs, was observed in video footage of three children aged two to seven years. Seizures were brief (2-8 seconds) and awareness rapidly returned [
Clinical photosensitivity (i.e., seizures triggered by photic stimulation) is a distinguishing feature reported in a total of 80% (20/25) of individuals where it was specifically queried. A small number of individuals could self-induce seizures, suggesting an unusually strong degree of photosensitivity. In contrast, a photoparoxysmal response (an epileptiform EEG response to intermittent photic stimulation) has only been recorded in two affected individuals [
Seizures are often refractory to currently available anti-seizure medications (ASMs). Only 13 of 33 affected individuals have been reported to be seizure free on ASM treatment for two to five years (see
## Genotype-Phenotype Correlations
No genotype-phenotype correlation has been observed between the location/nature of the pathogenic variant and clinical outcome.
## Penetrance
Penetrance for
## Prevalence
The prevalence of
A
In each of four studies of exome-based sequencing of hundreds to thousands of individuals with neurodevelopmental disorders including intellectual disability and autism spectrum disorders, one to three individuals with a
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Phenotypic features associated with
## Management
To establish the extent of disease and needs in an individual diagnosed with a
Recommended Evaluations Following Initial Diagnosis in Individuals with
To assess degree of epileptic encephalopathy
May lead to more focused use of ASMs
To differentiate genetic epilepsy from lesional epilepsy
May lead to intensified conservative treatment rather than presurgical work up
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ASMs = anti-seizure medications; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment of Manifestations in Individuals with
Many ASMs may be effective; none have been demonstrated effective specifically for this disorder.
Education of parents/caregivers
ASMs = anti-seizure medications
Most individuals remain refractory to treatment and require multiple ASMs.
Although a ketogenic diet may be a treatment option, it was not effective in three affected individuals [
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IPE be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Recommended Surveillance for Individuals with
Because clinical photosensitivity may result in injuries due to the consequences of induced seizures, the following are recommended:
Avoid flickering lights that may provoke seizures.
Advise affected individuals and families that exposure to intensely flickering lights may provoke seizures including eyelid myoclonias, absence seizures, and generalized tonic-clonic seizures. Of note, most televisions do not transmit in the frequency range that is particularly provocative.
See
Search
• To assess degree of epileptic encephalopathy
• May lead to more focused use of ASMs
• To differentiate genetic epilepsy from lesional epilepsy
• May lead to intensified conservative treatment rather than presurgical work up
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Many ASMs may be effective; none have been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IPE be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IPE be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IPE be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Avoid flickering lights that may provoke seizures.
• Advise affected individuals and families that exposure to intensely flickering lights may provoke seizures including eyelid myoclonias, absence seizures, and generalized tonic-clonic seizures. Of note, most televisions do not transmit in the frequency range that is particularly provocative.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a
Recommended Evaluations Following Initial Diagnosis in Individuals with
To assess degree of epileptic encephalopathy
May lead to more focused use of ASMs
To differentiate genetic epilepsy from lesional epilepsy
May lead to intensified conservative treatment rather than presurgical work up
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ASMs = anti-seizure medications; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• To assess degree of epileptic encephalopathy
• May lead to more focused use of ASMs
• To differentiate genetic epilepsy from lesional epilepsy
• May lead to intensified conservative treatment rather than presurgical work up
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
Many ASMs may be effective; none have been demonstrated effective specifically for this disorder.
Education of parents/caregivers
ASMs = anti-seizure medications
Most individuals remain refractory to treatment and require multiple ASMs.
Although a ketogenic diet may be a treatment option, it was not effective in three affected individuals [
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IPE be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Many ASMs may be effective; none have been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IPE be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IPE be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IPE be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IPE be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IPE be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IPE be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IPE be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Recommended Surveillance for Individuals with
## Agents/Circumstances to Avoid
Because clinical photosensitivity may result in injuries due to the consequences of induced seizures, the following are recommended:
Avoid flickering lights that may provoke seizures.
Advise affected individuals and families that exposure to intensely flickering lights may provoke seizures including eyelid myoclonias, absence seizures, and generalized tonic-clonic seizures. Of note, most televisions do not transmit in the frequency range that is particularly provocative.
• Avoid flickering lights that may provoke seizures.
• Advise affected individuals and families that exposure to intensely flickering lights may provoke seizures including eyelid myoclonias, absence seizures, and generalized tonic-clonic seizures. Of note, most televisions do not transmit in the frequency range that is particularly provocative.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Almost all individuals diagnosed with a
In rare families, individuals diagnosed with a
A child with a severe presentation of
A child with epilepsy and myoclonic seizures inherited a splice variant from his apparently unaffected heterozygous father [
Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Presumed parental germline mosaicism was reported in a family with unaffected parents and sib recurrence [
The family history of an individual diagnosed with a
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
If the proband has a known
If the parents have not been tested for the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a child with a
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Almost all individuals diagnosed with a
• In rare families, individuals diagnosed with a
• A child with a severe presentation of
• A child with epilepsy and myoclonic seizures inherited a splice variant from his apparently unaffected heterozygous father [
• A child with a severe presentation of
• A child with epilepsy and myoclonic seizures inherited a splice variant from his apparently unaffected heterozygous father [
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Presumed parental germline mosaicism was reported in a family with unaffected parents and sib recurrence [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Presumed parental germline mosaicism was reported in a family with unaffected parents and sib recurrence [
• The family history of an individual diagnosed with a
• A child with a severe presentation of
• A child with epilepsy and myoclonic seizures inherited a splice variant from his apparently unaffected heterozygous father [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Presumed parental germline mosaicism was reported in a family with unaffected parents and sib recurrence [
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the proband has a known
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a child with a
## Mode of Inheritance
## Risk to Family Members
Almost all individuals diagnosed with a
In rare families, individuals diagnosed with a
A child with a severe presentation of
A child with epilepsy and myoclonic seizures inherited a splice variant from his apparently unaffected heterozygous father [
Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Presumed parental germline mosaicism was reported in a family with unaffected parents and sib recurrence [
The family history of an individual diagnosed with a
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
If the proband has a known
If the parents have not been tested for the
• Almost all individuals diagnosed with a
• In rare families, individuals diagnosed with a
• A child with a severe presentation of
• A child with epilepsy and myoclonic seizures inherited a splice variant from his apparently unaffected heterozygous father [
• A child with a severe presentation of
• A child with epilepsy and myoclonic seizures inherited a splice variant from his apparently unaffected heterozygous father [
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Presumed parental germline mosaicism was reported in a family with unaffected parents and sib recurrence [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Presumed parental germline mosaicism was reported in a family with unaffected parents and sib recurrence [
• The family history of an individual diagnosed with a
• A child with a severe presentation of
• A child with epilepsy and myoclonic seizures inherited a splice variant from his apparently unaffected heterozygous father [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Presumed parental germline mosaicism was reported in a family with unaffected parents and sib recurrence [
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the proband has a known
• If the parents have not been tested for the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a child with a
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a child with a
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
•
•
•
•
•
•
•
• Canada
•
•
•
•
•
•
•
•
## Molecular Genetics
CHD2-Related Neurodevelopmental Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CHD2-Related Neurodevelopmental Disorders (
The overwhelming majority of
To date the majority of individuals with a
## Molecular Pathogenesis
The overwhelming majority of
To date the majority of individuals with a
## Chapter Notes
The Epilepsiome: A knowledge base for genes related to human epilepsies:
Gemma Carvill, PhD (2015-present)Ingo Helbig, MD; Children's Hospital of Philadelphia (2015-2021)Heather Mefford, MD, PhD (2015-present)
21 January 2021 (sw) Comprehensive update posted live
10 December 2015 (bp) Review posted live
14 May 2015 (hm/gc) Original submission
• 21 January 2021 (sw) Comprehensive update posted live
• 10 December 2015 (bp) Review posted live
• 14 May 2015 (hm/gc) Original submission
## Author Notes
The Epilepsiome: A knowledge base for genes related to human epilepsies:
## Author History
Gemma Carvill, PhD (2015-present)Ingo Helbig, MD; Children's Hospital of Philadelphia (2015-2021)Heather Mefford, MD, PhD (2015-present)
## Revision History
21 January 2021 (sw) Comprehensive update posted live
10 December 2015 (bp) Review posted live
14 May 2015 (hm/gc) Original submission
• 21 January 2021 (sw) Comprehensive update posted live
• 10 December 2015 (bp) Review posted live
• 14 May 2015 (hm/gc) Original submission
## References
## Literature Cited
|
[
"AS Allen, SF Berkovic, P Cossette, N Delanty, D Dlugos, EE Eichler, MP Epstein, T Glauser, DB Goldstein, Y Han, EL Heinzen, Y Hitomi, KB Howell, MR Johnson, R Kuzniecky, DH Lowenstein, YF Lu, MR Madou, AG Marson, HC Mefford, S Esmaeeli Nieh, TJ O'Brien, R Ottman, S Petrovski, A Poduri, EK Ruzzo, IE Scheffer, EH Sherr, CJ Yuskaitis, B Abou-Khalil, BK Alldredge, JF Bautista, A Boro, GD Cascino, D Consalvo, P Crumrine, O Devinsky, M Fiol, NB Fountain, J French, D Friedman, EB Geller, S Glynn, SR Haut, J Hayward, SL Helmers, S Joshi, A Kanner, HE Kirsch, RC Knowlton, EH Kossoff, R Kuperman, SM McGuire, PV Motika, EJ Novotny, JM Paolicchi, JM Parent, K Park, RA Shellhaas, JJ Shih, R Singh, J Sirven, MC Smith, J Sullivan, L Lin Thio, A Venkat, EP Vining, GK Von Allmen, JL Weisenberg, P Widdess-Walsh, MR Winawer. De novo mutations in epileptic encephalopathies.. Nature. 2013;501:217-21",
"E Aref-Eshghi, J Kerkhof, VP Pedro, DI Groupe. France, Barat-Houari M, Ruiz-Pallares N, Andrau JC, Lacombe D, Van-Gils J, Fergelot P, Dubourg C, Cormier-Daire V, Rondeau S, Lecoquierre F, Saugier-Veber P, Nicolas G, Lesca G, Chatron N, Sanlaville D, Vitobello A, Faivre L, Thauvin-Robinet C, Laumonnier F, Raynaud M, Alders M, Mannens M, Henneman P, Hennekam RC, Velasco G, Francastel C, Ulveling D, Ciolfi A, Pizzi S, Tartaglia M, Heide S, Héron D, Mignot C, Keren B, Whalen S, Afenjar A, Bienvenu T, Campeau PM, Rousseau J, Levy MA, Brick L, Kozenko M, Balci TB, Siu VM, Stuart A, Kadour M, Masters J, Takano K, Kleefstra T, de Leeuw N, Field M, Shaw M, Gecz J, Ainsworth PJ, Lin H, Rodenhiser DI, Friez MJ, Tedder M, Lee JA, DuPont BR, Stevenson RE, Skinner SA, Schwartz CE, Genevieve D, Sadikovic B. Evaluation of DNA methylation episignatures for diagnosis and phenotype correlations in 42 Mendelian neurodevelopmental disorders.. Am J Hum Genet. 2020;106:356-70",
"K Bouazoune, RE Kingston. Chromatin remodeling by the CHD7 protein is impaired by mutations that cause human developmental disorders.. Proc Natl Acad Sci U S A. 2012;109:19238-43",
"LP Capelli, AC Krepischi, J Gurgel-Giannetti, MF Mendes, T Rodrigues, MC Varela, CP Koiffmann, C Rosenberg. Deletion of the RMGA and CHD2 genes in a child with epilepsy and mental deficiency.. Eur J Med Genet. 2012;55:132-4",
"GL Carvill, SB Heavin, SC Yendle, JM McMahon, BJ O'Roak, J Cook, A Khan, MO Dorschner, M Weaver, S Calvert, S Malone, G Wallace, T Stanley, AM Bye, A Bleasel, KB Howell, S Kivity, MT Mackay, V Rodriguez-Casero, R Webster, A Korczyn, Z Afawi, N Zelnick, T Lerman-Sagie, D Lev, RS Moller, D Gill, DM Andrade, JL Freeman, LG Sadleir, J Shendure, SF Berkovic, IE Scheffer, HC Mefford. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.. Nat Genet. 2013;45:825-30",
"J Chen, J Zhang, A Liu, L Zhang, H Li, Q Zeng, Z Yang, X Yang, X Wu, Y. Zhang. CHD2-related epilepsy: novel mutations and new phenotypes.. Dev Med Child Neurol. 2020;62:647-53",
"S Chénier, G Yoon, B Argiropoulos, J Lauzon, R Laframboise, JW Ahn, CM Ogilvie, AC Lionel, CR Marshall, AK Vaags, B Hashemi, K Boisvert, G Mathonnet, F Tihy, J So, SW Scherer, E Lemyre, DJ Stavropoulos. CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems.. J Neurodev Disord. 2014;6:9",
"C Courage, G Houge, S Gallati, J Schjelderup, C. Rieubland. 15q26.1 microdeletion encompassing only CHD2 and RGMA in two adults with moderate intellectual disability, epilepsy and truncal obesity.. Eur J Med Genet. 2014;57:520-3",
"R Dhamija, G Breningstall, L Wong-Kisiel, M Dolan, B Hirsch, E. Wirrell. Microdeletion of chromosome 15q26.1 in a child with intractable generalized epilepsy.. Pediatr Neurol. 2011;45:60-2",
"Large-scale discovery of novel genetic causes of developmental disorders.. Nature. 2015;519:223-8",
"EC Galizia, CT Myers, C Leu, CGF de Kovel, T Afrikanova, ML Cordero-Maldonado, TG Martins, M Jacmin, S Drury, VK Chinthapalli, H Muhle, M Pendziwiat, T Sander, A-K Ruppert, RS Moller, H Thiele, R Krause, J Schubert, A-E Lehesjoki, P Nurnberg, H Lerche, A Palotie, A Coppola, S Striano, L Del Gaudio, C Boustred, AL Schneider, N Lench, B Jocic-Jakubi, A Covanis, G Capovilla, P Veggotti, M Piccioli, P Parisi, L Cantonetti, LG Sadleir, SA Mullen, SF Berkovic, U Stephani, I Helbig, AD Crawford, CV Esguerra, DGA Kasteleijn-Nolst Trenite, BPC Koeleman, HC Mefford, IE Scheffer, SM Sisodiya. CHD2 variants are a risk factor for photosensitivity in epilepsy.. Brain 2015;138:1198-207",
"HO Heyne, T Singh, H Stamberger, R Abou Jamra, H Caglayan, D Craiu, P De Jonghe, R Guerrini, KL Helbig, BPC Koeleman, JA Kosmicki, T Linnankivi, P May, H Muhle, RS Møller, BA Neubauer, A Palotie, M Pendziwiat, P Striano, S Tang, S Wu. EuroEPINOMICS RES Consortium, Poduri A, Weber YG, Weckhuysen S, Sisodiya SM, Daly MJ, Helbig I, Lal D, Lemke JR. De novo variants in neurodevelopmental disorders with epilepsy.. Nat Genet. 2018;50:1048-53",
"YJ Kim, S Khoshkhoo, JC Frankowski, B Zhu, S Abbasi, S Lee, YE Wu, RF Hunt. Chd2 is necessary for neural circuit development and long-term memory neuron.. Neuron. 2018;100:1180-93.e6",
"A Ko, SE Youn, SH Kim, JS Lee, S Kim, JR Choi, HD Kim, ST Lee, HC Kang. Targeted gene panel and genotype-phenotype correlation in children with developmental and epileptic encephalopathy.. Epilepsy Res. 2018;141:48-55",
"N Lebrun, P Parent, J Gendras, P Billuart, K Poirier, T Bienvenu. Autism spectrum disorder recurrence, resulting of germline mosaicism for a CHD2 gene missense variant.. Clin Genet. 2017;92:669-70",
"JC Liu, CG Ferreira, T Yusufzai. Human CHD2 is a chromatin assembly ATPase regulated by its chromo- and DNA-binding domains.. J Biol Chem. 2015;290:25-34",
"C Lund, E Brodtkorb, AM Oye, O Rosby, KK Selmer. CHD2 mutations in Lennox-Gastaut syndrome.. Epilepsy Behav. 2014;33:18-21",
"CG Marfella, AN Imbalzano. The Chd family of chromatin remodelers.. Mutat Res. 2007;618:30-40",
"K Meganathan, EMA Lewis, P Gontarz, S Liu, EG Stanley, AG Elefanty, JE Huettner, B Zhang, KL Kroll. Regulatory networks specifying cortical interneurons from human embryonic stem cells reveal roles for CHD2 in interneuron development. Proc Natl Acad Sci U S A. 2017;114:E11180-9",
"CT Myers, G Hollingsworth, AM Muir, AL Schneider, Z Thuesmunn, A Knupp, C King, A Lacroix, MG Mehaffey, SF Berkovic, GL Carvill, LG Sadleir, IE Scheffer, HC Mefford. Parental mosaicism in \"de novo\" epileptic encephalopathies.. N Engl J Med. 2018;378:1646-8",
"BM Neale, Y Kou, L Liu, A Ma'ayan, KE Samocha, A Sabo, CF Lin, C Stevens, LS Wang, V Makarov, P Polak, S Yoon, J Maguire, EL Crawford, NG Campbell, ET Geller, O Valladares, C Schafer, H Liu, T Zhao, G Cai, J Lihm, R Dannenfelser, O Jabado, Z Peralta, U Nagaswamy, D Muzny, JG Reid, I Newsham, Y Wu, L Lewis, Y Han, BF Voight, E Lim, E Rossin, A Kirby, J Flannick, M Fromer, K Shakir, T Fennell, K Garimella, E Banks, R Poplin, S Gabriel, M DePristo, JR Wimbish, BE Boone, SE Levy, C Betancur, S Sunyaev, E Boerwinkle, JD Buxbaum, EH Cook, B Devlin, RA Gibbs, K Roeder, GD Schellenberg, JS Sutcliffe, MJ Daly. Patterns and rates of exonic de novo mutations in autism spectrum disorders.. Nature. 2012;485:242-5",
"BJ O'Roak, HA Stessman, EA Boyle, KT Witherspoon, B Martin, C Lee, L Vives, C Baker, JB Hiatt, DA Nickerson, R Bernier, J Shendure, EE Eichler. Recurrent de novo mutations implicate novel genes underlying simplex autism risk.. Nat Commun. 2014;5:5595",
"AK Petersen, H Streff, M Tokita, BL Bostwick. The first reported case of an inherited pathogenic CHD2 variant in a clinically affected mother and daughter.. Am J Med Genet A. 2018;176:1667-9",
"D Pinto, E Delaby, D Merico, M Barbosa, A Merikangas, L Klei, B Thiruvahindrapuram, X Xu, R Ziman, Z Wang, JA Vorstman, A Thompson, R Regan, M Pilorge, G Pellecchia, AT Pagnamenta, B Oliveira, CR Marshall, TR Magalhaes, JK Lowe, JL Howe, AJ Griswold, J Gilbert, E Duketis, BA Dombroski, MV De Jonge, M Cuccaro, EL Crawford, CT Correia, J Conroy, IC Conceição, AG Chiocchetti, JP Casey, G Cai, C Cabrol, N Bolshakova, E Bacchelli, R Anney, S Gallinger, M Cotterchio, G Casey, L Zwaigenbaum, K Wittemeyer, K Wing, S Wallace, H van Engeland, A Tryfon, S Thomson, L Soorya, B Rogé, W Roberts, F Poustka, S Mouga, N Minshew, LA McInnes, SG McGrew, C Lord, M Leboyer, AS Le Couteur, A Kolevzon, P Jiménez González, S Jacob, R Holt, S Guter, J Green, A Green, C Gillberg, BA Fernandez, F Duque, R Delorme, G Dawson, P Chaste, C Café, S Brennan, T Bourgeron, PF Bolton, S Bölte, R Bernier, G Baird, AJ Bailey, E Anagnostou, J Almeida, EM Wijsman, VJ Vieland, AM Vicente, GD Schellenberg, M Pericak-Vance, AD Paterson, JR Parr, G Oliveira, JI Nurnberger, AP Monaco, E Maestrini, SM Klauck, H Hakonarson, JL Haines, DH Geschwind, CM Freitag, SE Folstein, S Ennis, H Coon, A Battaglia, P Szatmari, JS Sutcliffe, J Hallmayer, M Gill, EH Cook, JD Buxbaum, B Devlin, L Gallagher, C Betancur, SW Scherer. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.. Am J Hum Genet. 2014;94:677-94",
"A Poisson, N Chatron, A Labalme, P Fourneret, D Ville, ML Mathieu, D Sanlaville, C Demily, G Lesca. Chromatin remodeling dysfunction extends the etiological spectrum of schizophrenia: a case report.. BMC Med Genet. 2020;21:10",
"A Rauch, D Wieczorek, E Graf, T Wieland, S Endele, T Schwarzmayr, B Albrecht, D Bartholdi, J Beygo, N Di Donato, A Dufke, K Cremer, M Hempel, D Horn, J Hoyer, P Joset, A Ropke, U Moog, A Riess, CT Thiel, A Tzschach, A Wiesener, E Wohlleber, C Zweier, AB Ekici, AM Zink, A Rump, C Meisinger, H Grallert, H Sticht, A Schenck, H Engels, G Rappold, E Schrock, P Wieacker, O Riess, T Meitinger, A Reis, TM Strom. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.. Lancet. 2012;380:1674-82",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"IE Scheffer, S Berkovic, G Capovilla, MB Connolly, J French, L Guilhoto, E Hirsch, S Jain, GW Mathern, SL Moshé, DR Nordli, E Perucca, T Tomson, S Wiebe, YH Zhang, SM Zuberi. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology.. Epilepsia. 2017;58:512-21",
"A Suls, JA Jaehn, A Kecskes, Y Weber, S Weckhuysen, DC Craiu, A Siekierska, T Djemie, T Afrikanova, P Gormley, S von Spiczak, G Kluger, CM Iliescu, T Talvik, I Talvik, C Meral, HS Caglayan, BG Giraldez, J Serratosa, JR Lemke, D Hoffman-Zacharska, E Szczepanik, N Barisic, V Komarek, H Hjalgrim, RS Moller, T Linnankivi, P Dimova, P Striano, F Zara, C Marini, R Guerrini, C Depienne, S Baulac, G Kuhlenbaumer, AD Crawford, AE Lehesjoki, PA de Witte, A Palotie, H Lerche, CV Esguerra, P De Jonghe, I Helbig. De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome.. Am J Hum Genet. 2013;93:967-75",
"RH Thomas, LM Zhang, GL Carvill, JS Archer, SB Heavin, SA Mandelstam, D Craiu, SF Berkovic, DS Gill, HC Mefford, IE Scheffer. CHD2 myoclonic encephalopathy is frequently associated with self-induced seizures.. Neurology. 2015;84:951-8",
"M Trivisano, P Striano, J Sartorelli, L Giordano, M Traverso, P Accorsi, S Cappelletti, DJ Claps, F Vigevano, F Zara, N Specchio. CHD2 mutations are a rare cause of generalized epilepsy with myoclonic-atonic seizures.. Epilepsy Behav. 2015;51:53-6",
"R Truty, N Patil, R Sankar, J Sullivan, J Millichap, G Carvill, A Entezam, ED Esplin, A Fuller, M Hogue, B Johnson, A Khouzam, Y Kobayashi, R Lewis, K Nykamp, D Riethmaier, J Westbrook, M Zeman, RL Nussbaum, S Aradhya. Possible precision medicine implications from genetic testing using combined detection of sequence and intragenic copy number variants in a large cohort with childhood epilepsy.. Epilepsia Open. 2019;4:397-408"
] |
10/12/2015
|
21/1/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
chd4-ndd
|
chd4-ndd
|
[
"Sifrim-Hitz-Weiss Syndrome",
"SIHIWES",
"Sifrim–Hitz–Weiss Syndrome (SIHIWES)",
"Chromodomain-helicase-DNA-binding protein 4",
"CHD4",
"CHD4 Neurodevelopmental Disorder"
] |
Karin Weiss, Katherine Lachlan
|
Summary The diagnosis of
|
## Diagnosis
Formal diagnostic criteria for
Generalized hypotonia of infancy
Macrocephaly or relative macrocephaly
Congenital heart defects (septal defects, conotruncal anomalies, and valvular abnormalities)
Skeletal and limb anomalies (vertebral fusion, carpal/tarsal coalition, syndactyly, polydactyly)
Hypogonadism in males (cryptorchidism and/or microphallus)
Ophthalmologic abnormalities (strabismus, hypermetropia, astigmatism)
Hearing impairment (conductive and/or sensorineural)
Moyamoya disease with congenital or infantile stroke
Mild-to-moderate ventriculomegaly (in 41%)
Chiari 1 malformation (29%)
Hydrocephalus requiring shunting (18%)
Other. Thin corpus callosum and syringomyelia
The diagnosis of
Note: Identification of a heterozygous
If CMA is not diagnostic, the next step is typically either a multigene panel or exome sequencing. Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Generalized hypotonia of infancy
• Macrocephaly or relative macrocephaly
• Congenital heart defects (septal defects, conotruncal anomalies, and valvular abnormalities)
• Skeletal and limb anomalies (vertebral fusion, carpal/tarsal coalition, syndactyly, polydactyly)
• Hypogonadism in males (cryptorchidism and/or microphallus)
• Ophthalmologic abnormalities (strabismus, hypermetropia, astigmatism)
• Hearing impairment (conductive and/or sensorineural)
• Moyamoya disease with congenital or infantile stroke
• Mild-to-moderate ventriculomegaly (in 41%)
• Chiari 1 malformation (29%)
• Hydrocephalus requiring shunting (18%)
• Other. Thin corpus callosum and syringomyelia
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Generalized hypotonia of infancy
Macrocephaly or relative macrocephaly
Congenital heart defects (septal defects, conotruncal anomalies, and valvular abnormalities)
Skeletal and limb anomalies (vertebral fusion, carpal/tarsal coalition, syndactyly, polydactyly)
Hypogonadism in males (cryptorchidism and/or microphallus)
Ophthalmologic abnormalities (strabismus, hypermetropia, astigmatism)
Hearing impairment (conductive and/or sensorineural)
Moyamoya disease with congenital or infantile stroke
Mild-to-moderate ventriculomegaly (in 41%)
Chiari 1 malformation (29%)
Hydrocephalus requiring shunting (18%)
Other. Thin corpus callosum and syringomyelia
• Generalized hypotonia of infancy
• Macrocephaly or relative macrocephaly
• Congenital heart defects (septal defects, conotruncal anomalies, and valvular abnormalities)
• Skeletal and limb anomalies (vertebral fusion, carpal/tarsal coalition, syndactyly, polydactyly)
• Hypogonadism in males (cryptorchidism and/or microphallus)
• Ophthalmologic abnormalities (strabismus, hypermetropia, astigmatism)
• Hearing impairment (conductive and/or sensorineural)
• Moyamoya disease with congenital or infantile stroke
• Mild-to-moderate ventriculomegaly (in 41%)
• Chiari 1 malformation (29%)
• Hydrocephalus requiring shunting (18%)
• Other. Thin corpus callosum and syringomyelia
## Establishing the Diagnosis
The diagnosis of
Note: Identification of a heterozygous
If CMA is not diagnostic, the next step is typically either a multigene panel or exome sequencing. Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
To date, 33 individuals have been identified with a heterozygous
Select Features of
The average age of independent ambulation is 30 months. Three children achieved independent ambulation after age five years.
Hydrocephalus requiring shunting has been associated with intellectual disability ranging from mild to moderate.
Because some individuals with
To date, there are no reports of hypogonadism or infertility in females; however, the majority of individuals reported to date are children.
Significant vision impairment has not been reported, but ophthalmic anomalies (by frequency) include: strabismus, astigmatism, hypermetropia, glaucoma, small optic nerves, iris coloboma, and myopia.
The majority of
Because the vast majority of individuals with
## Clinical Description
To date, 33 individuals have been identified with a heterozygous
Select Features of
The average age of independent ambulation is 30 months. Three children achieved independent ambulation after age five years.
Hydrocephalus requiring shunting has been associated with intellectual disability ranging from mild to moderate.
Because some individuals with
To date, there are no reports of hypogonadism or infertility in females; however, the majority of individuals reported to date are children.
Significant vision impairment has not been reported, but ophthalmic anomalies (by frequency) include: strabismus, astigmatism, hypermetropia, glaucoma, small optic nerves, iris coloboma, and myopia.
## Genotype-Phenotype Correlations
The majority of
## Penetrance
Because the vast majority of individuals with
## Prevalence
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Because the phenotypic features associated with
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Evidence of congenital or infantile stroke;
Signs of ↑ intracranial pressure / herniation / cord compression.
Brain & cervical spine MRI for detection of hydrocephalus / Chiari 1/ syringomyelia;
MRA for persons w/suspected stroke or infants undergoing brain imaging.
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
For skeletal & limb anomalies;
Gross motor & fine motor skills;
Mobility, ADLs, & need for adaptive devices;
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
Flexion-extension radiographs of lateral cervical spine
Flexion-extension MRI if instability & compression seen on radiographs or interpretation is limited (e.g., in young persons w/delayed ossification of cervical vertebral bodies)
Assess for cryptorchidism & microphallus.
Refer to endocrinologist & obtain FSH/LH & testosterone levels in 1st yr of life & in puberty.
Community or
Social work involvement for parental support.
ADHD = attention-deficit/hyperactivity disorder; ADL = activity of daily living; ASD = autism spectrum disorder; FSH = follicle-stimulating hormone; LH = luteinizing hormone; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; US = ultrasound
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment of Manifestations in Individuals with
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
OT = occupational therapy; PT = physical therapy
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Recommended Surveillance for Individuals with
OT = occupational therapy; PT = physical therapy
Avoid activities that involve rapid neck motion and/or possible trauma to the head and neck region (e.g., contact sports or thrill rides at amusement parks) because of the possible increased risk for cervical spine instability.
See
Search
• Evidence of congenital or infantile stroke;
• Signs of ↑ intracranial pressure / herniation / cord compression.
• Brain & cervical spine MRI for detection of hydrocephalus / Chiari 1/ syringomyelia;
• MRA for persons w/suspected stroke or infants undergoing brain imaging.
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• For skeletal & limb anomalies;
• Gross motor & fine motor skills;
• Mobility, ADLs, & need for adaptive devices;
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
• Flexion-extension radiographs of lateral cervical spine
• Flexion-extension MRI if instability & compression seen on radiographs or interpretation is limited (e.g., in young persons w/delayed ossification of cervical vertebral bodies)
• Assess for cryptorchidism & microphallus.
• Refer to endocrinologist & obtain FSH/LH & testosterone levels in 1st yr of life & in puberty.
• Community or
• Social work involvement for parental support.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Evidence of congenital or infantile stroke;
Signs of ↑ intracranial pressure / herniation / cord compression.
Brain & cervical spine MRI for detection of hydrocephalus / Chiari 1/ syringomyelia;
MRA for persons w/suspected stroke or infants undergoing brain imaging.
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
For skeletal & limb anomalies;
Gross motor & fine motor skills;
Mobility, ADLs, & need for adaptive devices;
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
Flexion-extension radiographs of lateral cervical spine
Flexion-extension MRI if instability & compression seen on radiographs or interpretation is limited (e.g., in young persons w/delayed ossification of cervical vertebral bodies)
Assess for cryptorchidism & microphallus.
Refer to endocrinologist & obtain FSH/LH & testosterone levels in 1st yr of life & in puberty.
Community or
Social work involvement for parental support.
ADHD = attention-deficit/hyperactivity disorder; ADL = activity of daily living; ASD = autism spectrum disorder; FSH = follicle-stimulating hormone; LH = luteinizing hormone; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; US = ultrasound
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Evidence of congenital or infantile stroke;
• Signs of ↑ intracranial pressure / herniation / cord compression.
• Brain & cervical spine MRI for detection of hydrocephalus / Chiari 1/ syringomyelia;
• MRA for persons w/suspected stroke or infants undergoing brain imaging.
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• For skeletal & limb anomalies;
• Gross motor & fine motor skills;
• Mobility, ADLs, & need for adaptive devices;
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
• Flexion-extension radiographs of lateral cervical spine
• Flexion-extension MRI if instability & compression seen on radiographs or interpretation is limited (e.g., in young persons w/delayed ossification of cervical vertebral bodies)
• Assess for cryptorchidism & microphallus.
• Refer to endocrinologist & obtain FSH/LH & testosterone levels in 1st yr of life & in puberty.
• Community or
• Social work involvement for parental support.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
OT = occupational therapy; PT = physical therapy
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Recommended Surveillance for Individuals with
OT = occupational therapy; PT = physical therapy
## Agents/Circumstances to Avoid
Avoid activities that involve rapid neck motion and/or possible trauma to the head and neck region (e.g., contact sports or thrill rides at amusement parks) because of the possible increased risk for cervical spine instability.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Almost all probands reported to date with
Presumed parent-to-child transmission was reported in one family in which the parent had features of
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
Theoretically, if the parent is the individual in whom the
If a parent of the proband has the
If the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
Risk to future pregnancies is presumed to be low as the proband most likely has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Almost all probands reported to date with
• Presumed parent-to-child transmission was reported in one family in which the parent had features of
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
• Theoretically, if the parent is the individual in whom the
• If a parent of the proband has the
• If the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
## Risk to Family Members
Almost all probands reported to date with
Presumed parent-to-child transmission was reported in one family in which the parent had features of
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
Theoretically, if the parent is the individual in whom the
If a parent of the proband has the
If the
• Almost all probands reported to date with
• Presumed parent-to-child transmission was reported in one family in which the parent had features of
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
• Theoretically, if the parent is the individual in whom the
• If a parent of the proband has the
• If the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Risk to future pregnancies is presumed to be low as the proband most likely has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
•
•
## Molecular Genetics
CHD4 Neurodevelopmental Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CHD4 Neurodevelopmental Disorder (
## Molecular Pathogenesis
## References
## Literature Cited
## Chapter Notes
3 September 2020 (bp) Review posted live
28 January 2020 (kw) Original submission
• 3 September 2020 (bp) Review posted live
• 28 January 2020 (kw) Original submission
## Revision History
3 September 2020 (bp) Review posted live
28 January 2020 (kw) Original submission
• 3 September 2020 (bp) Review posted live
• 28 January 2020 (kw) Original submission
|
[
"A Pinard, S Guey, D Guo, AC Cecchi, N Kharas, S Wallace, ES Regalado, EM Hostetler, AZ Sharrief, F Bergametti, M Kossorotoff, D Hervé, M Kraemer, MJ Bamshad, DA Nickerson, ER Smith, E Tournier-Lasserve, DM Milewicz. The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.. Genet Med. 2020;22:427-31",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"A Sifrim, MP Hitz, A Wilsdon, J Breckpot, SH Turki, B Thienpont, J McRae, TW Fitzgerald, T Singh, GJ Swaminathan, E Prigmore, D Rajan, H Abdul-Khaliq, S Banka, UM Bauer, J Bentham, F Berger, S Bhattacharya, FA Bulock, N Canham, IG Colgiu, C Cosgrove, H Cox, I Daehnert, A Daly, J Danesh, A Fryer, M Gewillig, E Hobson, K Hoff, T Homfray, AK Kahlert, A Ketley, HH Kramer, K Lachlan, AK Lampe, JJ Louw, AK Manickara, D Manase, KP McCarthy, K Metcalfe, C Moore, R Newbury-Ecob, SO Omer, WH Ouwehand, SM Park, MJ Parker, T Pickardt, MO Pollard, L Robert, DJ Roberts, J Sambrook, K Setchfield, B Stiller, C Thornborough, O Toka, H Watkins, D Williams, M Wright, S Mital, PE Daubeney, B Keavney, J Goodship, RM Abu-Sulaiman, S Klaassen, CF Wright, HV Firth, JC Barrett, K Devriendt, DR FitzPatrick, JD Brook, ME Hurles. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.. Nat Genet. 2016;48:1060-5",
"K Weiss, HP Lazar, A Kurolap, AF Martinez, T Paperna, L Cohen, MF Smeland, S Whalen, S Heide, B Keren, P Terhal, M Irving, M Takaku, JD Roberts, RM Petrovich, SA Schrier Vergano, A Kenney, H Hove, E DeChene, SC Quinonez, E Colin, A Ziegler, M Rumple, M Jain, D Monteil, ER Roeder, K Nugent, A van Haeringen, M Gambello, A Santani, L Medne, B Krock, CM Skraban, EH Zackai, HA Dubbs, T Smol, J Ghoumid, MJ Parker, M Wright, P Turnpenny, J Clayton-Smith, K Metcalfe, H Kurumizaka, BD Gelb, H Baris Feldman, PM Campeau, M Muenke, PA Wade, K Lachlan. The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype-phenotype correlations, and molecular basis.. Genet Med. 2020;22:389-97",
"K Weiss, PA Terhal, L Cohen, M Bruccoleri, M Irving, AF Martinez, JA Rosenfeld, K Machol, Y Yang, P Liu, M Walkiewicz, J Beuten, N Gomez-Ospina, K Haude, CT Fong, GM Enns, JA Bernstein, J Fan, G Gotway, M Ghorbani, K van Gassen, GR Monroe, G van Haaften, L Basel-Vanagaite, XJ Yang, PM Campeau, M Muenke. De novo mutations in CHD4, an ATP-dependent chromatin remodeler gene, cause an intellectual disability syndrome with distinctive dysmorphisms.. Am J Hum Genet. 2016;99:934-41"
] |
3/9/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
chd8-ndd-og
|
chd8-ndd-og
|
[
"Chromodomain-helicase-DNA-binding protein 8",
"CHD8",
"CHD8-Related Neurodevelopmental Disorder with Overgrowth"
] |
Marissa W Mitchel, Scott M Myers, Alexis R Heidlebaugh, Cora M Taylor, Hannah Rea, Emily Neuhaus, Evangeline C Kurtz-Nelson, Rachel Earl, Raphael Bernier, David H Ledbetter, Christa L Martin, Evan E Eichler
|
Summary The diagnosis of
|
## Diagnosis
No consensus clinical diagnostic criteria for
Developmental delay (DD) and/or intellectual disability (ID) (typically in the mild-to-moderate range)
Neuropsychiatric disorders, including autism spectrum disorder (ASD)
Generalized overgrowth, including tall stature and macrocephaly
Sleep disturbance
Gastrointestinal problems, especially constipation
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
The vast majority of exon-level deletions/duplications in
• Developmental delay (DD) and/or intellectual disability (ID) (typically in the mild-to-moderate range)
• Neuropsychiatric disorders, including autism spectrum disorder (ASD)
• Generalized overgrowth, including tall stature and macrocephaly
• Sleep disturbance
• Gastrointestinal problems, especially constipation
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Developmental delay (DD) and/or intellectual disability (ID) (typically in the mild-to-moderate range)
Neuropsychiatric disorders, including autism spectrum disorder (ASD)
Generalized overgrowth, including tall stature and macrocephaly
Sleep disturbance
Gastrointestinal problems, especially constipation
• Developmental delay (DD) and/or intellectual disability (ID) (typically in the mild-to-moderate range)
• Neuropsychiatric disorders, including autism spectrum disorder (ASD)
• Generalized overgrowth, including tall stature and macrocephaly
• Sleep disturbance
• Gastrointestinal problems, especially constipation
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
The vast majority of exon-level deletions/duplications in
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
To date, 115 individuals have been identified with a pathogenic heterozygous sequence variant in
Of the 103 individuals for whom sex is known, 69 (67%) are male. This suggests a 2:1 male-to-female ratio, which is lower than the sex disparity previously reported [
The following description of the phenotypic features associated with
Select Features of
Most, if not all, affected persons have some degree of DD.
Speech & motor delays are common.
ID is usually mild to moderate.
Possible developmental regression is observed in up to half of affected persons.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disorder
When reported, delayed early motor milestones are present in 90% of affected individuals.
For those with delays, independent walking is usually achieved by age two years, although there is significant variability; one affected child was not yet walking at age nine years [
Some affected individuals experience ongoing motor coordination difficulties, including poor fine motor skills [
The severity ranges from mild to severe, although most individuals show cognitive impairment in the mild-to-moderate range.
Some individuals do not have ID but may have borderline intellectual functioning or learning disabilities [
The average severity of autism symptoms is within the moderate range as measured by the Autism Diagnostic Observation Schedule (ADOS-2) [
A majority of affected individuals (approximately 80%) with
However, the majority of reports in the current literature describe children and may underrepresent the prevalence of adult-onset psychiatric conditions.
There are several case reports of more severe adult-onset psychiatric manifestations, including psychosis, schizophrenia, and catatonia [
Aggression and self-injury have also been noted in several individuals with
Ventriculomegaly (3 affected individuals)
Increased signal of periventricular white matter (2 affected individuals)
Cerebellar vermis atrophy (2 affected individuals)
Lack of white matter bulk (1 affected individual)
Chiari I malformation (3 affected individuals who all also had macrocephaly)
Macrocephaly is sometimes apparent at birth but often develops or is accentuated in infancy [
Tall stature often becomes apparent in puberty [
While some individuals are also reported to be overweight [
Inflammatory bowel disease
Gastropathy (without further definition of the specific issues in this particular affected individual [
Cyclical vomiting
Gastroesophageal reflux
Eosinophilic esophagitis
Autoimmune diabetes mellitus was reported in one individual with progressive dystonia [
Precocious puberty was diagnosed in two girls [
No genotype-phenotype correlations have been identified.
Large population-based studies are lacking, making prevalence estimates difficult to calculate for the general population.
In one study, nine in 2,446 individuals with autism spectrum disorder and eight in 3,730 individuals with a variety of neurodevelopmental disorders were found to have a
• Most, if not all, affected persons have some degree of DD.
• Speech & motor delays are common.
• ID is usually mild to moderate.
• Possible developmental regression is observed in up to half of affected persons.
•
• When reported, delayed early motor milestones are present in 90% of affected individuals.
• For those with delays, independent walking is usually achieved by age two years, although there is significant variability; one affected child was not yet walking at age nine years [
• Some affected individuals experience ongoing motor coordination difficulties, including poor fine motor skills [
• When reported, delayed early motor milestones are present in 90% of affected individuals.
• For those with delays, independent walking is usually achieved by age two years, although there is significant variability; one affected child was not yet walking at age nine years [
• Some affected individuals experience ongoing motor coordination difficulties, including poor fine motor skills [
• The severity ranges from mild to severe, although most individuals show cognitive impairment in the mild-to-moderate range.
• Some individuals do not have ID but may have borderline intellectual functioning or learning disabilities [
• The severity ranges from mild to severe, although most individuals show cognitive impairment in the mild-to-moderate range.
• Some individuals do not have ID but may have borderline intellectual functioning or learning disabilities [
• The average severity of autism symptoms is within the moderate range as measured by the Autism Diagnostic Observation Schedule (ADOS-2) [
• A majority of affected individuals (approximately 80%) with
• The average severity of autism symptoms is within the moderate range as measured by the Autism Diagnostic Observation Schedule (ADOS-2) [
• A majority of affected individuals (approximately 80%) with
• However, the majority of reports in the current literature describe children and may underrepresent the prevalence of adult-onset psychiatric conditions.
• There are several case reports of more severe adult-onset psychiatric manifestations, including psychosis, schizophrenia, and catatonia [
• Aggression and self-injury have also been noted in several individuals with
• However, the majority of reports in the current literature describe children and may underrepresent the prevalence of adult-onset psychiatric conditions.
• There are several case reports of more severe adult-onset psychiatric manifestations, including psychosis, schizophrenia, and catatonia [
• Aggression and self-injury have also been noted in several individuals with
• When reported, delayed early motor milestones are present in 90% of affected individuals.
• For those with delays, independent walking is usually achieved by age two years, although there is significant variability; one affected child was not yet walking at age nine years [
• Some affected individuals experience ongoing motor coordination difficulties, including poor fine motor skills [
• The severity ranges from mild to severe, although most individuals show cognitive impairment in the mild-to-moderate range.
• Some individuals do not have ID but may have borderline intellectual functioning or learning disabilities [
• The average severity of autism symptoms is within the moderate range as measured by the Autism Diagnostic Observation Schedule (ADOS-2) [
• A majority of affected individuals (approximately 80%) with
• However, the majority of reports in the current literature describe children and may underrepresent the prevalence of adult-onset psychiatric conditions.
• There are several case reports of more severe adult-onset psychiatric manifestations, including psychosis, schizophrenia, and catatonia [
• Aggression and self-injury have also been noted in several individuals with
• Ventriculomegaly (3 affected individuals)
• Increased signal of periventricular white matter (2 affected individuals)
• Cerebellar vermis atrophy (2 affected individuals)
• Lack of white matter bulk (1 affected individual)
• Chiari I malformation (3 affected individuals who all also had macrocephaly)
• Ventriculomegaly (3 affected individuals)
• Increased signal of periventricular white matter (2 affected individuals)
• Cerebellar vermis atrophy (2 affected individuals)
• Lack of white matter bulk (1 affected individual)
• Chiari I malformation (3 affected individuals who all also had macrocephaly)
• Ventriculomegaly (3 affected individuals)
• Increased signal of periventricular white matter (2 affected individuals)
• Cerebellar vermis atrophy (2 affected individuals)
• Lack of white matter bulk (1 affected individual)
• Chiari I malformation (3 affected individuals who all also had macrocephaly)
• Macrocephaly is sometimes apparent at birth but often develops or is accentuated in infancy [
• Tall stature often becomes apparent in puberty [
• While some individuals are also reported to be overweight [
• Inflammatory bowel disease
• Gastropathy (without further definition of the specific issues in this particular affected individual [
• Cyclical vomiting
• Gastroesophageal reflux
• Eosinophilic esophagitis
•
• Autoimmune diabetes mellitus was reported in one individual with progressive dystonia [
• Precocious puberty was diagnosed in two girls [
• Autoimmune diabetes mellitus was reported in one individual with progressive dystonia [
• Precocious puberty was diagnosed in two girls [
• Autoimmune diabetes mellitus was reported in one individual with progressive dystonia [
• Precocious puberty was diagnosed in two girls [
## Clinical Description
To date, 115 individuals have been identified with a pathogenic heterozygous sequence variant in
Of the 103 individuals for whom sex is known, 69 (67%) are male. This suggests a 2:1 male-to-female ratio, which is lower than the sex disparity previously reported [
The following description of the phenotypic features associated with
Select Features of
Most, if not all, affected persons have some degree of DD.
Speech & motor delays are common.
ID is usually mild to moderate.
Possible developmental regression is observed in up to half of affected persons.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disorder
When reported, delayed early motor milestones are present in 90% of affected individuals.
For those with delays, independent walking is usually achieved by age two years, although there is significant variability; one affected child was not yet walking at age nine years [
Some affected individuals experience ongoing motor coordination difficulties, including poor fine motor skills [
The severity ranges from mild to severe, although most individuals show cognitive impairment in the mild-to-moderate range.
Some individuals do not have ID but may have borderline intellectual functioning or learning disabilities [
The average severity of autism symptoms is within the moderate range as measured by the Autism Diagnostic Observation Schedule (ADOS-2) [
A majority of affected individuals (approximately 80%) with
However, the majority of reports in the current literature describe children and may underrepresent the prevalence of adult-onset psychiatric conditions.
There are several case reports of more severe adult-onset psychiatric manifestations, including psychosis, schizophrenia, and catatonia [
Aggression and self-injury have also been noted in several individuals with
Ventriculomegaly (3 affected individuals)
Increased signal of periventricular white matter (2 affected individuals)
Cerebellar vermis atrophy (2 affected individuals)
Lack of white matter bulk (1 affected individual)
Chiari I malformation (3 affected individuals who all also had macrocephaly)
Macrocephaly is sometimes apparent at birth but often develops or is accentuated in infancy [
Tall stature often becomes apparent in puberty [
While some individuals are also reported to be overweight [
Inflammatory bowel disease
Gastropathy (without further definition of the specific issues in this particular affected individual [
Cyclical vomiting
Gastroesophageal reflux
Eosinophilic esophagitis
Autoimmune diabetes mellitus was reported in one individual with progressive dystonia [
Precocious puberty was diagnosed in two girls [
• Most, if not all, affected persons have some degree of DD.
• Speech & motor delays are common.
• ID is usually mild to moderate.
• Possible developmental regression is observed in up to half of affected persons.
•
• When reported, delayed early motor milestones are present in 90% of affected individuals.
• For those with delays, independent walking is usually achieved by age two years, although there is significant variability; one affected child was not yet walking at age nine years [
• Some affected individuals experience ongoing motor coordination difficulties, including poor fine motor skills [
• When reported, delayed early motor milestones are present in 90% of affected individuals.
• For those with delays, independent walking is usually achieved by age two years, although there is significant variability; one affected child was not yet walking at age nine years [
• Some affected individuals experience ongoing motor coordination difficulties, including poor fine motor skills [
• The severity ranges from mild to severe, although most individuals show cognitive impairment in the mild-to-moderate range.
• Some individuals do not have ID but may have borderline intellectual functioning or learning disabilities [
• The severity ranges from mild to severe, although most individuals show cognitive impairment in the mild-to-moderate range.
• Some individuals do not have ID but may have borderline intellectual functioning or learning disabilities [
• The average severity of autism symptoms is within the moderate range as measured by the Autism Diagnostic Observation Schedule (ADOS-2) [
• A majority of affected individuals (approximately 80%) with
• The average severity of autism symptoms is within the moderate range as measured by the Autism Diagnostic Observation Schedule (ADOS-2) [
• A majority of affected individuals (approximately 80%) with
• However, the majority of reports in the current literature describe children and may underrepresent the prevalence of adult-onset psychiatric conditions.
• There are several case reports of more severe adult-onset psychiatric manifestations, including psychosis, schizophrenia, and catatonia [
• Aggression and self-injury have also been noted in several individuals with
• However, the majority of reports in the current literature describe children and may underrepresent the prevalence of adult-onset psychiatric conditions.
• There are several case reports of more severe adult-onset psychiatric manifestations, including psychosis, schizophrenia, and catatonia [
• Aggression and self-injury have also been noted in several individuals with
• When reported, delayed early motor milestones are present in 90% of affected individuals.
• For those with delays, independent walking is usually achieved by age two years, although there is significant variability; one affected child was not yet walking at age nine years [
• Some affected individuals experience ongoing motor coordination difficulties, including poor fine motor skills [
• The severity ranges from mild to severe, although most individuals show cognitive impairment in the mild-to-moderate range.
• Some individuals do not have ID but may have borderline intellectual functioning or learning disabilities [
• The average severity of autism symptoms is within the moderate range as measured by the Autism Diagnostic Observation Schedule (ADOS-2) [
• A majority of affected individuals (approximately 80%) with
• However, the majority of reports in the current literature describe children and may underrepresent the prevalence of adult-onset psychiatric conditions.
• There are several case reports of more severe adult-onset psychiatric manifestations, including psychosis, schizophrenia, and catatonia [
• Aggression and self-injury have also been noted in several individuals with
• Ventriculomegaly (3 affected individuals)
• Increased signal of periventricular white matter (2 affected individuals)
• Cerebellar vermis atrophy (2 affected individuals)
• Lack of white matter bulk (1 affected individual)
• Chiari I malformation (3 affected individuals who all also had macrocephaly)
• Ventriculomegaly (3 affected individuals)
• Increased signal of periventricular white matter (2 affected individuals)
• Cerebellar vermis atrophy (2 affected individuals)
• Lack of white matter bulk (1 affected individual)
• Chiari I malformation (3 affected individuals who all also had macrocephaly)
• Ventriculomegaly (3 affected individuals)
• Increased signal of periventricular white matter (2 affected individuals)
• Cerebellar vermis atrophy (2 affected individuals)
• Lack of white matter bulk (1 affected individual)
• Chiari I malformation (3 affected individuals who all also had macrocephaly)
• Macrocephaly is sometimes apparent at birth but often develops or is accentuated in infancy [
• Tall stature often becomes apparent in puberty [
• While some individuals are also reported to be overweight [
• Inflammatory bowel disease
• Gastropathy (without further definition of the specific issues in this particular affected individual [
• Cyclical vomiting
• Gastroesophageal reflux
• Eosinophilic esophagitis
•
• Autoimmune diabetes mellitus was reported in one individual with progressive dystonia [
• Precocious puberty was diagnosed in two girls [
• Autoimmune diabetes mellitus was reported in one individual with progressive dystonia [
• Precocious puberty was diagnosed in two girls [
• Autoimmune diabetes mellitus was reported in one individual with progressive dystonia [
• Precocious puberty was diagnosed in two girls [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Prevalence
Large population-based studies are lacking, making prevalence estimates difficult to calculate for the general population.
In one study, nine in 2,446 individuals with autism spectrum disorder and eight in 3,730 individuals with a variety of neurodevelopmental disorders were found to have a
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Overgrowth Conditions to Consider in the Differential Diagnosis of
AD = autosomal dominant; ASD = autism spectrum disorder;
Beckwith-Wiedemann syndrome is associated with abnormal regulation of gene transcription in two imprinted domains on chromosome 11p15.5 (also known as the BWS critical region). Regulation may be disrupted by any one of numerous mechanisms (see
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
To incl eval of cognitive, speech-language, adaptive, social/emotional, & motor skills
Eval for early intervention / special education
Consider referral to developmental pediatrician, psychologist, &/or speech-language pathologist as warranted.
Incl screening for concerns such as sleep disturbances, ADHD, anxiety, & findings suggestive of ASD
Consider referral to psychologist &/or psychiatrist as warranted.
To incl brain MRI if HC ≥3 SDs above mean, person has rapidly ↑ HC, or signs/symptoms of CSF obstruction
To incl spinal cord MRI if signs/symptoms of spinal cord dysfunction
To incl EEG if history of signs/symptoms suggestive of seizures
Consider neurology consultation as clinically indicated.
Assessment for signs/symptoms of sleep problems
Consider polysomnogram.
To incl assessment for difficulty falling asleep & frequent or prolonged awakenings at night
Consider referral to sleep medicine &/or psychologist, as warranted.
To incl eval for constipation & other GI problems
Consider referral to gastroenterologist, as warranted.
Community &
Social work involvement for parental support;
Other services such as home nursing.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; CSF = cerebrospinal fluid; EEG = electroencephalography; GI = gastrointestinal; HC = head circumference; MOI = mode of inheritance; MRI = magnetic resonance imaging; SD = standard deviation
For example, for weakness, abnormal tone, abnormal deep tendon reflexes, loss of pain and temperature sensation, numbness/tingling of hands or feet
For example, valsalva-induced occipital headache or cervical pain
For example, dysphagia, central sleep apnea, hoarseness or dysarthria, dizziness, tinnitus, ataxia
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for
Treatment of Manifestations in Individuals with
Many ASMs may be effective; none has been demonstrated effective specifically for
Education of parents/caregivers
Behavioral interventions
Pharmacologic interventions may also be considered.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; C1 = first cervical vertebra; GI = gastrointestinal
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
For example, cognitive behavioral therapy, including sleep restriction therapy
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA-based interventions, including naturalistic developmental behavioral interventions (NDBI), are targeted to the individual child's behavioral, social, and adaptive strengths/weaknesses and typically performed or supervised by a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, or other psychiatric or behavioral symptoms when necessary.
Concerns about aggressive or self-injurious behavior can be addressed by a pediatric psychiatrist or board-certified behavior analyst.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended.
Recommended Surveillance for Individuals with
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
Head circumference should be measured until adulthood.
For example, valsalva-induced occipital headache or cervical pain
For example, dysphagia, central sleep apnea, hoarseness or dysarthria, dizziness, tinnitus, ataxia
For example, weakness, abnormal tone, abnormal deep tendon reflexes, loss of pain and temperature sensation, numbness/tingling of hands or feet
In some situations, an asymptomatic or minimally symptomatic Chiari I malformation that does not require immediate surgical intervention may be detected and may require clinical and MRI monitoring.
See
Search
• To incl eval of cognitive, speech-language, adaptive, social/emotional, & motor skills
• Eval for early intervention / special education
• Consider referral to developmental pediatrician, psychologist, &/or speech-language pathologist as warranted.
• Incl screening for concerns such as sleep disturbances, ADHD, anxiety, & findings suggestive of ASD
• Consider referral to psychologist &/or psychiatrist as warranted.
• To incl brain MRI if HC ≥3 SDs above mean, person has rapidly ↑ HC, or signs/symptoms of CSF obstruction
• To incl spinal cord MRI if signs/symptoms of spinal cord dysfunction
• To incl EEG if history of signs/symptoms suggestive of seizures
• Consider neurology consultation as clinically indicated.
• Assessment for signs/symptoms of sleep problems
• Consider polysomnogram.
• To incl assessment for difficulty falling asleep & frequent or prolonged awakenings at night
• Consider referral to sleep medicine &/or psychologist, as warranted.
• To incl eval for constipation & other GI problems
• Consider referral to gastroenterologist, as warranted.
• Community &
• Social work involvement for parental support;
• Other services such as home nursing.
• Many ASMs may be effective; none has been demonstrated effective specifically for
• Education of parents/caregivers
• Behavioral interventions
• Pharmacologic interventions may also be considered.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
To incl eval of cognitive, speech-language, adaptive, social/emotional, & motor skills
Eval for early intervention / special education
Consider referral to developmental pediatrician, psychologist, &/or speech-language pathologist as warranted.
Incl screening for concerns such as sleep disturbances, ADHD, anxiety, & findings suggestive of ASD
Consider referral to psychologist &/or psychiatrist as warranted.
To incl brain MRI if HC ≥3 SDs above mean, person has rapidly ↑ HC, or signs/symptoms of CSF obstruction
To incl spinal cord MRI if signs/symptoms of spinal cord dysfunction
To incl EEG if history of signs/symptoms suggestive of seizures
Consider neurology consultation as clinically indicated.
Assessment for signs/symptoms of sleep problems
Consider polysomnogram.
To incl assessment for difficulty falling asleep & frequent or prolonged awakenings at night
Consider referral to sleep medicine &/or psychologist, as warranted.
To incl eval for constipation & other GI problems
Consider referral to gastroenterologist, as warranted.
Community &
Social work involvement for parental support;
Other services such as home nursing.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; CSF = cerebrospinal fluid; EEG = electroencephalography; GI = gastrointestinal; HC = head circumference; MOI = mode of inheritance; MRI = magnetic resonance imaging; SD = standard deviation
For example, for weakness, abnormal tone, abnormal deep tendon reflexes, loss of pain and temperature sensation, numbness/tingling of hands or feet
For example, valsalva-induced occipital headache or cervical pain
For example, dysphagia, central sleep apnea, hoarseness or dysarthria, dizziness, tinnitus, ataxia
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl eval of cognitive, speech-language, adaptive, social/emotional, & motor skills
• Eval for early intervention / special education
• Consider referral to developmental pediatrician, psychologist, &/or speech-language pathologist as warranted.
• Incl screening for concerns such as sleep disturbances, ADHD, anxiety, & findings suggestive of ASD
• Consider referral to psychologist &/or psychiatrist as warranted.
• To incl brain MRI if HC ≥3 SDs above mean, person has rapidly ↑ HC, or signs/symptoms of CSF obstruction
• To incl spinal cord MRI if signs/symptoms of spinal cord dysfunction
• To incl EEG if history of signs/symptoms suggestive of seizures
• Consider neurology consultation as clinically indicated.
• Assessment for signs/symptoms of sleep problems
• Consider polysomnogram.
• To incl assessment for difficulty falling asleep & frequent or prolonged awakenings at night
• Consider referral to sleep medicine &/or psychologist, as warranted.
• To incl eval for constipation & other GI problems
• Consider referral to gastroenterologist, as warranted.
• Community &
• Social work involvement for parental support;
• Other services such as home nursing.
## Treatment of Manifestations
There is no cure for
Treatment of Manifestations in Individuals with
Many ASMs may be effective; none has been demonstrated effective specifically for
Education of parents/caregivers
Behavioral interventions
Pharmacologic interventions may also be considered.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; C1 = first cervical vertebra; GI = gastrointestinal
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
For example, cognitive behavioral therapy, including sleep restriction therapy
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA-based interventions, including naturalistic developmental behavioral interventions (NDBI), are targeted to the individual child's behavioral, social, and adaptive strengths/weaknesses and typically performed or supervised by a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, or other psychiatric or behavioral symptoms when necessary.
Concerns about aggressive or self-injurious behavior can be addressed by a pediatric psychiatrist or board-certified behavior analyst.
• Many ASMs may be effective; none has been demonstrated effective specifically for
• Education of parents/caregivers
• Behavioral interventions
• Pharmacologic interventions may also be considered.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA-based interventions, including naturalistic developmental behavioral interventions (NDBI), are targeted to the individual child's behavioral, social, and adaptive strengths/weaknesses and typically performed or supervised by a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, or other psychiatric or behavioral symptoms when necessary.
Concerns about aggressive or self-injurious behavior can be addressed by a pediatric psychiatrist or board-certified behavior analyst.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended.
Recommended Surveillance for Individuals with
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
Head circumference should be measured until adulthood.
For example, valsalva-induced occipital headache or cervical pain
For example, dysphagia, central sleep apnea, hoarseness or dysarthria, dizziness, tinnitus, ataxia
For example, weakness, abnormal tone, abnormal deep tendon reflexes, loss of pain and temperature sensation, numbness/tingling of hands or feet
In some situations, an asymptomatic or minimally symptomatic Chiari I malformation that does not require immediate surgical intervention may be detected and may require clinical and MRI monitoring.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Most probands (85%-90%) reported to date with
An individual diagnosed with
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If a parent of the proband is known to have the
If the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Most probands (85%-90%) reported to date with
• An individual diagnosed with
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is known to have the
• If the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
## Risk to Family Members
Most probands (85%-90%) reported to date with
An individual diagnosed with
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If a parent of the proband is known to have the
If the
• Most probands (85%-90%) reported to date with
• An individual diagnosed with
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is known to have the
• If the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
• United Kingdom
•
•
•
•
## Molecular Genetics
CHD8-Related Neurodevelopmental Disorder with Overgrowth: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CHD8-Related Neurodevelopmental Disorder with Overgrowth (
Preliminary research in a zebra fish model suggests that gastrointestinal problems associated with
Somatic
Heterozygous pathogenic loss-of-function variants cause
## Molecular Pathogenesis
Preliminary research in a zebra fish model suggests that gastrointestinal problems associated with
Somatic
Heterozygous pathogenic loss-of-function variants cause
## Chapter Notes
This work was supported by the National Institute of Mental Health of the National Institutes of Health, grant numbers U01MH119705 and R01MH074090. The authors would also like to thank all of the individuals and families with
27 October 2022 (ma) Review posted live
22 March 2022 (cm) Original submission
• 27 October 2022 (ma) Review posted live
• 22 March 2022 (cm) Original submission
## Acknowledgments
This work was supported by the National Institute of Mental Health of the National Institutes of Health, grant numbers U01MH119705 and R01MH074090. The authors would also like to thank all of the individuals and families with
## Revision History
27 October 2022 (ma) Review posted live
22 March 2022 (cm) Original submission
• 27 October 2022 (ma) Review posted live
• 22 March 2022 (cm) Original submission
## References
## Literature Cited
|
[] |
27/10/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
chediak-higashi
|
chediak-higashi
|
[
"Classic Chediak-Higashi Syndrome",
"Atypical Chediak-Higashi Syndrome",
"Lysosomal-trafficking regulator",
"LYST",
"Chediak-Higashi Syndrome"
] |
Chediak-Higashi Syndrome
|
Camilo Toro, Marie Morimoto, May Christine Malicdan, David R Adams, Wendy J Introne
|
Summary Chediak-Higashi syndrome (CHS) is characterized by partial oculocutaneous albinism (OCA), immunodeficiency, a mild bleeding tendency, and late adolescent- to adult-onset neurologic manifestations (e.g., learning difficulties, peripheral neuropathy, ataxia, and parkinsonism). While present in nearly all individuals with CHS, these clinical findings vary in severity. Of note, all individuals with CHS are at risk of developing neurologic manifestations and hemophagocytic lymphohistiocytosis (HLH). Individuals with severe childhood-onset presentations are considered to have "classic" CHS, whereas individuals with milder adolescent- to adult-onset presentations are considered to have "atypical" CHS. Because of the considerable overlap between classic CHS and atypical CHS, the disorder is best understood as a continuum of severe to milder phenotypes, with the universal feature being the pathognomonic giant granules within leukocytes observed on peripheral blood smear. The clinical diagnosis of CHS is established in a proband with suggestive clinical findings by identification of the pathognomonic giant granules within leukocytes on peripheral blood smear and/or biallelic pathogenic variants in CHS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
Chediak-Higashi syndrome (CHS) is characterized by partial oculocutaneous albinism (OCA), immunodeficiency, a mild bleeding tendency, and late adolescent- to adult-onset neurologic manifestations (e.g., learning difficulties, peripheral neuropathy, ataxia, and parkinsonism). All individuals are at risk of developing hemophagocytic lymphohistiocytosis (HLH).
While present in nearly all individuals with CHS, these clinical findings vary in severity. Individuals with severe presentations (see
Based on
CHS = Chediak-Higashi syndrome; HLH = hemophagocytic lymphohistiocytosis; OCA = oculocutaneous albinism
Also called "accelerated phase"
## Diagnosis
The diagnosis of Chediak-Higashi syndrome (CHS)
Signs and symptoms of low vision typical of OCA
Reduced iris pigmentation (manifesting as iris transillumination often only on ophthalmologic examination). Note that irides may be darker than the light blue that is often associated with OCA.
Reduced retinal pigmentation
Hair that may have a silvery-gray sheen
A significant history of infections (particularly bacterial) of the skin and respiratory tract; also increased susceptibility to periodontal disease
Mild bleeding tendency associated with platelet dysfunction such as epistaxis, gum/mucosal bleeding, and easy bruising
Increased risk for hemophagocytic lymphohistiocytosis (HLH) (previously called "CHS accelerated phase"). Clinical findings and diagnostic criteria are the same as those for
Childhood- to early adult-onset neurologic manifestations, including:
Learning difficulties
Peripheral neuropathy
Ataxia
Parkinsonism
White blood cell (WBC) giant granules (also called "inclusions"), peroxidase-positive granules primarily in polymorphonuclear neutrophils (PMNs) and to a lesser extent in lymphocytes (
Although the giant granules are seen using routine staining techniques, in some individuals with atypical CHS the presence of these giant granules can be less striking and thus missed by routine evaluation.
Slide review is optimally conducted by a hematologist or other specialist with experience reviewing blood smears for the presence of abnormal granules.
Because the finding of WBC giant granules is the most reliable clinical diagnostic criterion for CHS, the combination of any of the other hematologic findings listed below should prompt review of a peripheral blood smear to evaluate for giant granules.
Other hematologic findings:
Absent or reduced number and/or irregular morphology of platelet-dense bodies (required for the secondary wave of platelet aggregation) on whole-mount electron microscopy (
Normal or reduced number of natural killer cells with abnormal (reduced) function
Neutropenia
Normal immunoglobulins, complement, antibody production, and delayed hypersensitivity
The
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Chediak-Higashi Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Several pathogenic variants were identified that were determined to lead to exon skipping by cDNA Sanger sequencing, but the exact genomic variant leading to these exon-skipping events has not been determined [
• Signs and symptoms of low vision typical of OCA
• Reduced iris pigmentation (manifesting as iris transillumination often only on ophthalmologic examination). Note that irides may be darker than the light blue that is often associated with OCA.
• Reduced retinal pigmentation
• Hair that may have a silvery-gray sheen
• Signs and symptoms of low vision typical of OCA
• Reduced iris pigmentation (manifesting as iris transillumination often only on ophthalmologic examination). Note that irides may be darker than the light blue that is often associated with OCA.
• Reduced retinal pigmentation
• Hair that may have a silvery-gray sheen
• A significant history of infections (particularly bacterial) of the skin and respiratory tract; also increased susceptibility to periodontal disease
• Mild bleeding tendency associated with platelet dysfunction such as epistaxis, gum/mucosal bleeding, and easy bruising
• Increased risk for hemophagocytic lymphohistiocytosis (HLH) (previously called "CHS accelerated phase"). Clinical findings and diagnostic criteria are the same as those for
• Childhood- to early adult-onset neurologic manifestations, including:
• Learning difficulties
• Peripheral neuropathy
• Ataxia
• Parkinsonism
• Learning difficulties
• Peripheral neuropathy
• Ataxia
• Parkinsonism
• Signs and symptoms of low vision typical of OCA
• Reduced iris pigmentation (manifesting as iris transillumination often only on ophthalmologic examination). Note that irides may be darker than the light blue that is often associated with OCA.
• Reduced retinal pigmentation
• Hair that may have a silvery-gray sheen
• Learning difficulties
• Peripheral neuropathy
• Ataxia
• Parkinsonism
• White blood cell (WBC) giant granules (also called "inclusions"), peroxidase-positive granules primarily in polymorphonuclear neutrophils (PMNs) and to a lesser extent in lymphocytes (
• Although the giant granules are seen using routine staining techniques, in some individuals with atypical CHS the presence of these giant granules can be less striking and thus missed by routine evaluation.
• Slide review is optimally conducted by a hematologist or other specialist with experience reviewing blood smears for the presence of abnormal granules.
• Because the finding of WBC giant granules is the most reliable clinical diagnostic criterion for CHS, the combination of any of the other hematologic findings listed below should prompt review of a peripheral blood smear to evaluate for giant granules.
• Although the giant granules are seen using routine staining techniques, in some individuals with atypical CHS the presence of these giant granules can be less striking and thus missed by routine evaluation.
• Slide review is optimally conducted by a hematologist or other specialist with experience reviewing blood smears for the presence of abnormal granules.
• Because the finding of WBC giant granules is the most reliable clinical diagnostic criterion for CHS, the combination of any of the other hematologic findings listed below should prompt review of a peripheral blood smear to evaluate for giant granules.
• Other hematologic findings:
• Absent or reduced number and/or irregular morphology of platelet-dense bodies (required for the secondary wave of platelet aggregation) on whole-mount electron microscopy (
• Normal or reduced number of natural killer cells with abnormal (reduced) function
• Neutropenia
• Normal immunoglobulins, complement, antibody production, and delayed hypersensitivity
• Absent or reduced number and/or irregular morphology of platelet-dense bodies (required for the secondary wave of platelet aggregation) on whole-mount electron microscopy (
• Normal or reduced number of natural killer cells with abnormal (reduced) function
• Neutropenia
• Normal immunoglobulins, complement, antibody production, and delayed hypersensitivity
• Although the giant granules are seen using routine staining techniques, in some individuals with atypical CHS the presence of these giant granules can be less striking and thus missed by routine evaluation.
• Slide review is optimally conducted by a hematologist or other specialist with experience reviewing blood smears for the presence of abnormal granules.
• Because the finding of WBC giant granules is the most reliable clinical diagnostic criterion for CHS, the combination of any of the other hematologic findings listed below should prompt review of a peripheral blood smear to evaluate for giant granules.
• Absent or reduced number and/or irregular morphology of platelet-dense bodies (required for the secondary wave of platelet aggregation) on whole-mount electron microscopy (
• Normal or reduced number of natural killer cells with abnormal (reduced) function
• Neutropenia
• Normal immunoglobulins, complement, antibody production, and delayed hypersensitivity
## Suggestive Findings
The diagnosis of Chediak-Higashi syndrome (CHS)
Signs and symptoms of low vision typical of OCA
Reduced iris pigmentation (manifesting as iris transillumination often only on ophthalmologic examination). Note that irides may be darker than the light blue that is often associated with OCA.
Reduced retinal pigmentation
Hair that may have a silvery-gray sheen
A significant history of infections (particularly bacterial) of the skin and respiratory tract; also increased susceptibility to periodontal disease
Mild bleeding tendency associated with platelet dysfunction such as epistaxis, gum/mucosal bleeding, and easy bruising
Increased risk for hemophagocytic lymphohistiocytosis (HLH) (previously called "CHS accelerated phase"). Clinical findings and diagnostic criteria are the same as those for
Childhood- to early adult-onset neurologic manifestations, including:
Learning difficulties
Peripheral neuropathy
Ataxia
Parkinsonism
White blood cell (WBC) giant granules (also called "inclusions"), peroxidase-positive granules primarily in polymorphonuclear neutrophils (PMNs) and to a lesser extent in lymphocytes (
Although the giant granules are seen using routine staining techniques, in some individuals with atypical CHS the presence of these giant granules can be less striking and thus missed by routine evaluation.
Slide review is optimally conducted by a hematologist or other specialist with experience reviewing blood smears for the presence of abnormal granules.
Because the finding of WBC giant granules is the most reliable clinical diagnostic criterion for CHS, the combination of any of the other hematologic findings listed below should prompt review of a peripheral blood smear to evaluate for giant granules.
Other hematologic findings:
Absent or reduced number and/or irregular morphology of platelet-dense bodies (required for the secondary wave of platelet aggregation) on whole-mount electron microscopy (
Normal or reduced number of natural killer cells with abnormal (reduced) function
Neutropenia
Normal immunoglobulins, complement, antibody production, and delayed hypersensitivity
• Signs and symptoms of low vision typical of OCA
• Reduced iris pigmentation (manifesting as iris transillumination often only on ophthalmologic examination). Note that irides may be darker than the light blue that is often associated with OCA.
• Reduced retinal pigmentation
• Hair that may have a silvery-gray sheen
• Signs and symptoms of low vision typical of OCA
• Reduced iris pigmentation (manifesting as iris transillumination often only on ophthalmologic examination). Note that irides may be darker than the light blue that is often associated with OCA.
• Reduced retinal pigmentation
• Hair that may have a silvery-gray sheen
• A significant history of infections (particularly bacterial) of the skin and respiratory tract; also increased susceptibility to periodontal disease
• Mild bleeding tendency associated with platelet dysfunction such as epistaxis, gum/mucosal bleeding, and easy bruising
• Increased risk for hemophagocytic lymphohistiocytosis (HLH) (previously called "CHS accelerated phase"). Clinical findings and diagnostic criteria are the same as those for
• Childhood- to early adult-onset neurologic manifestations, including:
• Learning difficulties
• Peripheral neuropathy
• Ataxia
• Parkinsonism
• Learning difficulties
• Peripheral neuropathy
• Ataxia
• Parkinsonism
• Signs and symptoms of low vision typical of OCA
• Reduced iris pigmentation (manifesting as iris transillumination often only on ophthalmologic examination). Note that irides may be darker than the light blue that is often associated with OCA.
• Reduced retinal pigmentation
• Hair that may have a silvery-gray sheen
• Learning difficulties
• Peripheral neuropathy
• Ataxia
• Parkinsonism
• White blood cell (WBC) giant granules (also called "inclusions"), peroxidase-positive granules primarily in polymorphonuclear neutrophils (PMNs) and to a lesser extent in lymphocytes (
• Although the giant granules are seen using routine staining techniques, in some individuals with atypical CHS the presence of these giant granules can be less striking and thus missed by routine evaluation.
• Slide review is optimally conducted by a hematologist or other specialist with experience reviewing blood smears for the presence of abnormal granules.
• Because the finding of WBC giant granules is the most reliable clinical diagnostic criterion for CHS, the combination of any of the other hematologic findings listed below should prompt review of a peripheral blood smear to evaluate for giant granules.
• Although the giant granules are seen using routine staining techniques, in some individuals with atypical CHS the presence of these giant granules can be less striking and thus missed by routine evaluation.
• Slide review is optimally conducted by a hematologist or other specialist with experience reviewing blood smears for the presence of abnormal granules.
• Because the finding of WBC giant granules is the most reliable clinical diagnostic criterion for CHS, the combination of any of the other hematologic findings listed below should prompt review of a peripheral blood smear to evaluate for giant granules.
• Other hematologic findings:
• Absent or reduced number and/or irregular morphology of platelet-dense bodies (required for the secondary wave of platelet aggregation) on whole-mount electron microscopy (
• Normal or reduced number of natural killer cells with abnormal (reduced) function
• Neutropenia
• Normal immunoglobulins, complement, antibody production, and delayed hypersensitivity
• Absent or reduced number and/or irregular morphology of platelet-dense bodies (required for the secondary wave of platelet aggregation) on whole-mount electron microscopy (
• Normal or reduced number of natural killer cells with abnormal (reduced) function
• Neutropenia
• Normal immunoglobulins, complement, antibody production, and delayed hypersensitivity
• Although the giant granules are seen using routine staining techniques, in some individuals with atypical CHS the presence of these giant granules can be less striking and thus missed by routine evaluation.
• Slide review is optimally conducted by a hematologist or other specialist with experience reviewing blood smears for the presence of abnormal granules.
• Because the finding of WBC giant granules is the most reliable clinical diagnostic criterion for CHS, the combination of any of the other hematologic findings listed below should prompt review of a peripheral blood smear to evaluate for giant granules.
• Absent or reduced number and/or irregular morphology of platelet-dense bodies (required for the secondary wave of platelet aggregation) on whole-mount electron microscopy (
• Normal or reduced number of natural killer cells with abnormal (reduced) function
• Neutropenia
• Normal immunoglobulins, complement, antibody production, and delayed hypersensitivity
## Establishing the Diagnosis
The
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Chediak-Higashi Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Several pathogenic variants were identified that were determined to lead to exon skipping by cDNA Sanger sequencing, but the exact genomic variant leading to these exon-skipping events has not been determined [
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Chediak-Higashi Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Several pathogenic variants were identified that were determined to lead to exon skipping by cDNA Sanger sequencing, but the exact genomic variant leading to these exon-skipping events has not been determined [
## Clinical Characteristics
Chediak-Higashi syndrome (CHS) is characterized by partial oculocutaneous albinism (OCA), immunodeficiency, and a mild bleeding tendency. These features are present in nearly all individuals with CHS but to a very variable degree. Affected individuals with severe presentations (i.e., OCA; early-onset, recurrent, severe infections; and a bleeding diathesis) are considered to have "classic" CHS. Individuals with milder phenotypes (e.g., later-onset, milder pigmentary, immunologic, and hematologic features) are considered to have "atypical" CHS (also referred to as "mild" or "adolescent" CHS). Both groups of individuals are at risk of developing hemophagocytic lymphohistiocytosis (HLH), previously called "the accelerated phase," with the highest risk of HLH (~85%) in individuals with classic CHS.
Over time, it has become apparent that the classification of CHS into "classic" vs "atypical" phenotypes is arbitrary, as the considerable overlap of the two groups means that this disorder is best understood as a continuum of severe to milder phenotypes, with the universal feature being the pathognomonic giant granules within leukocytes observed on peripheral blood smear.
Although the proportion of individuals with atypical CHS is unknown [
Chediak-Higashi Syndrome: Phenotypic Continuum
Based on
The same CHS-related features are present in nearly all individuals with classic and atypical CHS but to a very variable degree.
Also called "accelerated phase"
Reduced iris pigmentation and iris transillumination may be subtle. Affected individuals may have decreased retinal pigmentation and nystagmus. Visual acuity varies from normal to moderately reduced.
The hair has a "silvery" or metallic appearance. Pigment clumping within the shaft of the hair is generally observed by light microscopy (
Skin pigment dilution may not be appreciated unless compared to the pigmentation of family members. Individuals with darker skin tone may observe areas with scattered hyper- and hypopigmentation.
Although partial OCA was once thought to be a diagnostic criterion for CHS, at least two individuals with atypical CHS had no evidence of OCA [
Bacterial infections are most common, with
Periodontitis, an important manifestation of immunologic dysfunction [
Neutropenia may be present and, in some individuals, cycles between normal absolute neutrophil counts and neutropenia (also called "cyclic neutropenia").
Neurologic features are similar across the CHS phenotypic spectrum; thus, individuals with classic and atypical CHS cannot be distinguished neurologically [
Learning difficulties in childhood [
Sensory neuropathy. Onset in late adolescence or early third decade and slowly progresses to sensorimotor neuropathies and/or diffuse motor neuronopathy [
Cerebellar dysfunction. Onset in late adolescence or early adulthood [
Optic neuropathy. Onset in late adolescence or early adulthood [
Spastic paraplegia. Onset in early to middle adulthood [
Tremor, which can include kinetic and postural tremor
Parkinsonism, including L-dopa-responsive parkinsonism, may occur as early as the second or third decade [
Progressive cognitive decline late in the disease course
Originally thought to be a malignancy resembling lymphoma, the "accelerated phase" is now known to be HLH characterized by multiorgan inflammation. Manifestations include fever, lymphadenopathy, hepatosplenomegaly, anemia, neutropenia, and thrombocytopenia.
Triggers of HLH remain unclear. Although infection with Epstein-Barr virus is thought to hasten development of HLH, this relationship has never been proven. Abnormal function of NK cells and cytolytic T cells is also believed to contribute to development of HLH [
Clinical phenotypes of CHS have been correlated with classes of
Loss-of-function
Missense pathogenic variants and in-frame deletions of
Fewer than 500 individuals with CHS have been reported [
Exact prevalence is difficult to determine, as some individuals have been reported in the literature more than once. In addition, the broad phenotypic spectrum that has become evident since the early descriptions of CHS suggests that many mildly affected individuals may be underrecognized or underreported.
• Learning difficulties in childhood [
• Sensory neuropathy. Onset in late adolescence or early third decade and slowly progresses to sensorimotor neuropathies and/or diffuse motor neuronopathy [
• Cerebellar dysfunction. Onset in late adolescence or early adulthood [
• Optic neuropathy. Onset in late adolescence or early adulthood [
• Spastic paraplegia. Onset in early to middle adulthood [
• Tremor, which can include kinetic and postural tremor
• Parkinsonism, including L-dopa-responsive parkinsonism, may occur as early as the second or third decade [
• Progressive cognitive decline late in the disease course
• Loss-of-function
• Missense pathogenic variants and in-frame deletions of
## Clinical Description
Chediak-Higashi syndrome (CHS) is characterized by partial oculocutaneous albinism (OCA), immunodeficiency, and a mild bleeding tendency. These features are present in nearly all individuals with CHS but to a very variable degree. Affected individuals with severe presentations (i.e., OCA; early-onset, recurrent, severe infections; and a bleeding diathesis) are considered to have "classic" CHS. Individuals with milder phenotypes (e.g., later-onset, milder pigmentary, immunologic, and hematologic features) are considered to have "atypical" CHS (also referred to as "mild" or "adolescent" CHS). Both groups of individuals are at risk of developing hemophagocytic lymphohistiocytosis (HLH), previously called "the accelerated phase," with the highest risk of HLH (~85%) in individuals with classic CHS.
Over time, it has become apparent that the classification of CHS into "classic" vs "atypical" phenotypes is arbitrary, as the considerable overlap of the two groups means that this disorder is best understood as a continuum of severe to milder phenotypes, with the universal feature being the pathognomonic giant granules within leukocytes observed on peripheral blood smear.
Although the proportion of individuals with atypical CHS is unknown [
Chediak-Higashi Syndrome: Phenotypic Continuum
Based on
The same CHS-related features are present in nearly all individuals with classic and atypical CHS but to a very variable degree.
Also called "accelerated phase"
Reduced iris pigmentation and iris transillumination may be subtle. Affected individuals may have decreased retinal pigmentation and nystagmus. Visual acuity varies from normal to moderately reduced.
The hair has a "silvery" or metallic appearance. Pigment clumping within the shaft of the hair is generally observed by light microscopy (
Skin pigment dilution may not be appreciated unless compared to the pigmentation of family members. Individuals with darker skin tone may observe areas with scattered hyper- and hypopigmentation.
Although partial OCA was once thought to be a diagnostic criterion for CHS, at least two individuals with atypical CHS had no evidence of OCA [
Bacterial infections are most common, with
Periodontitis, an important manifestation of immunologic dysfunction [
Neutropenia may be present and, in some individuals, cycles between normal absolute neutrophil counts and neutropenia (also called "cyclic neutropenia").
Neurologic features are similar across the CHS phenotypic spectrum; thus, individuals with classic and atypical CHS cannot be distinguished neurologically [
Learning difficulties in childhood [
Sensory neuropathy. Onset in late adolescence or early third decade and slowly progresses to sensorimotor neuropathies and/or diffuse motor neuronopathy [
Cerebellar dysfunction. Onset in late adolescence or early adulthood [
Optic neuropathy. Onset in late adolescence or early adulthood [
Spastic paraplegia. Onset in early to middle adulthood [
Tremor, which can include kinetic and postural tremor
Parkinsonism, including L-dopa-responsive parkinsonism, may occur as early as the second or third decade [
Progressive cognitive decline late in the disease course
Originally thought to be a malignancy resembling lymphoma, the "accelerated phase" is now known to be HLH characterized by multiorgan inflammation. Manifestations include fever, lymphadenopathy, hepatosplenomegaly, anemia, neutropenia, and thrombocytopenia.
Triggers of HLH remain unclear. Although infection with Epstein-Barr virus is thought to hasten development of HLH, this relationship has never been proven. Abnormal function of NK cells and cytolytic T cells is also believed to contribute to development of HLH [
• Learning difficulties in childhood [
• Sensory neuropathy. Onset in late adolescence or early third decade and slowly progresses to sensorimotor neuropathies and/or diffuse motor neuronopathy [
• Cerebellar dysfunction. Onset in late adolescence or early adulthood [
• Optic neuropathy. Onset in late adolescence or early adulthood [
• Spastic paraplegia. Onset in early to middle adulthood [
• Tremor, which can include kinetic and postural tremor
• Parkinsonism, including L-dopa-responsive parkinsonism, may occur as early as the second or third decade [
• Progressive cognitive decline late in the disease course
## Genotype-Phenotype Correlations
Clinical phenotypes of CHS have been correlated with classes of
Loss-of-function
Missense pathogenic variants and in-frame deletions of
• Loss-of-function
• Missense pathogenic variants and in-frame deletions of
## Prevalence
Fewer than 500 individuals with CHS have been reported [
Exact prevalence is difficult to determine, as some individuals have been reported in the literature more than once. In addition, the broad phenotypic spectrum that has become evident since the early descriptions of CHS suggests that many mildly affected individuals may be underrecognized or underreported.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The diagnosis of Chediak-Higashi syndrome (CHS) should be considered in individuals with pigment dilution defects of the hair, skin, or eyes; congenital or transient neutropenia; immunodeficiency; and otherwise unexplained neurologic abnormalities or neurodegeneration. Each of these findings may be variably represented or absent in affected individuals; therefore, heightened suspicion is needed to pursue an accurate diagnosis.
Genes of Interest in the Differential Diagnosis of Chediak-Higashi Syndrome
OCA & a bleeding diathesis secondary to absent platelet-dense bodies
Of the HPS subtypes,
Cutaneous & ocular hypopigmentation
Impaired melanin biosynthesis leads to hypopigmentation in the skin, hair, & eyes w/characteristic ocular abnormalities.
Neither an infectious history resulting from neutropenia nor neurologic abnormalities accompany the nonsyndromic OCA types.
OCA is common enough (~1:18,000) that it may coexist w/other conditions, incl primary immunodeficiencies.
Vici syndrome (defined as a neurodevelopmental disorder w/agenesis of the corpus callosum, cataracts, hypopigmentation, cardiomyopathy, combined immunodeficiency, microcephaly, & failure to gain weight) is at the most severe end of the spectrum.
Milder, attenuated neurodevelopmental phenotypes w/a variable degree of multisystem involvement are increasingly recognized.
Defects of the corpus callosum & cardiac involvement are not typical for CHS.
Giant intracellular granules will not be seen in
Immunodeficiency syndrome identified in 4 members of a Mennonite family
Clinical features incl partial albinism, short stature, congenital neutropenia, & lymphoid deficiency.
Neutrophils show altered azurophilic granule ultrastructure & less than normal microbicidal function of phagosomes, in contrast to the giant granules seen in neutrophils in CHS.
Neurologic dysfunction was not described in affected family members.
Mild skin hypopigmentation & silvery-gray hair plus severe neurologic involvement in
Hypopigmentation is the only clinical characteristic of
Platelet-dense bodies are present & platelet function is normal.
Giant granules w/in neutrophils are not present in GS.
Immune deficiency characterized by overactivation & excessive proliferation of T lymphocytes & macrophages, leading to infiltration & damage of organs incl bone marrow, liver, spleen, & brain
Familial HLH usually presents as an acute illness w/prolonged & high fever, cytopenias, & hepatosplenomegaly.
Persons w/fHLH may also exhibit liver dysfunction & neurologic abnormalities.
Although manifestations of fHLH are usually evident w/in 1st mos or yrs of life & may develop in utero, symptomatic presentation can occur throughout childhood & into adulthood.
AR = autosomal recessive; CHS = Chediak-Higashi syndrome; HLH = hemophagocytic lymphohistiocytosis; MOI = mode of inheritance; OCA = oculocutaneous albinism
• OCA & a bleeding diathesis secondary to absent platelet-dense bodies
• Of the HPS subtypes,
• Cutaneous & ocular hypopigmentation
• Impaired melanin biosynthesis leads to hypopigmentation in the skin, hair, & eyes w/characteristic ocular abnormalities.
• Neither an infectious history resulting from neutropenia nor neurologic abnormalities accompany the nonsyndromic OCA types.
• OCA is common enough (~1:18,000) that it may coexist w/other conditions, incl primary immunodeficiencies.
• Vici syndrome (defined as a neurodevelopmental disorder w/agenesis of the corpus callosum, cataracts, hypopigmentation, cardiomyopathy, combined immunodeficiency, microcephaly, & failure to gain weight) is at the most severe end of the spectrum.
• Milder, attenuated neurodevelopmental phenotypes w/a variable degree of multisystem involvement are increasingly recognized.
• Defects of the corpus callosum & cardiac involvement are not typical for CHS.
• Giant intracellular granules will not be seen in
• Immunodeficiency syndrome identified in 4 members of a Mennonite family
• Clinical features incl partial albinism, short stature, congenital neutropenia, & lymphoid deficiency.
• Neutrophils show altered azurophilic granule ultrastructure & less than normal microbicidal function of phagosomes, in contrast to the giant granules seen in neutrophils in CHS.
• Neurologic dysfunction was not described in affected family members.
• Mild skin hypopigmentation & silvery-gray hair plus severe neurologic involvement in
• Hypopigmentation is the only clinical characteristic of
• Platelet-dense bodies are present & platelet function is normal.
• Giant granules w/in neutrophils are not present in GS.
• Immune deficiency characterized by overactivation & excessive proliferation of T lymphocytes & macrophages, leading to infiltration & damage of organs incl bone marrow, liver, spleen, & brain
• Familial HLH usually presents as an acute illness w/prolonged & high fever, cytopenias, & hepatosplenomegaly.
• Persons w/fHLH may also exhibit liver dysfunction & neurologic abnormalities.
• Although manifestations of fHLH are usually evident w/in 1st mos or yrs of life & may develop in utero, symptomatic presentation can occur throughout childhood & into adulthood.
## Management
No clinical practice guidelines for Chediak-Higashi syndrome (CHS) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.
To establish the extent of disease and needs in an individual diagnosed with Chediak-Higashi syndrome (CHS), the evaluations summarized in
Chediak-Higashi Syndrome: Recommended Evaluations Following Initial Diagnosis
Assess for signs of ↓ pigment (see
Consider OCT to provide baseline retinal fiber thickness.
Neurologic exam
Specialized testing if abnormalities identified on clinical exam
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / need for IEP &/or 504 plan
History of unexplained, persistent, or recurrent fever
Assessment for hepatosplenomegaly by physical exam & ultrasound imaging
Complete blood count
Ferritin concentration
Soluble interleukin-2 receptor level
Consideration of bone marrow biopsy
Consideration of lumbar puncture
Serum triglyceride concentration
Fibrinogen level
Community or
Social work involvement for parental support
Home nursing referral
CHS = Chediak-Higashi syndrome; EM = electron microscopy; HSCT = hematopoietic stem cell transplantation; IEP = individualized education plan; MOI = mode of inheritance; OCT = optical coherence tomography
For evidence of cytopenia involving at least two cell lines
Elevated serum ferritin and soluble interleukin-2 receptor level are associated with hemophagocytic lymphohistiocytosis (HLH).
To assess for hemophagocytosis
Hypertriglyceridemia and hypofibrinogenemia are suggestive of liver dysfunction, which can be associated with HLH.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for Chediak-Higashi syndrome.
Preparation for HSCT is often initiated as soon as the diagnosis of CHS is confirmed. HSCT protocols vary by institution.
Best outcomes for HSCT are achieved if initiated prior to the development of hemophagocytic lymphohistiocytosis (HLH); however, if HLH occurs, treatment following the Histiocyte Society HLH-94 protocol is recommended. Once remission of HLH is achieved, HSCT may be performed.
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in relevant fields (see
Chediak-Higashi Syndrome: Supportive Treatment of Manifestations
Corrective lenses for refractive errors
Sunglasses to protect eyes from UV light
Children: per educational setting
Adults: low vision clinic
Live vaccines not recommended
Protection from infectious exposures as much as practical
Intensive rehab (or coordinative PT)
Canes/walkers to prevent falls
Home modifications to accommodate motorized chairs as needed
Weighted eating utensils & dressing hooks
Weight control, as obesity can exacerbate difficulties w/ambulation & mobility
HLH-94 protocol is current standard of care & uses combination therapy consisting of etoposide & dexamethasone, w/continuation phase adding cyclosporine A.
Select persons may also receive intrathecal methotrexate.
Preparation for HSCT is often initiated as soon as diagnosis is confirmed.
The most favorable outcome is achieved when HSCT is performed prior to development of HLH.
If signs of HLH are present, hemophagocytosis must be brought into clinical remission before HSCT can be performed.
HLH = hemophagocytic lymphohistiocytosis; HSCT = hematopoietic stem cell transplantation; IEP = individualized education plan; OT = occupational therapist/therapy; PT = physical therapist/therapy
For individuals with compromised immune systems and neutropenia who will be undergoing invasive dental procedures or procedures that cause significant bleeding, prophylaxis should be considered (see
Better HLH control at the time of HSCT leads to better long-term outcome.
Recent evaluation of the HLH-2004 protocol did not find statistical evidence for superiority over the HLH-94 regimen; therefore, HLH-94 remains the standard of care [
The remission induction rate may be as high as 71% when considering all heritable causes of HLH [
This treatment is also effective at inducing remission in CHS so that HSCT can be performed [
This is the only treatment that cures the hematologic and immunologic deficits.
The conditioning regimen is at the discretion of the treatment center; however, reduced-intensity conditioning regimens have demonstrated improved survival over traditional myeloablative protocols.
Although not specific for CHS, in a cohort of 40 individuals with genetic forms of HLH including CHS, the three-year post-HSCT survival was 92% following reduced-intensity conditioning regimens [
The overall five-year survival rate in 35 children with CHS who underwent HSCT was 62% [
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in
Chediak-Higashi Syndrome: Recommended Surveillance
Abdominal ultrasound
Complete blood count
Ferritin concentration
Serum triglycerides
Fibrinogen level
Soluble interleukin-2 receptor level
HLH = hemophagocytic lymphohistiocytosis; HSCT= hematopoietic stem cell transplantation; OT = occupational therapy; PT = physical therapy
Especially in those who undergo HSCT with reduced-intensity conditioning, as the incidence of mixed chimerism in the bone marrow is higher than in those who undergo traditional conditioning.
Recent studies suggest that 20%-30% donor chimerism is likely enough to protect against reactivation [
Avoid the following:
Live vaccines given the risk of infection due to immunodeficiency
All nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen) given the risk of exacerbating the bleeding tendency
Molecular genetic testing if the
Examination of peripheral blood for the presence of giant granules in white blood cells if the
See
Based on the limited number of pregnancies in females with CHS reported in the literature to date, pregnancy, labor, and delivery were uneventful [
Bleeding during delivery and the postpartum period are a concern; thus, prior to delivery developing a plan to deal with possible bleeding is recommended.
A natural history study at the NIH (Study of Chediak-Higashi Syndrome,
Search
• Assess for signs of ↓ pigment (see
• Consider OCT to provide baseline retinal fiber thickness.
• Neurologic exam
• Specialized testing if abnormalities identified on clinical exam
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / need for IEP &/or 504 plan
• History of unexplained, persistent, or recurrent fever
• Assessment for hepatosplenomegaly by physical exam & ultrasound imaging
• Complete blood count
• Ferritin concentration
• Soluble interleukin-2 receptor level
• Consideration of bone marrow biopsy
• Consideration of lumbar puncture
• Serum triglyceride concentration
• Fibrinogen level
• Community or
• Social work involvement for parental support
• Home nursing referral
• Corrective lenses for refractive errors
• Sunglasses to protect eyes from UV light
• Children: per educational setting
• Adults: low vision clinic
• Live vaccines not recommended
• Protection from infectious exposures as much as practical
• Intensive rehab (or coordinative PT)
• Canes/walkers to prevent falls
• Home modifications to accommodate motorized chairs as needed
• Weighted eating utensils & dressing hooks
• Weight control, as obesity can exacerbate difficulties w/ambulation & mobility
• HLH-94 protocol is current standard of care & uses combination therapy consisting of etoposide & dexamethasone, w/continuation phase adding cyclosporine A.
• Select persons may also receive intrathecal methotrexate.
• Preparation for HSCT is often initiated as soon as diagnosis is confirmed.
• The most favorable outcome is achieved when HSCT is performed prior to development of HLH.
• If signs of HLH are present, hemophagocytosis must be brought into clinical remission before HSCT can be performed.
• Abdominal ultrasound
• Complete blood count
• Ferritin concentration
• Serum triglycerides
• Fibrinogen level
• Soluble interleukin-2 receptor level
• Live vaccines given the risk of infection due to immunodeficiency
• All nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen) given the risk of exacerbating the bleeding tendency
• Molecular genetic testing if the
• Examination of peripheral blood for the presence of giant granules in white blood cells if the
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Chediak-Higashi syndrome (CHS), the evaluations summarized in
Chediak-Higashi Syndrome: Recommended Evaluations Following Initial Diagnosis
Assess for signs of ↓ pigment (see
Consider OCT to provide baseline retinal fiber thickness.
Neurologic exam
Specialized testing if abnormalities identified on clinical exam
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / need for IEP &/or 504 plan
History of unexplained, persistent, or recurrent fever
Assessment for hepatosplenomegaly by physical exam & ultrasound imaging
Complete blood count
Ferritin concentration
Soluble interleukin-2 receptor level
Consideration of bone marrow biopsy
Consideration of lumbar puncture
Serum triglyceride concentration
Fibrinogen level
Community or
Social work involvement for parental support
Home nursing referral
CHS = Chediak-Higashi syndrome; EM = electron microscopy; HSCT = hematopoietic stem cell transplantation; IEP = individualized education plan; MOI = mode of inheritance; OCT = optical coherence tomography
For evidence of cytopenia involving at least two cell lines
Elevated serum ferritin and soluble interleukin-2 receptor level are associated with hemophagocytic lymphohistiocytosis (HLH).
To assess for hemophagocytosis
Hypertriglyceridemia and hypofibrinogenemia are suggestive of liver dysfunction, which can be associated with HLH.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Assess for signs of ↓ pigment (see
• Consider OCT to provide baseline retinal fiber thickness.
• Neurologic exam
• Specialized testing if abnormalities identified on clinical exam
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / need for IEP &/or 504 plan
• History of unexplained, persistent, or recurrent fever
• Assessment for hepatosplenomegaly by physical exam & ultrasound imaging
• Complete blood count
• Ferritin concentration
• Soluble interleukin-2 receptor level
• Consideration of bone marrow biopsy
• Consideration of lumbar puncture
• Serum triglyceride concentration
• Fibrinogen level
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for Chediak-Higashi syndrome.
Preparation for HSCT is often initiated as soon as the diagnosis of CHS is confirmed. HSCT protocols vary by institution.
Best outcomes for HSCT are achieved if initiated prior to the development of hemophagocytic lymphohistiocytosis (HLH); however, if HLH occurs, treatment following the Histiocyte Society HLH-94 protocol is recommended. Once remission of HLH is achieved, HSCT may be performed.
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in relevant fields (see
Chediak-Higashi Syndrome: Supportive Treatment of Manifestations
Corrective lenses for refractive errors
Sunglasses to protect eyes from UV light
Children: per educational setting
Adults: low vision clinic
Live vaccines not recommended
Protection from infectious exposures as much as practical
Intensive rehab (or coordinative PT)
Canes/walkers to prevent falls
Home modifications to accommodate motorized chairs as needed
Weighted eating utensils & dressing hooks
Weight control, as obesity can exacerbate difficulties w/ambulation & mobility
HLH-94 protocol is current standard of care & uses combination therapy consisting of etoposide & dexamethasone, w/continuation phase adding cyclosporine A.
Select persons may also receive intrathecal methotrexate.
Preparation for HSCT is often initiated as soon as diagnosis is confirmed.
The most favorable outcome is achieved when HSCT is performed prior to development of HLH.
If signs of HLH are present, hemophagocytosis must be brought into clinical remission before HSCT can be performed.
HLH = hemophagocytic lymphohistiocytosis; HSCT = hematopoietic stem cell transplantation; IEP = individualized education plan; OT = occupational therapist/therapy; PT = physical therapist/therapy
For individuals with compromised immune systems and neutropenia who will be undergoing invasive dental procedures or procedures that cause significant bleeding, prophylaxis should be considered (see
Better HLH control at the time of HSCT leads to better long-term outcome.
Recent evaluation of the HLH-2004 protocol did not find statistical evidence for superiority over the HLH-94 regimen; therefore, HLH-94 remains the standard of care [
The remission induction rate may be as high as 71% when considering all heritable causes of HLH [
This treatment is also effective at inducing remission in CHS so that HSCT can be performed [
This is the only treatment that cures the hematologic and immunologic deficits.
The conditioning regimen is at the discretion of the treatment center; however, reduced-intensity conditioning regimens have demonstrated improved survival over traditional myeloablative protocols.
Although not specific for CHS, in a cohort of 40 individuals with genetic forms of HLH including CHS, the three-year post-HSCT survival was 92% following reduced-intensity conditioning regimens [
The overall five-year survival rate in 35 children with CHS who underwent HSCT was 62% [
• Corrective lenses for refractive errors
• Sunglasses to protect eyes from UV light
• Children: per educational setting
• Adults: low vision clinic
• Live vaccines not recommended
• Protection from infectious exposures as much as practical
• Intensive rehab (or coordinative PT)
• Canes/walkers to prevent falls
• Home modifications to accommodate motorized chairs as needed
• Weighted eating utensils & dressing hooks
• Weight control, as obesity can exacerbate difficulties w/ambulation & mobility
• HLH-94 protocol is current standard of care & uses combination therapy consisting of etoposide & dexamethasone, w/continuation phase adding cyclosporine A.
• Select persons may also receive intrathecal methotrexate.
• Preparation for HSCT is often initiated as soon as diagnosis is confirmed.
• The most favorable outcome is achieved when HSCT is performed prior to development of HLH.
• If signs of HLH are present, hemophagocytosis must be brought into clinical remission before HSCT can be performed.
## Targeted Therapy
Preparation for HSCT is often initiated as soon as the diagnosis of CHS is confirmed. HSCT protocols vary by institution.
Best outcomes for HSCT are achieved if initiated prior to the development of hemophagocytic lymphohistiocytosis (HLH); however, if HLH occurs, treatment following the Histiocyte Society HLH-94 protocol is recommended. Once remission of HLH is achieved, HSCT may be performed.
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in relevant fields (see
Chediak-Higashi Syndrome: Supportive Treatment of Manifestations
Corrective lenses for refractive errors
Sunglasses to protect eyes from UV light
Children: per educational setting
Adults: low vision clinic
Live vaccines not recommended
Protection from infectious exposures as much as practical
Intensive rehab (or coordinative PT)
Canes/walkers to prevent falls
Home modifications to accommodate motorized chairs as needed
Weighted eating utensils & dressing hooks
Weight control, as obesity can exacerbate difficulties w/ambulation & mobility
HLH-94 protocol is current standard of care & uses combination therapy consisting of etoposide & dexamethasone, w/continuation phase adding cyclosporine A.
Select persons may also receive intrathecal methotrexate.
Preparation for HSCT is often initiated as soon as diagnosis is confirmed.
The most favorable outcome is achieved when HSCT is performed prior to development of HLH.
If signs of HLH are present, hemophagocytosis must be brought into clinical remission before HSCT can be performed.
HLH = hemophagocytic lymphohistiocytosis; HSCT = hematopoietic stem cell transplantation; IEP = individualized education plan; OT = occupational therapist/therapy; PT = physical therapist/therapy
For individuals with compromised immune systems and neutropenia who will be undergoing invasive dental procedures or procedures that cause significant bleeding, prophylaxis should be considered (see
Better HLH control at the time of HSCT leads to better long-term outcome.
Recent evaluation of the HLH-2004 protocol did not find statistical evidence for superiority over the HLH-94 regimen; therefore, HLH-94 remains the standard of care [
The remission induction rate may be as high as 71% when considering all heritable causes of HLH [
This treatment is also effective at inducing remission in CHS so that HSCT can be performed [
This is the only treatment that cures the hematologic and immunologic deficits.
The conditioning regimen is at the discretion of the treatment center; however, reduced-intensity conditioning regimens have demonstrated improved survival over traditional myeloablative protocols.
Although not specific for CHS, in a cohort of 40 individuals with genetic forms of HLH including CHS, the three-year post-HSCT survival was 92% following reduced-intensity conditioning regimens [
The overall five-year survival rate in 35 children with CHS who underwent HSCT was 62% [
• Corrective lenses for refractive errors
• Sunglasses to protect eyes from UV light
• Children: per educational setting
• Adults: low vision clinic
• Live vaccines not recommended
• Protection from infectious exposures as much as practical
• Intensive rehab (or coordinative PT)
• Canes/walkers to prevent falls
• Home modifications to accommodate motorized chairs as needed
• Weighted eating utensils & dressing hooks
• Weight control, as obesity can exacerbate difficulties w/ambulation & mobility
• HLH-94 protocol is current standard of care & uses combination therapy consisting of etoposide & dexamethasone, w/continuation phase adding cyclosporine A.
• Select persons may also receive intrathecal methotrexate.
• Preparation for HSCT is often initiated as soon as diagnosis is confirmed.
• The most favorable outcome is achieved when HSCT is performed prior to development of HLH.
• If signs of HLH are present, hemophagocytosis must be brought into clinical remission before HSCT can be performed.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in
Chediak-Higashi Syndrome: Recommended Surveillance
Abdominal ultrasound
Complete blood count
Ferritin concentration
Serum triglycerides
Fibrinogen level
Soluble interleukin-2 receptor level
HLH = hemophagocytic lymphohistiocytosis; HSCT= hematopoietic stem cell transplantation; OT = occupational therapy; PT = physical therapy
Especially in those who undergo HSCT with reduced-intensity conditioning, as the incidence of mixed chimerism in the bone marrow is higher than in those who undergo traditional conditioning.
Recent studies suggest that 20%-30% donor chimerism is likely enough to protect against reactivation [
• Abdominal ultrasound
• Complete blood count
• Ferritin concentration
• Serum triglycerides
• Fibrinogen level
• Soluble interleukin-2 receptor level
## Agents/Circumstances to Avoid
Avoid the following:
Live vaccines given the risk of infection due to immunodeficiency
All nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen) given the risk of exacerbating the bleeding tendency
• Live vaccines given the risk of infection due to immunodeficiency
• All nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen) given the risk of exacerbating the bleeding tendency
## Evaluation of Relatives at Risk
Molecular genetic testing if the
Examination of peripheral blood for the presence of giant granules in white blood cells if the
See
• Molecular genetic testing if the
• Examination of peripheral blood for the presence of giant granules in white blood cells if the
## Pregnancy Management
Based on the limited number of pregnancies in females with CHS reported in the literature to date, pregnancy, labor, and delivery were uneventful [
Bleeding during delivery and the postpartum period are a concern; thus, prior to delivery developing a plan to deal with possible bleeding is recommended.
## Therapies Under Investigation
A natural history study at the NIH (Study of Chediak-Higashi Syndrome,
Search
## Genetic Counseling
Chediak-Higashi syndrome (CHS) is inherited in an autosomal recessive manner.
The parents of an affected individual are usually heterozygous for a
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Two individuals with CHS caused by uniparental disomy of chromosome 1 have been reported [
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Sibs who inherit the same biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are usually heterozygous for a
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Two individuals with CHS caused by uniparental disomy of chromosome 1 have been reported [
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Two individuals with CHS caused by uniparental disomy of chromosome 1 have been reported [
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Two individuals with CHS caused by uniparental disomy of chromosome 1 have been reported [
• If both parents are known to be heterozygous for a
• Sibs who inherit the same biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Chediak-Higashi syndrome (CHS) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are usually heterozygous for a
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Two individuals with CHS caused by uniparental disomy of chromosome 1 have been reported [
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Sibs who inherit the same biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected individual are usually heterozygous for a
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Two individuals with CHS caused by uniparental disomy of chromosome 1 have been reported [
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Two individuals with CHS caused by uniparental disomy of chromosome 1 have been reported [
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Two individuals with CHS caused by uniparental disomy of chromosome 1 have been reported [
• If both parents are known to be heterozygous for a
• Sibs who inherit the same biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
•
•
• United Kingdom
•
•
•
•
•
## Molecular Genetics
Chediak-Higashi Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Chediak-Higashi Syndrome (
## Molecular Pathogenesis
## Chapter Notes
Dr Toro is a movement disorder neurologist who works with the National Institutes of Health Undiagnosed Diseases Program.
Dr Morimoto is a scientist who performs translational research in the National Institutes of Health Undiagnosed Diseases Program.
Dr Malicdan is a neurologist and a scientist whose main interest is the study of rare diseases. She performs basic and translational research on rare diseases in the National Institutes of Health Undiagnosed Diseases Program.
Dr Adams is a pediatrician, medical geneticist, and biochemical geneticist who performs clinical and basic research on rare diseases at the National Institutes of Health.
Dr Introne (
The authors would like to gratefully acknowledge the patients with Chediak-Higashi syndrome and their families for contributing to our understanding of CHS over the years. Special thanks to the Chediak-Higashi Syndrome Association and the Hermansky-Pudlak Syndrome Network for their long-standing dedication to research and patient advocacy.
The authors would like to respectfully acknowledge the authors of the Familial Hemophagocytic Lymphohistiocytosis
This work was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
David R Adams, MD, PhD (2009-present)Gretchen A Golas, RN, MS, CRNP; National Human Genome Research Institute (2009-2018)Wendy J Introne, MD (2009-present)May Christine Malicdan, MD, PhD (2018-present) Marie Morimoto, PhD (2023-present)Elena-Raluca Nicoli, PharmR, PhD; National Human Genome Research Institute (2018-2023)Camilo Toro, MD (2018-present)Wendy Westbroek, PhD; National Human Genome Research Institute (2009-2018)
21 December 2023 (bp) Comprehensive update posted live
5 July 2018 (ma) Comprehensive update posted live
15 January 2015 (me) Comprehensive update posted live
16 February 2012 (me) Comprehensive update posted live
3 March 2009 (me) Review posted live
2 October 2008 (wji) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 21 December 2023 (bp) Comprehensive update posted live
• 5 July 2018 (ma) Comprehensive update posted live
• 15 January 2015 (me) Comprehensive update posted live
• 16 February 2012 (me) Comprehensive update posted live
• 3 March 2009 (me) Review posted live
• 2 October 2008 (wji) Original submission
## Author Notes
Dr Toro is a movement disorder neurologist who works with the National Institutes of Health Undiagnosed Diseases Program.
Dr Morimoto is a scientist who performs translational research in the National Institutes of Health Undiagnosed Diseases Program.
Dr Malicdan is a neurologist and a scientist whose main interest is the study of rare diseases. She performs basic and translational research on rare diseases in the National Institutes of Health Undiagnosed Diseases Program.
Dr Adams is a pediatrician, medical geneticist, and biochemical geneticist who performs clinical and basic research on rare diseases at the National Institutes of Health.
Dr Introne (
## Acknowledgments
The authors would like to gratefully acknowledge the patients with Chediak-Higashi syndrome and their families for contributing to our understanding of CHS over the years. Special thanks to the Chediak-Higashi Syndrome Association and the Hermansky-Pudlak Syndrome Network for their long-standing dedication to research and patient advocacy.
The authors would like to respectfully acknowledge the authors of the Familial Hemophagocytic Lymphohistiocytosis
This work was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
## Author History
David R Adams, MD, PhD (2009-present)Gretchen A Golas, RN, MS, CRNP; National Human Genome Research Institute (2009-2018)Wendy J Introne, MD (2009-present)May Christine Malicdan, MD, PhD (2018-present) Marie Morimoto, PhD (2023-present)Elena-Raluca Nicoli, PharmR, PhD; National Human Genome Research Institute (2018-2023)Camilo Toro, MD (2018-present)Wendy Westbroek, PhD; National Human Genome Research Institute (2009-2018)
## Revision History
21 December 2023 (bp) Comprehensive update posted live
5 July 2018 (ma) Comprehensive update posted live
15 January 2015 (me) Comprehensive update posted live
16 February 2012 (me) Comprehensive update posted live
3 March 2009 (me) Review posted live
2 October 2008 (wji) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 21 December 2023 (bp) Comprehensive update posted live
• 5 July 2018 (ma) Comprehensive update posted live
• 15 January 2015 (me) Comprehensive update posted live
• 16 February 2012 (me) Comprehensive update posted live
• 3 March 2009 (me) Review posted live
• 2 October 2008 (wji) Original submission
## Key Sections in this
## References
## Literature Cited
Examples of granules in polymorphonuclear neutrophils, platelet-dense bodies, and pigment in hair shafts for controls, classic Chediak-Higashi syndrome (CHS), and atypical CHS
a. Whole-mount electron microscopy (EM) of control platelets shows several dense bodies per platelet (arrows).
b. Some CHS platelets have no dense bodies (asterisk) and others have irregular electron-dense granules (arrows).
c. Normal control polymorphonuclear neutrophils (PMNs) contain numerous small cytoplasmic granules.
d. The blood smear derived from an individual with classic severe CHS shows PMNs that contain enlarged intracytoplasmic granules.
e. PMNs from an adult-onset, mildly affected individual with atypical CHS contain many granules that are larger than normal but smaller than those of the individual with classic CHS seen in 1d.
f. Control hair shows pigment that is evenly distributed throughout the shaft.
g. Hair of an individual with classic CHS shows an irregular distribution of large and small pigment clumps.
|
[] |
3/3/2009
|
21/12/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
chek2-cpd
|
chek2-cpd
|
[
"Serine/threonine-protein kinase Chk2",
"CHEK2",
"CHEK2-Related Cancer Predisposition"
] |
Helen Hanson, Tuya Pal, Marc Tischkowitz, Douglas Stewart
|
Summary The diagnosis of
|
## Diagnosis
Estrogen receptor (ER)-positive breast cancer, particularly young onset and/or bilateral breast cancer in a proband with a family history of breast cancer in close relatives
Prostate cancer, particularly in a proband with a family history of prostate and/or breast cancer
Results from a risk assessment model incorporating family history, personal risk factors, ER status of breast cancer, and breast cancer diagnoses in a family indicates an increased likelihood of identifying a
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include use of a multigene panel or single-gene testing.
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
The proportion of
• Estrogen receptor (ER)-positive breast cancer, particularly young onset and/or bilateral breast cancer in a proband with a family history of breast cancer in close relatives
• Prostate cancer, particularly in a proband with a family history of prostate and/or breast cancer
• Results from a risk assessment model incorporating family history, personal risk factors, ER status of breast cancer, and breast cancer diagnoses in a family indicates an increased likelihood of identifying a
• For an introduction to multigene panels click
## Suggestive Findings
Estrogen receptor (ER)-positive breast cancer, particularly young onset and/or bilateral breast cancer in a proband with a family history of breast cancer in close relatives
Prostate cancer, particularly in a proband with a family history of prostate and/or breast cancer
Results from a risk assessment model incorporating family history, personal risk factors, ER status of breast cancer, and breast cancer diagnoses in a family indicates an increased likelihood of identifying a
• Estrogen receptor (ER)-positive breast cancer, particularly young onset and/or bilateral breast cancer in a proband with a family history of breast cancer in close relatives
• Prostate cancer, particularly in a proband with a family history of prostate and/or breast cancer
• Results from a risk assessment model incorporating family history, personal risk factors, ER status of breast cancer, and breast cancer diagnoses in a family indicates an increased likelihood of identifying a
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include use of a multigene panel or single-gene testing.
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
The proportion of
• For an introduction to multigene panels click
## Clinical Characteristics
Cancer Risk in
See Cancer Research UK,
The magnitude of increased risk of breast cancer in
Similar to breast cancers occurring in the general population, breast cancers occurring in
There have been mixed reports about the impact of
Radiotherapy has not been demonstrated to impact CBC risk for
Individuals homozygous for
A small number of case reports have described a cancer predisposition syndrome with early adult onset and/or multiple primary cancers with somatic chromosome instability and multiple cytogenetic abnormalities identified in tumor tissue in individuals with
The largest study of individuals with biallelic
Cancer risk estimates for
However, genotype-phenotype correlations have been difficult to determine due to inclusion of low-penetrance missense variants in studies of cancer risk, thus influencing the risk for missense variants as a whole. Some missense variants historically considered pathogenic are now recognized as low-penetrance variants that in isolation do not reach a level of clinical actionability. The most notable examples are
To further compare cancer risk associated with truncating versus missense variants, a commercial laboratory-based study of 6,000
The penetrance of breast and other cancers associated with pathogenic variants in
Individuals containing pathogenic variants in both
A cohort study of 3,783 individuals heterozygous for pathogenic / likely pathogenic (P/LP) and low-risk
The
Several other
## Clinical Description
Cancer Risk in
See Cancer Research UK,
The magnitude of increased risk of breast cancer in
Similar to breast cancers occurring in the general population, breast cancers occurring in
There have been mixed reports about the impact of
Radiotherapy has not been demonstrated to impact CBC risk for
## Homozygous / Compound Heterozygous Individuals
Individuals homozygous for
A small number of case reports have described a cancer predisposition syndrome with early adult onset and/or multiple primary cancers with somatic chromosome instability and multiple cytogenetic abnormalities identified in tumor tissue in individuals with
The largest study of individuals with biallelic
## Genotype-Phenotype Correlations
Cancer risk estimates for
However, genotype-phenotype correlations have been difficult to determine due to inclusion of low-penetrance missense variants in studies of cancer risk, thus influencing the risk for missense variants as a whole. Some missense variants historically considered pathogenic are now recognized as low-penetrance variants that in isolation do not reach a level of clinical actionability. The most notable examples are
To further compare cancer risk associated with truncating versus missense variants, a commercial laboratory-based study of 6,000
## Penetrance
The penetrance of breast and other cancers associated with pathogenic variants in
## Genetic Modifiers
Individuals containing pathogenic variants in both
A cohort study of 3,783 individuals heterozygous for pathogenic / likely pathogenic (P/LP) and low-risk
## Prevalence
The
Several other
## Genetically Related (Allelic) Disorders
No phenotypes other than
Many types of
## Differential Diagnosis
Genes Associated with Cancer Susceptibility to Consider in the Differential Diagnosis of
Breast & ovarian cancer, predominantly young onset
Assoc w/triple-negative breast cancer (
Breast cancer (lobular)
Diffuse gastric cancer
Majority of cancers occur age <40 yrs
High-penetrance breast cancer
Ovarian cancer
Male breast cancer
Pancreatic cancer
Breast cancer
Other cancers: thyroid, RCC, endometrial, colorectal
Multiple hamartomas, macrocephaly, trichilemmomas, papillomatous papules
Affected persons usually present by late 20s.
Breast cancer
Other cancers: GI, ovarian (mostly SCTAT), cervical (adenoma malignum), pancreatic, Sertoli cell testicular
GI polyposis, mucocutaneous pigmentation, hyperpigmented macules on fingers
Breast cancer (often premenopausal)
Other cancers: soft tissue sarcoma, osteosarcoma, brain, adrenocortical carcinoma, leukemias
Early onset & multiple primary cancers
Specific
↑ risk for other types of tumors such as pancreatic cancer & prostate cancer
Ovarian cancer
Moderate-penetrance breast cancer (particularly ER/PR-negative breast cancer)
Ovarian cancer
Moderate-penetrance breast cancer (particularly ER/PR-negative breast cancer)
AD = autosomal dominant; ER = estrogen receptor; GI = gastrointestinal; MOI = mode of inheritance; PR = progesterone receptor; RCC = renal cell carcinoma; SCTAT = sex cord tumor with annular tubules
• Breast & ovarian cancer, predominantly young onset
• Assoc w/triple-negative breast cancer (
• Breast cancer (lobular)
• Diffuse gastric cancer
• Majority of cancers occur age <40 yrs
• High-penetrance breast cancer
• Ovarian cancer
• Male breast cancer
• Pancreatic cancer
• Breast cancer
• Other cancers: thyroid, RCC, endometrial, colorectal
• Multiple hamartomas, macrocephaly, trichilemmomas, papillomatous papules
• Affected persons usually present by late 20s.
• Breast cancer
• Other cancers: GI, ovarian (mostly SCTAT), cervical (adenoma malignum), pancreatic, Sertoli cell testicular
• GI polyposis, mucocutaneous pigmentation, hyperpigmented macules on fingers
• Breast cancer (often premenopausal)
• Other cancers: soft tissue sarcoma, osteosarcoma, brain, adrenocortical carcinoma, leukemias
• Early onset & multiple primary cancers
• Specific
• ↑ risk for other types of tumors such as pancreatic cancer & prostate cancer
• Ovarian cancer
• Moderate-penetrance breast cancer (particularly ER/PR-negative breast cancer)
• Ovarian cancer
• Moderate-penetrance breast cancer (particularly ER/PR-negative breast cancer)
## Management
Clinical management recommendations for
Individuals who have a germline pathogenic variant in
At present there is insufficient evidence to recommend specific cancer treatment based on identification of
To date there are no available data on the benefit of bilateral risk-reducing mastectomy for individuals with a heterozygous
To monitor existing manifestations and the emergence of new manifestations, the evaluations summarized in
NCCN guidelines (US): Consider annually from age 30-35 yrs in those w/strong family history, other risk factors (e.g., age, breast density), & preference of affected person.
UK: Consider annually from age 30 yrs based on personal risk assessment w/
CRC = colorectal cancer; MOI = mode of inheritance; NCCN = National Comprehensive Cancer Network; PSA = prostate-specific antigen
For individuals with a
Recommendations for breast MRI vary by region. A modeling analysis based on data from population-based studies evaluated annual mammography alone versus mammography with breast MRI starting at different ages in
Although
See National Health Service (NHS) England,
Once a cancer-predisposing
See
A number of ongoing studies are investigating novel approaches to the treatment of
Search
• NCCN guidelines (US): Consider annually from age 30-35 yrs in those w/strong family history, other risk factors (e.g., age, breast density), & preference of affected person.
• UK: Consider annually from age 30 yrs based on personal risk assessment w/
## Evaluations Following Initial Diagnosis
Individuals who have a germline pathogenic variant in
## Treatment of Manifestations
At present there is insufficient evidence to recommend specific cancer treatment based on identification of
## Prevention of Primary Manifestations
To date there are no available data on the benefit of bilateral risk-reducing mastectomy for individuals with a heterozygous
## Surveillance
To monitor existing manifestations and the emergence of new manifestations, the evaluations summarized in
NCCN guidelines (US): Consider annually from age 30-35 yrs in those w/strong family history, other risk factors (e.g., age, breast density), & preference of affected person.
UK: Consider annually from age 30 yrs based on personal risk assessment w/
CRC = colorectal cancer; MOI = mode of inheritance; NCCN = National Comprehensive Cancer Network; PSA = prostate-specific antigen
For individuals with a
Recommendations for breast MRI vary by region. A modeling analysis based on data from population-based studies evaluated annual mammography alone versus mammography with breast MRI starting at different ages in
Although
See National Health Service (NHS) England,
• NCCN guidelines (US): Consider annually from age 30-35 yrs in those w/strong family history, other risk factors (e.g., age, breast density), & preference of affected person.
• UK: Consider annually from age 30 yrs based on personal risk assessment w/
## Evaluation of Relatives at Risk
Once a cancer-predisposing
See
## Therapies Under Investigation
A number of ongoing studies are investigating novel approaches to the treatment of
Search
## Genetic Counseling
Most individuals with
The vast majority of individuals with a heterozygous germline
It is appropriate to offer molecular genetic testing to both parents of an individual with a
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.
Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the
If one parent has the germline
If both parents of the proband are heterozygous for a
The offspring of an individual with a heterozygous germline
All offspring of an individual with biallelic germline
The risk of developing cancer in offspring who inherit the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
At-risk adult relatives who have not inherited the cancer-predisposing germline pathogenic variant identified in the proband are presumed to be at or above the general population risk of developing cancer, depending on extent of family history of cancer attributed to the
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider decisions regarding prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors
• The vast majority of individuals with a heterozygous germline
• It is appropriate to offer molecular genetic testing to both parents of an individual with a
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If one parent has the germline
• If both parents of the proband are heterozygous for a
• The offspring of an individual with a heterozygous germline
• All offspring of an individual with biallelic germline
• The risk of developing cancer in offspring who inherit the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• At-risk adult relatives who have not inherited the cancer-predisposing germline pathogenic variant identified in the proband are presumed to be at or above the general population risk of developing cancer, depending on extent of family history of cancer attributed to the
## Mode of Inheritance
Most individuals with
## Risk to Family Members
The vast majority of individuals with a heterozygous germline
It is appropriate to offer molecular genetic testing to both parents of an individual with a
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.
Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the
If one parent has the germline
If both parents of the proband are heterozygous for a
The offspring of an individual with a heterozygous germline
All offspring of an individual with biallelic germline
The risk of developing cancer in offspring who inherit the
• The vast majority of individuals with a heterozygous germline
• It is appropriate to offer molecular genetic testing to both parents of an individual with a
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If one parent has the germline
• If both parents of the proband are heterozygous for a
• The offspring of an individual with a heterozygous germline
• All offspring of an individual with biallelic germline
• The risk of developing cancer in offspring who inherit the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
At-risk adult relatives who have not inherited the cancer-predisposing germline pathogenic variant identified in the proband are presumed to be at or above the general population risk of developing cancer, depending on extent of family history of cancer attributed to the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• At-risk adult relatives who have not inherited the cancer-predisposing germline pathogenic variant identified in the proband are presumed to be at or above the general population risk of developing cancer, depending on extent of family history of cancer attributed to the
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider decisions regarding prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors
## Resources
Facing Hereditary Cancer Empowered
National Human Genome Research Institute (NHGRI)
National Breast Cancer Coalition
•
• Facing Hereditary Cancer Empowered
•
•
•
•
•
•
•
• National Human Genome Research Institute (NHGRI)
•
•
•
•
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## Molecular Genetics
CHEK2-Related Cancer Predisposition: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CHEK2-Related Cancer Predisposition (
Identification of a
Sequencing analysis of
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
## Molecular Pathogenesis
Identification of a
Sequencing analysis of
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
## Chapter Notes
HH is supported by the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre (BRC).
MT is supported by the NIHR Cambridge BRC.
DRS is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, Rockville, MD.
29 May 2025 (sw) Review posted live
20 November 2024 (hh) Original submission
• 29 May 2025 (sw) Review posted live
• 20 November 2024 (hh) Original submission
## Acknowledgments
HH is supported by the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre (BRC).
MT is supported by the NIHR Cambridge BRC.
DRS is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, Rockville, MD.
## Revision History
29 May 2025 (sw) Review posted live
20 November 2024 (hh) Original submission
• 29 May 2025 (sw) Review posted live
• 20 November 2024 (hh) Original submission
## References
## Literature Cited
|
[] |
29/5/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
cherubism
|
cherubism
|
[
"Opioid growth factor receptor-like protein 1",
"SH3 domain-binding protein 2",
"OGFRL1",
"SH3BP2",
"Cherubism"
] |
Cherubism
|
Anne Morice, Natacha Kadlub, Amélie Coudert
|
Summary Cherubism is a childhood-onset autoinflammatory bone disease characterized by proliferative fibroosseous lesions limited to the mandible and maxilla. The phenotype ranges from no clinical manifestations to severe mandibular and maxillary bone lysis and cortical expansion with dental, orbital/ophthalmologic, respiratory, speech, and swallowing complications. In most affected persons, teeth are displaced, unerupted, hypoplastic, or absent, or they may appear to be floating in cyst-like spaces; malocclusion, premature exfoliation of deciduous teeth, and root resorption have also been reported. Respiratory manifestations can include obstructive sleep apnea and upper-airway obstruction. Orbital and ophthalmologic manifestations can occur with enlargement of the maxilla and orbital floor displacement. Intellect and development are typically normal. The course and duration of the active process of bone destruction varies between affected individuals; new lesions can occur until puberty, and rarely in adulthood. Regression of the lesions occurs as they become filled with bone and remodel during the second and third decade of life. By age 30 years, the facial abnormalities associated with cherubism are usually less obvious than during childhood. Diagnosis is established in a proband with typical clinical, radiographic, histologic, and family history findings and/or a heterozygous gain-of-function pathogenic variant in Cherubism can be inherited in an autosomal dominant (most commonly) or an autosomal recessive (rarely) manner. Approximately 80% of affected individuals have the disorder as the result of a heterozygous gain-of-function pathogenic variant in If the cherubism-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
|
## Diagnosis
No consensus clinical diagnostic criteria for cherubism have been published.
Cherubism
Onset usually between age two and seven years
Bilateral, symmetric progressive enlargement of the mandible (See
Symmetric or asymmetric enlargement of the maxilla
Swelling of submandibular and cervical lymph nodes (early in the disease course only)
Slow progression of the jaw lesions up to adolescence, with spontaneous regression typically starting after puberty and extending into the third decade
Exophthalmia in those with extensive maxillary lesions, through the orbital floor (See
Dental abnormalities such as congenitally missing second and third molars, premature exfoliation of the deciduous teeth and displacement of permanent teeth secondary to the jaw lesions, and malocclusion
Enlargement of the mandible typically with bilateral, symmetric lesions usually located at the angles and rami. The coronoid processes may be involved, whereas the condyles are rarely affected. Lesions can be symmetric or asymmetric in the maxilla and mandible (see
Imaging typically shows expansile remodeling of the involved bones, thinning of the cortices, and multilocular radiolucent areas with a coarse trabecular pattern [
Other cranial bones are usually unaffected.
The diagnosis of cherubism
A heterozygous gain-of-function pathogenic (or likely pathogenic) variant in
Biallelic loss-of-function pathogenic (or likely pathogenic) variants in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic findings suggest the diagnosis of cherubism, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by jaw lesions or the diagnosis of cherubism is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cherubism
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Cherubism caused by a heterozygous
Failure to identify a
• Onset usually between age two and seven years
• Bilateral, symmetric progressive enlargement of the mandible (See
• Symmetric or asymmetric enlargement of the maxilla
• Swelling of submandibular and cervical lymph nodes (early in the disease course only)
• Slow progression of the jaw lesions up to adolescence, with spontaneous regression typically starting after puberty and extending into the third decade
• Exophthalmia in those with extensive maxillary lesions, through the orbital floor (See
• Dental abnormalities such as congenitally missing second and third molars, premature exfoliation of the deciduous teeth and displacement of permanent teeth secondary to the jaw lesions, and malocclusion
• Enlargement of the mandible typically with bilateral, symmetric lesions usually located at the angles and rami. The coronoid processes may be involved, whereas the condyles are rarely affected. Lesions can be symmetric or asymmetric in the maxilla and mandible (see
• Imaging typically shows expansile remodeling of the involved bones, thinning of the cortices, and multilocular radiolucent areas with a coarse trabecular pattern [
• Other cranial bones are usually unaffected.
• A heterozygous gain-of-function pathogenic (or likely pathogenic) variant in
• Biallelic loss-of-function pathogenic (or likely pathogenic) variants in
• For an introduction to multigene panels click
## Suggestive Findings
Cherubism
Onset usually between age two and seven years
Bilateral, symmetric progressive enlargement of the mandible (See
Symmetric or asymmetric enlargement of the maxilla
Swelling of submandibular and cervical lymph nodes (early in the disease course only)
Slow progression of the jaw lesions up to adolescence, with spontaneous regression typically starting after puberty and extending into the third decade
Exophthalmia in those with extensive maxillary lesions, through the orbital floor (See
Dental abnormalities such as congenitally missing second and third molars, premature exfoliation of the deciduous teeth and displacement of permanent teeth secondary to the jaw lesions, and malocclusion
Enlargement of the mandible typically with bilateral, symmetric lesions usually located at the angles and rami. The coronoid processes may be involved, whereas the condyles are rarely affected. Lesions can be symmetric or asymmetric in the maxilla and mandible (see
Imaging typically shows expansile remodeling of the involved bones, thinning of the cortices, and multilocular radiolucent areas with a coarse trabecular pattern [
Other cranial bones are usually unaffected.
• Onset usually between age two and seven years
• Bilateral, symmetric progressive enlargement of the mandible (See
• Symmetric or asymmetric enlargement of the maxilla
• Swelling of submandibular and cervical lymph nodes (early in the disease course only)
• Slow progression of the jaw lesions up to adolescence, with spontaneous regression typically starting after puberty and extending into the third decade
• Exophthalmia in those with extensive maxillary lesions, through the orbital floor (See
• Dental abnormalities such as congenitally missing second and third molars, premature exfoliation of the deciduous teeth and displacement of permanent teeth secondary to the jaw lesions, and malocclusion
• Enlargement of the mandible typically with bilateral, symmetric lesions usually located at the angles and rami. The coronoid processes may be involved, whereas the condyles are rarely affected. Lesions can be symmetric or asymmetric in the maxilla and mandible (see
• Imaging typically shows expansile remodeling of the involved bones, thinning of the cortices, and multilocular radiolucent areas with a coarse trabecular pattern [
• Other cranial bones are usually unaffected.
## Establishing the Diagnosis
The diagnosis of cherubism
A heterozygous gain-of-function pathogenic (or likely pathogenic) variant in
Biallelic loss-of-function pathogenic (or likely pathogenic) variants in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic findings suggest the diagnosis of cherubism, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by jaw lesions or the diagnosis of cherubism is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cherubism
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Cherubism caused by a heterozygous
Failure to identify a
• A heterozygous gain-of-function pathogenic (or likely pathogenic) variant in
• Biallelic loss-of-function pathogenic (or likely pathogenic) variants in
• For an introduction to multigene panels click
## Option 1
When the phenotypic findings suggest the diagnosis of cherubism, molecular genetic testing approaches can include
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by jaw lesions or the diagnosis of cherubism is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cherubism
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Cherubism caused by a heterozygous
Failure to identify a
## Clinical Characteristics
Cherubism is a childhood-onset bone disease characterized by bilateral proliferative lesions typically limited to the mandible and maxilla. Regression of the lesions occurs during the second and third decade of life. Findings associated with cherubism range from clinically unrecognized features to severe mandibular and maxillary overgrowth with dental, orbital/ophthalmologic, respiratory, speech, and swallowing complications [
Severe malformation of the jaw may impede chewing and swallowing. An ache in the mouth and discomfort when eating food are frequently reported [
The facial disfigurement in cherubism can affect an individual's feelings of self-worth and be the source of bullying. However, one study reported that persons with cherubism were psychosocially well adapted and enjoyed a good quality of life [
Regression of the lesions occurs as they become filled with bone and remodel during the second and third decade of life. Although the facial disfigurement is expected to improve due to involution of the jaw lesions in early adulthood, this may not be the case for all individuals [
Lesions affecting the temporal bone, ribs, and humerus are rare [
Spondyloarthropathy has been reported in one individual [
No clinically relevant genotype-phenotype correlations have been identified.
Penetrance has not been systematically studied in cherubism. However, penetrance seems to be equivalent between males and females without ethnic predilection [
Cherubism was first described as "familial multilocular cystic disease of the jaws" by
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
Prevalence is unknown. Approximately 600 individuals have been reported in the medical literature. Clinical variability may result in underdiagnosis in children, especially in individuals with mild or asymptomatic cherubism. Furthermore, as bone remodeling occurs into adulthood, the radiologic findings during adulthood may not reflect the activity of the disease during childhood, despite the presence of a
No other phenotypes other than those discussed in this
• Lesions affecting the temporal bone, ribs, and humerus are rare [
• Spondyloarthropathy has been reported in one individual [
## Clinical Description
Cherubism is a childhood-onset bone disease characterized by bilateral proliferative lesions typically limited to the mandible and maxilla. Regression of the lesions occurs during the second and third decade of life. Findings associated with cherubism range from clinically unrecognized features to severe mandibular and maxillary overgrowth with dental, orbital/ophthalmologic, respiratory, speech, and swallowing complications [
Severe malformation of the jaw may impede chewing and swallowing. An ache in the mouth and discomfort when eating food are frequently reported [
The facial disfigurement in cherubism can affect an individual's feelings of self-worth and be the source of bullying. However, one study reported that persons with cherubism were psychosocially well adapted and enjoyed a good quality of life [
Regression of the lesions occurs as they become filled with bone and remodel during the second and third decade of life. Although the facial disfigurement is expected to improve due to involution of the jaw lesions in early adulthood, this may not be the case for all individuals [
Lesions affecting the temporal bone, ribs, and humerus are rare [
Spondyloarthropathy has been reported in one individual [
• Lesions affecting the temporal bone, ribs, and humerus are rare [
• Spondyloarthropathy has been reported in one individual [
## Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations have been identified.
## Penetrance
Penetrance has not been systematically studied in cherubism. However, penetrance seems to be equivalent between males and females without ethnic predilection [
## Nomenclature
Cherubism was first described as "familial multilocular cystic disease of the jaws" by
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
## Prevalence
Prevalence is unknown. Approximately 600 individuals have been reported in the medical literature. Clinical variability may result in underdiagnosis in children, especially in individuals with mild or asymptomatic cherubism. Furthermore, as bone remodeling occurs into adulthood, the radiologic findings during adulthood may not reflect the activity of the disease during childhood, despite the presence of a
## Genetically Related (Allelic) Disorders
No other phenotypes other than those discussed in this
## Differential Diagnosis
Disorders of interest in the differential diagnosis of cherubism are listed in
Genes of Interest in the Differential Diagnosis of Cherubism
Characteristic facial & neurocutaneous findings
Congenital anomalies in multiple systems
Benign ossifying fibromas of mandible or maxilla
Occasionally bilateral/multifocal & recurrent
Brown tumors (rare benign giant cell lesions) resulting from parathyroid hormone effects on bone tissue in persons w/hyperparathyroidism
Can occur in both maxilla & mandible
Lesions affecting other body parts incl femur, tibia, or ribs (exceptional in cherubism)
Absence of typical symmetric swelling of lower face (typical of cherubism)
On radiographs, characteristic ground-glass pattern
Café au lait macules
Endocrine abnormalities
Chronic bony involvement that does not resolve at puberty
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
"RASopathies" refers to disorders of the RAS-MAPK pathway.
Noonan syndrome is most often inherited in an autosomal dominant manner; Noonan syndrome caused by pathogenic variants in
Familial isolated hyperparathyroidism (FIHP) is characterized by parathyroid adenoma or hyperplasia without other associated endocrinopathies. Heterozygous
Fibrous dysplasia / McCune-Albright syndrome, a sporadically occurring disorder, is caused by an early embryonic postzygotic somatic activating (gain-of-function) pathogenic variant in
Disorders of Unknown Genetic Cause of Interest in the Differential Diagnosis of Cherubism
Benign lesion usually occurring in mandible & maxilla
Histologically, central giant cell granuloma cannot be distinguished from cherubism.
Short stature
Epilepsy
Intellectual disability
A somatic pathogenic variant in
• Characteristic facial & neurocutaneous findings
• Congenital anomalies in multiple systems
• Benign ossifying fibromas of mandible or maxilla
• Occasionally bilateral/multifocal & recurrent
• Brown tumors (rare benign giant cell lesions) resulting from parathyroid hormone effects on bone tissue in persons w/hyperparathyroidism
• Can occur in both maxilla & mandible
• Lesions affecting other body parts incl femur, tibia, or ribs (exceptional in cherubism)
• Absence of typical symmetric swelling of lower face (typical of cherubism)
• On radiographs, characteristic ground-glass pattern
• Café au lait macules
• Endocrine abnormalities
• Chronic bony involvement that does not resolve at puberty
• Benign lesion usually occurring in mandible & maxilla
• Histologically, central giant cell granuloma cannot be distinguished from cherubism.
• Short stature
• Epilepsy
• Intellectual disability
## Management
No clinical practice guidelines for cherubism have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.
To establish the extent of disease in an individual diagnosed with cherubism, the evaluations summarized in
Cherubism: Recommended Evaluations Following Initial Diagnosis
CT utilizing as little radiation as possible to evaluate maxillofacial bone lesions
Eval of lesions encroaching on neurovascular or ocular structures may require a multimodality approach incl MRI.
Community or
Social work involvement for parental support
Home nursing referral
MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Treatment protocols for the complications of cherubism are not well established and are evolving due to recent advances in the understanding of the autoinflammatory nature of this bone disease. Given that cherubism is considered to be a self-limited condition that improves over time, treatment should be tailored to the individual's presentation and the evolution of the disease. Depending on the severity, surgery may be needed for functional and esthetic concerns.
Note: Several pharmacologic treatments have been proposed and administrated to individuals with cherubism, mostly to treat severe forms, among them calcitonin, anti-TNF-α drugs, anti-calcineurin (tacrolimus), tyrosine kinase inhibitor (imatinib), and denosumab (human monoclonal antibody against RANKL). These treatments act within different mechanisms on the modulation of bone formation and resorption [
Cherubism: Treatment of Manifestations
Surgical interventions include curettage w/ or w/o bone grafting.
Liposuction has been used to recontour jaws.
Surgical interventions are likely to occur between ages 5 & 15 yrs in persons w/disfiguring enlargement of jaws or locally aggressive lesions assoc w/complications such as impaired swallowing, respiratory issues, nasal airway obstruction, or tongue displacement.
Surgical therapy needs to be individually tailored & avoid unrealistic expectations since recurrence of lesions is possible & surgery may not halt disease progression.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Cherubism: Recommended Surveillance
Annually during cyst development & growth
Every 2-3 yrs or as needed after cyst growth stops
It is appropriate to evaluate apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from surveillance and early intervention. Evaluations can include:
Molecular genetic testing if the pathogenic variant(s) in the family are known;
Clinical and radiographic evaluations if the pathogenic variant(s) in the family are not known.
See
Search
• CT utilizing as little radiation as possible to evaluate maxillofacial bone lesions
• Eval of lesions encroaching on neurovascular or ocular structures may require a multimodality approach incl MRI.
• Community or
• Social work involvement for parental support
• Home nursing referral
• Surgical interventions include curettage w/ or w/o bone grafting.
• Liposuction has been used to recontour jaws.
• Surgical interventions are likely to occur between ages 5 & 15 yrs in persons w/disfiguring enlargement of jaws or locally aggressive lesions assoc w/complications such as impaired swallowing, respiratory issues, nasal airway obstruction, or tongue displacement.
• Surgical therapy needs to be individually tailored & avoid unrealistic expectations since recurrence of lesions is possible & surgery may not halt disease progression.
• Annually during cyst development & growth
• Every 2-3 yrs or as needed after cyst growth stops
• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Clinical and radiographic evaluations if the pathogenic variant(s) in the family are not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with cherubism, the evaluations summarized in
Cherubism: Recommended Evaluations Following Initial Diagnosis
CT utilizing as little radiation as possible to evaluate maxillofacial bone lesions
Eval of lesions encroaching on neurovascular or ocular structures may require a multimodality approach incl MRI.
Community or
Social work involvement for parental support
Home nursing referral
MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• CT utilizing as little radiation as possible to evaluate maxillofacial bone lesions
• Eval of lesions encroaching on neurovascular or ocular structures may require a multimodality approach incl MRI.
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
Treatment protocols for the complications of cherubism are not well established and are evolving due to recent advances in the understanding of the autoinflammatory nature of this bone disease. Given that cherubism is considered to be a self-limited condition that improves over time, treatment should be tailored to the individual's presentation and the evolution of the disease. Depending on the severity, surgery may be needed for functional and esthetic concerns.
Note: Several pharmacologic treatments have been proposed and administrated to individuals with cherubism, mostly to treat severe forms, among them calcitonin, anti-TNF-α drugs, anti-calcineurin (tacrolimus), tyrosine kinase inhibitor (imatinib), and denosumab (human monoclonal antibody against RANKL). These treatments act within different mechanisms on the modulation of bone formation and resorption [
Cherubism: Treatment of Manifestations
Surgical interventions include curettage w/ or w/o bone grafting.
Liposuction has been used to recontour jaws.
Surgical interventions are likely to occur between ages 5 & 15 yrs in persons w/disfiguring enlargement of jaws or locally aggressive lesions assoc w/complications such as impaired swallowing, respiratory issues, nasal airway obstruction, or tongue displacement.
Surgical therapy needs to be individually tailored & avoid unrealistic expectations since recurrence of lesions is possible & surgery may not halt disease progression.
• Surgical interventions include curettage w/ or w/o bone grafting.
• Liposuction has been used to recontour jaws.
• Surgical interventions are likely to occur between ages 5 & 15 yrs in persons w/disfiguring enlargement of jaws or locally aggressive lesions assoc w/complications such as impaired swallowing, respiratory issues, nasal airway obstruction, or tongue displacement.
• Surgical therapy needs to be individually tailored & avoid unrealistic expectations since recurrence of lesions is possible & surgery may not halt disease progression.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Cherubism: Recommended Surveillance
Annually during cyst development & growth
Every 2-3 yrs or as needed after cyst growth stops
• Annually during cyst development & growth
• Every 2-3 yrs or as needed after cyst growth stops
## Evaluation of Relatives at Risk
It is appropriate to evaluate apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from surveillance and early intervention. Evaluations can include:
Molecular genetic testing if the pathogenic variant(s) in the family are known;
Clinical and radiographic evaluations if the pathogenic variant(s) in the family are not known.
See
• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Clinical and radiographic evaluations if the pathogenic variant(s) in the family are not known.
## Therapies Under Investigation
Search
## Genetic Counseling
Cherubism can be inherited in an autosomal dominant (most commonly) or an autosomal recessive (rarely) manner.
Approximately 80% of individuals with cherubism have the disorder as the result of a heterozygous gain-of-function pathogenic variant in
In two families reported to date, cherubism is caused by biallelic loss-of-function pathogenic variants in
Some individuals diagnosed with cherubism have an affected parent.
Most individuals diagnosed with cherubism represent simplex cases (i.e., a single occurrence in a family) and are presumed to have the disorder as the result of a
If a molecular diagnosis of
If the
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
* Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.
If a parent of the proband is affected and/or is known to have the
If a molecular diagnosis of
If the genetic status of the parents is unknown but they are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for cherubism because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism.
The parents of a child with
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a cherubism-related pathogenic variant.
If the cherubism-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Approximately 80% of individuals with cherubism have the disorder as the result of a heterozygous gain-of-function pathogenic variant in
• In two families reported to date, cherubism is caused by biallelic loss-of-function pathogenic variants in
• Some individuals diagnosed with cherubism have an affected parent.
• Most individuals diagnosed with cherubism represent simplex cases (i.e., a single occurrence in a family) and are presumed to have the disorder as the result of a
• If a molecular diagnosis of
• If the
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.
• If a parent of the proband is affected and/or is known to have the
• If a molecular diagnosis of
• If the genetic status of the parents is unknown but they are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for cherubism because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism.
• The parents of a child with
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a cherubism-related pathogenic variant.
## Mode of Inheritance
Cherubism can be inherited in an autosomal dominant (most commonly) or an autosomal recessive (rarely) manner.
Approximately 80% of individuals with cherubism have the disorder as the result of a heterozygous gain-of-function pathogenic variant in
In two families reported to date, cherubism is caused by biallelic loss-of-function pathogenic variants in
• Approximately 80% of individuals with cherubism have the disorder as the result of a heterozygous gain-of-function pathogenic variant in
• In two families reported to date, cherubism is caused by biallelic loss-of-function pathogenic variants in
## Autosomal Dominant Inheritance – Risk to Family Members
Some individuals diagnosed with cherubism have an affected parent.
Most individuals diagnosed with cherubism represent simplex cases (i.e., a single occurrence in a family) and are presumed to have the disorder as the result of a
If a molecular diagnosis of
If the
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
* Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.
If a parent of the proband is affected and/or is known to have the
If a molecular diagnosis of
If the genetic status of the parents is unknown but they are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for cherubism because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism.
• Some individuals diagnosed with cherubism have an affected parent.
• Most individuals diagnosed with cherubism represent simplex cases (i.e., a single occurrence in a family) and are presumed to have the disorder as the result of a
• If a molecular diagnosis of
• If the
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.
• If a parent of the proband is affected and/or is known to have the
• If a molecular diagnosis of
• If the genetic status of the parents is unknown but they are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for cherubism because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism.
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of a child with
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of a child with
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a cherubism-related pathogenic variant.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a cherubism-related pathogenic variant.
## Prenatal Testing and Preimplantation Genetic Testing
If the cherubism-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
•
•
• United Kingdom
•
•
•
## Molecular Genetics
Cherubism: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Cherubism (
The generation of mice models of cherubism helped to decipher the underlying molecular mechanisms leading to the development of giant cell granulomas and excessive bone resorption. A knock-in mouse model with the most common pathogenic variant in human 3BP-2 (p.Pro418Arg) developed severe osteoporosis associated with highly activated osteoclasts, demonstrating that pathogenic variants within this peptide sequence result in a gain-of-function activity [
Sequence analysis of exon 9 of
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
The generation of mice models of cherubism helped to decipher the underlying molecular mechanisms leading to the development of giant cell granulomas and excessive bone resorption. A knock-in mouse model with the most common pathogenic variant in human 3BP-2 (p.Pro418Arg) developed severe osteoporosis associated with highly activated osteoclasts, demonstrating that pathogenic variants within this peptide sequence result in a gain-of-function activity [
Sequence analysis of exon 9 of
Variants listed in the table have been provided by the authors.
## Chapter Notes
Our research team has investigated cherubism for several years. Our work helped to decipher new molecular and physiopathologic aspects in human cherubism (see PMIDs 23129383, 25491283, 27498064, 30236129, and 32825821), demonstrating that cherubism may not be restricted to the maxillofacial region and may be associated with systemic bone loss and inflammation, especially in those with severe disease (see PMID 32825821).
Natacha Kadlub
Amélie Coudert
Anne Morice
Natacha Kadlub, Amélie Coudert, and Anne Morice a are actively involved in clinical research regarding individuals with cherubism. They would be happy to communicate with persons who have any questions regarding diagnosis of cherubism or other considerations. They are also interested in hearing from clinicians treating families affected by cherubism in whom no causative variant has been identified in
We thank our colleagues from the radiology department (Dr Kahina Belhous) and the pathology department (Dr Philippe Drabent), Hôpital Necker-Enfants malades, APHP, Paris, France.
Berivan Baskin, PhD, FCCMG, FACMG; University Hospital Uppsala (2007-2025)Sarah Bowdin, BM, MSc, MRCPCH; Addenbrooke's Hospital Cambridge (2011-2025)Amelie Coudert, PhD (2025-present)Natacha Kadlub, MD, PhD (2025-present)Peter Kannu, MB ChB, PhD, DCH, FRACP, FRCPC; The Hospital for Sick Children (2018-2025)Anne Morice, MD, PhD (2025-present)Peter N Ray, PhD, FCCMG, FACMG; University of Toronto (2007-2018)Ahmad Teebi, MD, FRCPC, FACMG; Weill Cornell Medical College - Qatar (2007-2011)
20 March 2025 (sw) Comprehensive update posted live
21 November 2018 (ha) Comprehensive update posted live
1 September 2011 (me) Comprehensive update posted live
26 February 2007 (me) Review posted live
8 December 2006 (pr) Original submission
• 20 March 2025 (sw) Comprehensive update posted live
• 21 November 2018 (ha) Comprehensive update posted live
• 1 September 2011 (me) Comprehensive update posted live
• 26 February 2007 (me) Review posted live
• 8 December 2006 (pr) Original submission
## Author Notes
Our research team has investigated cherubism for several years. Our work helped to decipher new molecular and physiopathologic aspects in human cherubism (see PMIDs 23129383, 25491283, 27498064, 30236129, and 32825821), demonstrating that cherubism may not be restricted to the maxillofacial region and may be associated with systemic bone loss and inflammation, especially in those with severe disease (see PMID 32825821).
Natacha Kadlub
Amélie Coudert
Anne Morice
Natacha Kadlub, Amélie Coudert, and Anne Morice a are actively involved in clinical research regarding individuals with cherubism. They would be happy to communicate with persons who have any questions regarding diagnosis of cherubism or other considerations. They are also interested in hearing from clinicians treating families affected by cherubism in whom no causative variant has been identified in
## Acknowledgments
We thank our colleagues from the radiology department (Dr Kahina Belhous) and the pathology department (Dr Philippe Drabent), Hôpital Necker-Enfants malades, APHP, Paris, France.
## Author History
Berivan Baskin, PhD, FCCMG, FACMG; University Hospital Uppsala (2007-2025)Sarah Bowdin, BM, MSc, MRCPCH; Addenbrooke's Hospital Cambridge (2011-2025)Amelie Coudert, PhD (2025-present)Natacha Kadlub, MD, PhD (2025-present)Peter Kannu, MB ChB, PhD, DCH, FRACP, FRCPC; The Hospital for Sick Children (2018-2025)Anne Morice, MD, PhD (2025-present)Peter N Ray, PhD, FCCMG, FACMG; University of Toronto (2007-2018)Ahmad Teebi, MD, FRCPC, FACMG; Weill Cornell Medical College - Qatar (2007-2011)
## Revision History
20 March 2025 (sw) Comprehensive update posted live
21 November 2018 (ha) Comprehensive update posted live
1 September 2011 (me) Comprehensive update posted live
26 February 2007 (me) Review posted live
8 December 2006 (pr) Original submission
• 20 March 2025 (sw) Comprehensive update posted live
• 21 November 2018 (ha) Comprehensive update posted live
• 1 September 2011 (me) Comprehensive update posted live
• 26 February 2007 (me) Review posted live
• 8 December 2006 (pr) Original submission
## References
## Literature Cited
Bilateral mandibular swelling with characteristic facial features of cherubism in a young girl. Head CT showing lesions involving the mandible (arrow) and maxillary tuberosity without any sign of root resorption.
Reprinted with permission from
Coronal CT of child age six years with severe cherubism showing multilocular tissue expansion of the maxilla and mandible, bilaterally, with osteolysis and cortical bone expansion (arrows), tooth displacements (arrow heads), and elevation of the orbital floors (*)
Reprinted with permission from
|
[] |
26/2/2007
|
20/3/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
chh
|
chh
|
[
"Metaphyseal Dysplasia without Hypotrichosis (MDWH)",
"Anauxetic Dysplasia (AD)",
"Cartilage-Hair Hypoplasia (CHH)",
"Not applicable",
"RMRP",
"Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders"
] |
Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders
|
Outi Mäkitie, Svetlana Vakkilainen
|
Summary The cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum that includes the following phenotypes: Metaphyseal dysplasia without hypotrichosis (MDWH) Cartilage-hair hypoplasia (CHH) Anauxetic dysplasia (AD) CHH-AD spectrum disorders are characterized by severe disproportionate (short-limb) short stature that is usually recognized in the newborn, and occasionally prenatally because of the short extremities. Other findings include joint hypermobility, fine, silky hair, immunodeficiency, anemia, increased risk for malignancy, gastrointestinal dysfunction, and impaired spermatogenesis. The most severe phenotype, AD, has the most pronounced skeletal phenotype, may be associated with atlantoaxial subluxation in the newborn, and may include cognitive deficiency. The clinical manifestations of the CHH-AD spectrum disorders are variable, even within the same family. Diagnosis of a CHH-AD spectrum disorder is established in a proband with characteristic clinical and radiographic findings. If clinical and radiographic findings are inconclusive, identification of biallelic pathogenic variants in CHH-AD spectrum disorders are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
Metaphyseal dysplasia without hypotrichosis (MDWH)
Cartilage-hair hypoplasia (CHH)
Anauxetic dysplasia (AD)
For synonyms and outdated names see
• Metaphyseal dysplasia without hypotrichosis (MDWH)
• Cartilage-hair hypoplasia (CHH)
• Anauxetic dysplasia (AD)
## Diagnosis
There are no formal diagnostic criteria for cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders, as individuals present with highly variable phenotypes.
The CHH-AD spectrum disorders are a continuum ranging from short stature without hypotrichosis with only radiographic evidence of metaphyseal dysplasia (MDWH) [
Newborn screening for severe combined immunodeficiency (SCID) using detection of T cell receptor excision circles is able to identify some individuals with CHH prior to recognition of other findings [
A CHH-AD spectrum disorder
Mild-to-severe disproportionate short-limbed short stature
Presence of variable metaphyseal dysplasia, with epiphyseal and vertebral dysplasia at the severe end of the spectrum
Especially when accompanied by:
Short tubular bones
Bowed femora and tibiae
"Bullet"-shaped middle phalanges, cone-shaped epiphyses, and premature epiphyseal fusion on hand radiographs
Laxity of ligaments with joint hypermobility, but limited extension of the elbow
Fine, silky hair
Increased rate of infections or intestinal dysfunction or anemia
Disproportionate (short-limb) short stature
Short fingers and toes
Bowed femora and tibiae
Laxity of ligaments with hypermobility of joints
Limited extension of the elbows
Lumbar lordosis
Chest deformity
Blond, sparse, fine, silky hair
Impaired lymphocyte proliferation and T lymphocyte function with increased risk of infections in infancy and childhood, severe varicella infection, SCID, bronchiectasis, and cutaneous and visceral granulomas
Macrocytic, hypoplastic anemia in early childhood
Malignancies: lymphoma, leukemia, neoplasms of the skin, eye, and liver
Intestinal manifestations: congenital megacolon, Hirschsprung disease, intestinal malabsorption
Clinical features similar to CHH, but with normal hair
Absence of anemia and intestinal manifestations
Initial absence of immunodeficiency; late-onset immunodeficiency is possible [
Prenatal onset of extreme short-limb short stature (100% of affected individuals)
Barrel chest
Hyperlordosis and kyphoscoliosis
Dislocated hips
Atlantoaxial subluxation leading to cervical spine compression
Craniofacial features: midfacial hypoplasia, macroglossia, dental abnormalities
Mild intellectual disability
Note: Radiographic findings tend to be highly variable.
Short and thick tubular bones with metaphyseal dysplasia most prominent at the knees. Distal metaphyses are wide, flared, and occasionally scalloped with cystic areas and poor ossification with trabeculation. Epiphyses are normal or show only mild dysplasia of the femoral head.
Metacarpals and phalanges are short and bullet-shaped with cone-shaped epiphyses.
Vertebral bodies are normal or have mild biconvexity with increased height, lumbar lordosis, and reduced widening of interpediculate distance in the lumbar spine.
Vertebral bodies are late-maturing ovoid with concave dorsal surfaces in the lumbar region; dislocation is seen in the cervical spine.
Femora have small capital femoral epiphyses with hypoplastic femoral necks.
Iliac bodies are hypoplastic.
Acetabulae are shallow.
Metacarpals are short with widened shafts (I and V).
Phalanges are very short and broad with small, late ossifying epiphyses and bullet-shaped middle phalanges.
The diagnosis of a CHH-AD spectrum disorder
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotypes of CHH-AD spectrum disorders are broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of a CHH-AD spectrum disorder, molecular genetic testing approaches can include
Note: Targeted analysis for the common
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by short stature,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include nucleotide substitution and small intragenic deletions. Typically, whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date, no large deletions or duplications involving
• Mild-to-severe disproportionate short-limbed short stature
• Presence of variable metaphyseal dysplasia, with epiphyseal and vertebral dysplasia at the severe end of the spectrum
• Short tubular bones
• Bowed femora and tibiae
• "Bullet"-shaped middle phalanges, cone-shaped epiphyses, and premature epiphyseal fusion on hand radiographs
• Laxity of ligaments with joint hypermobility, but limited extension of the elbow
• Fine, silky hair
• Increased rate of infections or intestinal dysfunction or anemia
• Disproportionate (short-limb) short stature
• Short fingers and toes
• Bowed femora and tibiae
• Laxity of ligaments with hypermobility of joints
• Limited extension of the elbows
• Lumbar lordosis
• Chest deformity
• Blond, sparse, fine, silky hair
• Impaired lymphocyte proliferation and T lymphocyte function with increased risk of infections in infancy and childhood, severe varicella infection, SCID, bronchiectasis, and cutaneous and visceral granulomas
• Macrocytic, hypoplastic anemia in early childhood
• Malignancies: lymphoma, leukemia, neoplasms of the skin, eye, and liver
• Intestinal manifestations: congenital megacolon, Hirschsprung disease, intestinal malabsorption
• Clinical features similar to CHH, but with normal hair
• Absence of anemia and intestinal manifestations
• Initial absence of immunodeficiency; late-onset immunodeficiency is possible [
• Prenatal onset of extreme short-limb short stature (100% of affected individuals)
• Barrel chest
• Hyperlordosis and kyphoscoliosis
• Dislocated hips
• Atlantoaxial subluxation leading to cervical spine compression
• Craniofacial features: midfacial hypoplasia, macroglossia, dental abnormalities
• Mild intellectual disability
• Short and thick tubular bones with metaphyseal dysplasia most prominent at the knees. Distal metaphyses are wide, flared, and occasionally scalloped with cystic areas and poor ossification with trabeculation. Epiphyses are normal or show only mild dysplasia of the femoral head.
• Metacarpals and phalanges are short and bullet-shaped with cone-shaped epiphyses.
• Vertebral bodies are normal or have mild biconvexity with increased height, lumbar lordosis, and reduced widening of interpediculate distance in the lumbar spine.
• Vertebral bodies are late-maturing ovoid with concave dorsal surfaces in the lumbar region; dislocation is seen in the cervical spine.
• Femora have small capital femoral epiphyses with hypoplastic femoral necks.
• Iliac bodies are hypoplastic.
• Acetabulae are shallow.
• Metacarpals are short with widened shafts (I and V).
• Phalanges are very short and broad with small, late ossifying epiphyses and bullet-shaped middle phalanges.
• Note: Targeted analysis for the common
• For an introduction to multigene panels click
## Suggestive Findings
A CHH-AD spectrum disorder
Mild-to-severe disproportionate short-limbed short stature
Presence of variable metaphyseal dysplasia, with epiphyseal and vertebral dysplasia at the severe end of the spectrum
Especially when accompanied by:
Short tubular bones
Bowed femora and tibiae
"Bullet"-shaped middle phalanges, cone-shaped epiphyses, and premature epiphyseal fusion on hand radiographs
Laxity of ligaments with joint hypermobility, but limited extension of the elbow
Fine, silky hair
Increased rate of infections or intestinal dysfunction or anemia
Disproportionate (short-limb) short stature
Short fingers and toes
Bowed femora and tibiae
Laxity of ligaments with hypermobility of joints
Limited extension of the elbows
Lumbar lordosis
Chest deformity
Blond, sparse, fine, silky hair
Impaired lymphocyte proliferation and T lymphocyte function with increased risk of infections in infancy and childhood, severe varicella infection, SCID, bronchiectasis, and cutaneous and visceral granulomas
Macrocytic, hypoplastic anemia in early childhood
Malignancies: lymphoma, leukemia, neoplasms of the skin, eye, and liver
Intestinal manifestations: congenital megacolon, Hirschsprung disease, intestinal malabsorption
Clinical features similar to CHH, but with normal hair
Absence of anemia and intestinal manifestations
Initial absence of immunodeficiency; late-onset immunodeficiency is possible [
Prenatal onset of extreme short-limb short stature (100% of affected individuals)
Barrel chest
Hyperlordosis and kyphoscoliosis
Dislocated hips
Atlantoaxial subluxation leading to cervical spine compression
Craniofacial features: midfacial hypoplasia, macroglossia, dental abnormalities
Mild intellectual disability
Note: Radiographic findings tend to be highly variable.
Short and thick tubular bones with metaphyseal dysplasia most prominent at the knees. Distal metaphyses are wide, flared, and occasionally scalloped with cystic areas and poor ossification with trabeculation. Epiphyses are normal or show only mild dysplasia of the femoral head.
Metacarpals and phalanges are short and bullet-shaped with cone-shaped epiphyses.
Vertebral bodies are normal or have mild biconvexity with increased height, lumbar lordosis, and reduced widening of interpediculate distance in the lumbar spine.
Vertebral bodies are late-maturing ovoid with concave dorsal surfaces in the lumbar region; dislocation is seen in the cervical spine.
Femora have small capital femoral epiphyses with hypoplastic femoral necks.
Iliac bodies are hypoplastic.
Acetabulae are shallow.
Metacarpals are short with widened shafts (I and V).
Phalanges are very short and broad with small, late ossifying epiphyses and bullet-shaped middle phalanges.
• Mild-to-severe disproportionate short-limbed short stature
• Presence of variable metaphyseal dysplasia, with epiphyseal and vertebral dysplasia at the severe end of the spectrum
• Short tubular bones
• Bowed femora and tibiae
• "Bullet"-shaped middle phalanges, cone-shaped epiphyses, and premature epiphyseal fusion on hand radiographs
• Laxity of ligaments with joint hypermobility, but limited extension of the elbow
• Fine, silky hair
• Increased rate of infections or intestinal dysfunction or anemia
• Disproportionate (short-limb) short stature
• Short fingers and toes
• Bowed femora and tibiae
• Laxity of ligaments with hypermobility of joints
• Limited extension of the elbows
• Lumbar lordosis
• Chest deformity
• Blond, sparse, fine, silky hair
• Impaired lymphocyte proliferation and T lymphocyte function with increased risk of infections in infancy and childhood, severe varicella infection, SCID, bronchiectasis, and cutaneous and visceral granulomas
• Macrocytic, hypoplastic anemia in early childhood
• Malignancies: lymphoma, leukemia, neoplasms of the skin, eye, and liver
• Intestinal manifestations: congenital megacolon, Hirschsprung disease, intestinal malabsorption
• Clinical features similar to CHH, but with normal hair
• Absence of anemia and intestinal manifestations
• Initial absence of immunodeficiency; late-onset immunodeficiency is possible [
• Prenatal onset of extreme short-limb short stature (100% of affected individuals)
• Barrel chest
• Hyperlordosis and kyphoscoliosis
• Dislocated hips
• Atlantoaxial subluxation leading to cervical spine compression
• Craniofacial features: midfacial hypoplasia, macroglossia, dental abnormalities
• Mild intellectual disability
• Short and thick tubular bones with metaphyseal dysplasia most prominent at the knees. Distal metaphyses are wide, flared, and occasionally scalloped with cystic areas and poor ossification with trabeculation. Epiphyses are normal or show only mild dysplasia of the femoral head.
• Metacarpals and phalanges are short and bullet-shaped with cone-shaped epiphyses.
• Vertebral bodies are normal or have mild biconvexity with increased height, lumbar lordosis, and reduced widening of interpediculate distance in the lumbar spine.
• Vertebral bodies are late-maturing ovoid with concave dorsal surfaces in the lumbar region; dislocation is seen in the cervical spine.
• Femora have small capital femoral epiphyses with hypoplastic femoral necks.
• Iliac bodies are hypoplastic.
• Acetabulae are shallow.
• Metacarpals are short with widened shafts (I and V).
• Phalanges are very short and broad with small, late ossifying epiphyses and bullet-shaped middle phalanges.
## Clinical Findings by Phenotype
Disproportionate (short-limb) short stature
Short fingers and toes
Bowed femora and tibiae
Laxity of ligaments with hypermobility of joints
Limited extension of the elbows
Lumbar lordosis
Chest deformity
Blond, sparse, fine, silky hair
Impaired lymphocyte proliferation and T lymphocyte function with increased risk of infections in infancy and childhood, severe varicella infection, SCID, bronchiectasis, and cutaneous and visceral granulomas
Macrocytic, hypoplastic anemia in early childhood
Malignancies: lymphoma, leukemia, neoplasms of the skin, eye, and liver
Intestinal manifestations: congenital megacolon, Hirschsprung disease, intestinal malabsorption
Clinical features similar to CHH, but with normal hair
Absence of anemia and intestinal manifestations
Initial absence of immunodeficiency; late-onset immunodeficiency is possible [
Prenatal onset of extreme short-limb short stature (100% of affected individuals)
Barrel chest
Hyperlordosis and kyphoscoliosis
Dislocated hips
Atlantoaxial subluxation leading to cervical spine compression
Craniofacial features: midfacial hypoplasia, macroglossia, dental abnormalities
Mild intellectual disability
• Disproportionate (short-limb) short stature
• Short fingers and toes
• Bowed femora and tibiae
• Laxity of ligaments with hypermobility of joints
• Limited extension of the elbows
• Lumbar lordosis
• Chest deformity
• Blond, sparse, fine, silky hair
• Impaired lymphocyte proliferation and T lymphocyte function with increased risk of infections in infancy and childhood, severe varicella infection, SCID, bronchiectasis, and cutaneous and visceral granulomas
• Macrocytic, hypoplastic anemia in early childhood
• Malignancies: lymphoma, leukemia, neoplasms of the skin, eye, and liver
• Intestinal manifestations: congenital megacolon, Hirschsprung disease, intestinal malabsorption
• Clinical features similar to CHH, but with normal hair
• Absence of anemia and intestinal manifestations
• Initial absence of immunodeficiency; late-onset immunodeficiency is possible [
• Prenatal onset of extreme short-limb short stature (100% of affected individuals)
• Barrel chest
• Hyperlordosis and kyphoscoliosis
• Dislocated hips
• Atlantoaxial subluxation leading to cervical spine compression
• Craniofacial features: midfacial hypoplasia, macroglossia, dental abnormalities
• Mild intellectual disability
## Radiographic Findings by Phenotype
Note: Radiographic findings tend to be highly variable.
Short and thick tubular bones with metaphyseal dysplasia most prominent at the knees. Distal metaphyses are wide, flared, and occasionally scalloped with cystic areas and poor ossification with trabeculation. Epiphyses are normal or show only mild dysplasia of the femoral head.
Metacarpals and phalanges are short and bullet-shaped with cone-shaped epiphyses.
Vertebral bodies are normal or have mild biconvexity with increased height, lumbar lordosis, and reduced widening of interpediculate distance in the lumbar spine.
Vertebral bodies are late-maturing ovoid with concave dorsal surfaces in the lumbar region; dislocation is seen in the cervical spine.
Femora have small capital femoral epiphyses with hypoplastic femoral necks.
Iliac bodies are hypoplastic.
Acetabulae are shallow.
Metacarpals are short with widened shafts (I and V).
Phalanges are very short and broad with small, late ossifying epiphyses and bullet-shaped middle phalanges.
• Short and thick tubular bones with metaphyseal dysplasia most prominent at the knees. Distal metaphyses are wide, flared, and occasionally scalloped with cystic areas and poor ossification with trabeculation. Epiphyses are normal or show only mild dysplasia of the femoral head.
• Metacarpals and phalanges are short and bullet-shaped with cone-shaped epiphyses.
• Vertebral bodies are normal or have mild biconvexity with increased height, lumbar lordosis, and reduced widening of interpediculate distance in the lumbar spine.
• Vertebral bodies are late-maturing ovoid with concave dorsal surfaces in the lumbar region; dislocation is seen in the cervical spine.
• Femora have small capital femoral epiphyses with hypoplastic femoral necks.
• Iliac bodies are hypoplastic.
• Acetabulae are shallow.
• Metacarpals are short with widened shafts (I and V).
• Phalanges are very short and broad with small, late ossifying epiphyses and bullet-shaped middle phalanges.
## Establishing the Diagnosis
The diagnosis of a CHH-AD spectrum disorder
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotypes of CHH-AD spectrum disorders are broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of a CHH-AD spectrum disorder, molecular genetic testing approaches can include
Note: Targeted analysis for the common
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by short stature,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include nucleotide substitution and small intragenic deletions. Typically, whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date, no large deletions or duplications involving
• Note: Targeted analysis for the common
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of a CHH-AD spectrum disorder, molecular genetic testing approaches can include
Note: Targeted analysis for the common
For an introduction to multigene panels click
• Note: Targeted analysis for the common
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by short stature,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include nucleotide substitution and small intragenic deletions. Typically, whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date, no large deletions or duplications involving
## Clinical Characteristics
Cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum that includes three phenotypes:
Metaphyseal dysplasia without hypotrichosis (MDWH)
Cartilage-hair hypoplasia (CHH), with metaphyseal dysplasia and hypotrichosis
At the severe end, the rare anauxetic dysplasia (AD), the most pronounced skeletal phenotype
The mechanisms for phenotypic variability are incompletely understood (see
Marked inter- and intrafamilial variability of short stature has been observed. Growth curves for Finnish individuals with CHH have been published. Final adult height ranges from 104 to 151 cm in CHH (median: 131 cm in males; 122 cm in females) and less than 85 cm in AD [
The most frequently observed cancers are non-Hodgkin lymphoma, followed by squamous cell carcinoma, leukemia, and Hodgkin lymphoma; non-aggressive basal cell carcinoma was also common. There are isolated reports of uterine carcinoma and vocal cord carcinoma [
A case series of 16 individuals with CHH and lymphoma revealed that the most common lymphoma type was diffuse large B cell lymphoma [
Atlantoaxial subluxation with fatal cervical compression
Mild intellectual disability
The CHH-AD spectrum includes a range of phenotypes.
The milder phenotypes are usually caused by either of the following:
Compound heterozygous or homozygous pathogenic variants within the transcript resulting in little to intermediate effect on the function of RNase MRP (see
Compound heterozygosity for one pathogenic variant within the transcript and one pathogenic variant in the promoter region
AD is caused by either of the following:
Compound heterozygous or homozygous pathogenic variants that severely alter function
Compound heterozygosity for one pathogenic variant within the transcript that severely alters the RNase MRP function and a hypomorphic allele (e.g., pathogenic variant leading to an unstable transcript)
Cartilage-hair hypoplasia (CHH) or metaphyseal chondrodysplasia, McKusick type was first described in the Old Order Amish population [
Individuals with normal hair and metaphyseal dysplasia, called metaphyseal dysplasia without hypotrichosis (MDWH), were reported by
Anauxetic dysplasia was named after the Greek "not to permit growth" [
About 700 individuals are currently known to have a CHH-AD spectrum disorder [Kaitila, personal communication]. The most severe form, AD, is extremely rare: fewer than ten affected individuals have been reported.
Affected individuals have been reported in most populations; however, a high incidence of CHH was noted in the Old Order Amish population, with a prevalence of 1-2:1,000 (carrier frequency of 1:10), and in Finland, with an incidence of 1:23,000 (carrier frequency of 1:76) [
• Metaphyseal dysplasia without hypotrichosis (MDWH)
• Cartilage-hair hypoplasia (CHH), with metaphyseal dysplasia and hypotrichosis
• At the severe end, the rare anauxetic dysplasia (AD), the most pronounced skeletal phenotype
• Atlantoaxial subluxation with fatal cervical compression
• Mild intellectual disability
• Compound heterozygous or homozygous pathogenic variants within the transcript resulting in little to intermediate effect on the function of RNase MRP (see
• Compound heterozygosity for one pathogenic variant within the transcript and one pathogenic variant in the promoter region
• Compound heterozygous or homozygous pathogenic variants that severely alter function
• Compound heterozygosity for one pathogenic variant within the transcript that severely alters the RNase MRP function and a hypomorphic allele (e.g., pathogenic variant leading to an unstable transcript)
## Clinical Description
Cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum that includes three phenotypes:
Metaphyseal dysplasia without hypotrichosis (MDWH)
Cartilage-hair hypoplasia (CHH), with metaphyseal dysplasia and hypotrichosis
At the severe end, the rare anauxetic dysplasia (AD), the most pronounced skeletal phenotype
The mechanisms for phenotypic variability are incompletely understood (see
Marked inter- and intrafamilial variability of short stature has been observed. Growth curves for Finnish individuals with CHH have been published. Final adult height ranges from 104 to 151 cm in CHH (median: 131 cm in males; 122 cm in females) and less than 85 cm in AD [
The most frequently observed cancers are non-Hodgkin lymphoma, followed by squamous cell carcinoma, leukemia, and Hodgkin lymphoma; non-aggressive basal cell carcinoma was also common. There are isolated reports of uterine carcinoma and vocal cord carcinoma [
A case series of 16 individuals with CHH and lymphoma revealed that the most common lymphoma type was diffuse large B cell lymphoma [
Atlantoaxial subluxation with fatal cervical compression
Mild intellectual disability
• Metaphyseal dysplasia without hypotrichosis (MDWH)
• Cartilage-hair hypoplasia (CHH), with metaphyseal dysplasia and hypotrichosis
• At the severe end, the rare anauxetic dysplasia (AD), the most pronounced skeletal phenotype
• Atlantoaxial subluxation with fatal cervical compression
• Mild intellectual disability
## Genotype-Phenotype Correlations
The CHH-AD spectrum includes a range of phenotypes.
The milder phenotypes are usually caused by either of the following:
Compound heterozygous or homozygous pathogenic variants within the transcript resulting in little to intermediate effect on the function of RNase MRP (see
Compound heterozygosity for one pathogenic variant within the transcript and one pathogenic variant in the promoter region
AD is caused by either of the following:
Compound heterozygous or homozygous pathogenic variants that severely alter function
Compound heterozygosity for one pathogenic variant within the transcript that severely alters the RNase MRP function and a hypomorphic allele (e.g., pathogenic variant leading to an unstable transcript)
• Compound heterozygous or homozygous pathogenic variants within the transcript resulting in little to intermediate effect on the function of RNase MRP (see
• Compound heterozygosity for one pathogenic variant within the transcript and one pathogenic variant in the promoter region
• Compound heterozygous or homozygous pathogenic variants that severely alter function
• Compound heterozygosity for one pathogenic variant within the transcript that severely alters the RNase MRP function and a hypomorphic allele (e.g., pathogenic variant leading to an unstable transcript)
## Nomenclature
Cartilage-hair hypoplasia (CHH) or metaphyseal chondrodysplasia, McKusick type was first described in the Old Order Amish population [
Individuals with normal hair and metaphyseal dysplasia, called metaphyseal dysplasia without hypotrichosis (MDWH), were reported by
Anauxetic dysplasia was named after the Greek "not to permit growth" [
## Prevalence
About 700 individuals are currently known to have a CHH-AD spectrum disorder [Kaitila, personal communication]. The most severe form, AD, is extremely rare: fewer than ten affected individuals have been reported.
Affected individuals have been reported in most populations; however, a high incidence of CHH was noted in the Old Order Amish population, with a prevalence of 1-2:1,000 (carrier frequency of 1:10), and in Finland, with an incidence of 1:23,000 (carrier frequency of 1:76) [
## Genetically Related (Allelic) Disorders
Single individuals with biallelic
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders
Skeletal dysplasia
Immunodeficiency
Spondylometaphyseal dysplasia
DD, spasticity, intracranial calcifications
Short stature
Hematologic changes
Immunologic changes
Short stature & radiographic metaphyseal abnormalities resembling CHH
↑ infections
Anemia
Milder skeletal features (usually)
Principal manifestations: exocrine pancreatic insufficiency, neutropenia, poor weight gain, & growth deficiency
Skeletal dysplasia
Immunodeficiency
Spondyloepimetaphyseal dysplasia
DD, dysmorphic features, liver cysts
Short stature & metaphyseal dysplasia
Sparse scalp hair
Skeletal dysplasia
Immunodeficiency
Spondylometaphyseal dysplasia
Cardiovascular abnormalities, DD, dysmorphic features
Short stature & metaphyseal dysplasia
↓ peripheral blood mononuclear cell proliferation ability
Skeletal dysplasia
Immunodeficiency
Spondyloepiphyseal dysplasia
Humoral immunodeficiency
Retinal dystrophy, DD, characteristic facial features
Short stature
Cellular immune deficiency
Short stature caused by short trunk (vs short-limb short stature in CHH-AD spectrum disorders)
Characteristic facies
Vascular issues
Glomerulopathy, abnormal skin pigmentation
AD = autosomal dominant; AR = autosomal recessive; CHH = cartilage-hair hypoplasia; CHH-AD; cartilage-hair hypoplasia – anauxetic dysplasia; DD = developmental delay; MOI = mode of inheritance; XL = X-linked
Congenital neutropenia that occurs as part of a syndrome can be caused by pathogenic variants affecting glucose metabolism or lysosomal function.
If recurrent infections are present, milder forms of Schimke immunoosseous dysplasia may be confused with cartilage-hair hypoplasia [
• Skeletal dysplasia
• Immunodeficiency
• Spondylometaphyseal dysplasia
• DD, spasticity, intracranial calcifications
• Short stature
• Hematologic changes
• Immunologic changes
• Short stature & radiographic metaphyseal abnormalities resembling CHH
• ↑ infections
• Anemia
• Milder skeletal features (usually)
• Principal manifestations: exocrine pancreatic insufficiency, neutropenia, poor weight gain, & growth deficiency
• Skeletal dysplasia
• Immunodeficiency
• Spondyloepimetaphyseal dysplasia
• DD, dysmorphic features, liver cysts
• Short stature & metaphyseal dysplasia
• Sparse scalp hair
• Skeletal dysplasia
• Immunodeficiency
• Spondylometaphyseal dysplasia
• Cardiovascular abnormalities, DD, dysmorphic features
• Short stature & metaphyseal dysplasia
• ↓ peripheral blood mononuclear cell proliferation ability
• Skeletal dysplasia
• Immunodeficiency
• Spondyloepiphyseal dysplasia
• Humoral immunodeficiency
• Retinal dystrophy, DD, characteristic facial features
• Short stature
• Cellular immune deficiency
• Short stature caused by short trunk (vs short-limb short stature in CHH-AD spectrum disorders)
• Characteristic facies
• Vascular issues
• Glomerulopathy, abnormal skin pigmentation
## Management
No clinical practice guidelines for cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders have been published. Guidelines for the management of immunodeficiency in CHH have been published [
To establish the extent of disease and needs of an individual diagnosed with a CHH-AD spectrum disorder, the evaluations summarized in
Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders: Recommended Evaluations Following Initial Diagnosis
Serum concentration of IgG, IgA, IgM, & IgG subclasses
CD3, 4, 8, 19, 16/56
Post-vaccine titers
Other immunologic parameters: allogeneic lymphocyte cytotoxicity; T cell subsets, TREC analysis; T cell repertoire; proliferation response to PHA; proliferation response to anti-CD3
AD = anauxetic dysplasia; CBC = complete blood count; CHH = cartilage-hair hypoplasia; Ig = immunoglobulin; PHA = phytohemagglutinin; TREC = T cell receptor excision circles
There is no cure for CHH-AD spectrum disorders.
Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders: Treatment of Manifestations
If cervical spine abnormality &/or instability is identified, special care when general anesthesia is administered
In persons w/AD, surgery as needed to fuse malformed cervical vertebrae in infancy & to correct/prevent progression of kyphoscoliosis that can compromise lung function
Corrective osteotomies as needed in late childhood or adolescence for excessive varus deformity of lower extremities
Orthopedic surgery may be complicated by low bone density.
Treatment w/recombinant growth hormone has not shown any sustained benefit in persons w/CHH & cannot be recommended.
Treatment of underlying infections based on type, location, & severity
Immediate high-dose IV acyclovir w/onset of varicella infection to prevent complications
Consider prophylactic antibiotics for those w/recurrent infections, neutropenia, or severe lymphopenia.
Consider IVIG if immunoglobulin or IgG subclass levels are low, or if vaccine responses are inadequate.
Treatments for granulomas have included anti-TNF-α therapy & HSCT.
Consider HSCT in persons w/CHH w/recurrent infections & autoimmune manifestations or bone marrow dysplasia for whom a well-matched donor is available.
HSCT has resulted in normalization of T lymphocyte numbers & function, resolution of autoimmune manifestations, & catch-up growth, probably due to ↓ infections.
Overall survival rates have been reported at 63% for unrelated donor transplants & as high as 80% for matched sibs.
Red blood cell transfusions for severe anemia secondary to depressed erythropoiesis
HSCT is rarely needed.
Iron chelation for those requiring recurrent red blood cell transfusions
Standard treatments for congenital megacolon, Hirschsprung disease, intestinal malabsorption
Nutrition eval in those w/short bowel syndrome
AD = anauxetic dysplasia; CHH = cartilage-hair hypoplasia; HSCT = hematopoietic stem cell transplantation; Ig = immunoglobulin; IVIG = intravenous immunoglobulin
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders: Recommended Surveillance
Serum concentration of IgG, IgA, IgM
CD3, 4, 8, 19, 16/56
Post-vaccine titers
Other immunologic parameters: T cell subsets, TREC analysis; T cell repertoire; proliferation response to PHA; proliferation response to anti-CD3
At diagnosis in all persons
Frequency of follow-up labs is based on initial results.
Assess for skin changes, enlarged lymph nodes, hepatomegaly, splenomegaly, & other signs of malignancy.
CBC w/differential
LDH & uric acid
Annually in children
In adults, frequency of follow up is determined on individual basis.
Every 1-2 yrs in children
In adults, frequency of follow up is determined on individual basis.
AD = anauxetic dysplasia; CBC = complete blood count; CHH = cartilage-hair hypoplasia; Ig = immunoglobulin; LDH = lactate dehydrogenase; PHA = phytohemagglutinin; TREC = T cell receptor excision circles
No data are available on the likely timing of recurrence of anemia after successful treatment.
Severe anemia in adolescents and adults with CHH can be the presenting symptom of malignancy and may require extensive investigations with bone marrow evaluation and imaging studies.
Immunization with live vaccines should be carefully considered in those with CHH and evidence of abnormal immunologic function and should be avoided in those with CHH and severe combined immunodeficiency [
Note: (1) Routine immunizations with inactivated vaccines are safe in persons with CHH. (2) No serious adverse events have been recorded after immunization with live viral vaccines in individuals of Finnish ancestry with CHH. (3) Individuals with CHH generate humoral and cellular immune response to live viral vaccines. Immunization with live vaccines may be considered in selected individuals with CHH without immunodeficiency or with clinically mild immunodeficiency [
Early diagnosis of relatives (i.e., sibs) at risk for CHH-AD spectrum disorders is important for early recognition and management of manifestations that can be associated with significant morbidity (e.g., infections, immunization with live vaccines, malignancies). Relatives at risk should be tested if clinical features, especially short stature, are present; completely asymptomatic individuals need not be tested. Evaluations can include:
Molecular genetic testing if the pathogenic variants in the family are known;
Radiographic evaluation and
See
Despite significant short stature in women with CHH and other potential CHH-related effects on pregnancy outcome, most pregnancies lead to a term cesarean section delivery. Fetal growth is generally unaffected; therefore, planned cesarean section should be considered in term pregnancies due to cephalopelvic disproportion [
Search
• Serum concentration of IgG, IgA, IgM, & IgG subclasses
• CD3, 4, 8, 19, 16/56
• Post-vaccine titers
• Other immunologic parameters: allogeneic lymphocyte cytotoxicity; T cell subsets, TREC analysis; T cell repertoire; proliferation response to PHA; proliferation response to anti-CD3
• If cervical spine abnormality &/or instability is identified, special care when general anesthesia is administered
• In persons w/AD, surgery as needed to fuse malformed cervical vertebrae in infancy & to correct/prevent progression of kyphoscoliosis that can compromise lung function
• Corrective osteotomies as needed in late childhood or adolescence for excessive varus deformity of lower extremities
• Orthopedic surgery may be complicated by low bone density.
• Treatment w/recombinant growth hormone has not shown any sustained benefit in persons w/CHH & cannot be recommended.
• Treatment of underlying infections based on type, location, & severity
• Immediate high-dose IV acyclovir w/onset of varicella infection to prevent complications
• Consider prophylactic antibiotics for those w/recurrent infections, neutropenia, or severe lymphopenia.
• Consider IVIG if immunoglobulin or IgG subclass levels are low, or if vaccine responses are inadequate.
• Treatments for granulomas have included anti-TNF-α therapy & HSCT.
• Consider HSCT in persons w/CHH w/recurrent infections & autoimmune manifestations or bone marrow dysplasia for whom a well-matched donor is available.
• HSCT has resulted in normalization of T lymphocyte numbers & function, resolution of autoimmune manifestations, & catch-up growth, probably due to ↓ infections.
• Overall survival rates have been reported at 63% for unrelated donor transplants & as high as 80% for matched sibs.
• Red blood cell transfusions for severe anemia secondary to depressed erythropoiesis
• HSCT is rarely needed.
• Iron chelation for those requiring recurrent red blood cell transfusions
• Standard treatments for congenital megacolon, Hirschsprung disease, intestinal malabsorption
• Nutrition eval in those w/short bowel syndrome
• Serum concentration of IgG, IgA, IgM
• CD3, 4, 8, 19, 16/56
• Post-vaccine titers
• Other immunologic parameters: T cell subsets, TREC analysis; T cell repertoire; proliferation response to PHA; proliferation response to anti-CD3
• At diagnosis in all persons
• Frequency of follow-up labs is based on initial results.
• Assess for skin changes, enlarged lymph nodes, hepatomegaly, splenomegaly, & other signs of malignancy.
• CBC w/differential
• LDH & uric acid
• Annually in children
• In adults, frequency of follow up is determined on individual basis.
• Every 1-2 yrs in children
• In adults, frequency of follow up is determined on individual basis.
• Molecular genetic testing if the pathogenic variants in the family are known;
• Radiographic evaluation and
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with a CHH-AD spectrum disorder, the evaluations summarized in
Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders: Recommended Evaluations Following Initial Diagnosis
Serum concentration of IgG, IgA, IgM, & IgG subclasses
CD3, 4, 8, 19, 16/56
Post-vaccine titers
Other immunologic parameters: allogeneic lymphocyte cytotoxicity; T cell subsets, TREC analysis; T cell repertoire; proliferation response to PHA; proliferation response to anti-CD3
AD = anauxetic dysplasia; CBC = complete blood count; CHH = cartilage-hair hypoplasia; Ig = immunoglobulin; PHA = phytohemagglutinin; TREC = T cell receptor excision circles
• Serum concentration of IgG, IgA, IgM, & IgG subclasses
• CD3, 4, 8, 19, 16/56
• Post-vaccine titers
• Other immunologic parameters: allogeneic lymphocyte cytotoxicity; T cell subsets, TREC analysis; T cell repertoire; proliferation response to PHA; proliferation response to anti-CD3
## Treatment of Manifestations
There is no cure for CHH-AD spectrum disorders.
Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders: Treatment of Manifestations
If cervical spine abnormality &/or instability is identified, special care when general anesthesia is administered
In persons w/AD, surgery as needed to fuse malformed cervical vertebrae in infancy & to correct/prevent progression of kyphoscoliosis that can compromise lung function
Corrective osteotomies as needed in late childhood or adolescence for excessive varus deformity of lower extremities
Orthopedic surgery may be complicated by low bone density.
Treatment w/recombinant growth hormone has not shown any sustained benefit in persons w/CHH & cannot be recommended.
Treatment of underlying infections based on type, location, & severity
Immediate high-dose IV acyclovir w/onset of varicella infection to prevent complications
Consider prophylactic antibiotics for those w/recurrent infections, neutropenia, or severe lymphopenia.
Consider IVIG if immunoglobulin or IgG subclass levels are low, or if vaccine responses are inadequate.
Treatments for granulomas have included anti-TNF-α therapy & HSCT.
Consider HSCT in persons w/CHH w/recurrent infections & autoimmune manifestations or bone marrow dysplasia for whom a well-matched donor is available.
HSCT has resulted in normalization of T lymphocyte numbers & function, resolution of autoimmune manifestations, & catch-up growth, probably due to ↓ infections.
Overall survival rates have been reported at 63% for unrelated donor transplants & as high as 80% for matched sibs.
Red blood cell transfusions for severe anemia secondary to depressed erythropoiesis
HSCT is rarely needed.
Iron chelation for those requiring recurrent red blood cell transfusions
Standard treatments for congenital megacolon, Hirschsprung disease, intestinal malabsorption
Nutrition eval in those w/short bowel syndrome
AD = anauxetic dysplasia; CHH = cartilage-hair hypoplasia; HSCT = hematopoietic stem cell transplantation; Ig = immunoglobulin; IVIG = intravenous immunoglobulin
• If cervical spine abnormality &/or instability is identified, special care when general anesthesia is administered
• In persons w/AD, surgery as needed to fuse malformed cervical vertebrae in infancy & to correct/prevent progression of kyphoscoliosis that can compromise lung function
• Corrective osteotomies as needed in late childhood or adolescence for excessive varus deformity of lower extremities
• Orthopedic surgery may be complicated by low bone density.
• Treatment w/recombinant growth hormone has not shown any sustained benefit in persons w/CHH & cannot be recommended.
• Treatment of underlying infections based on type, location, & severity
• Immediate high-dose IV acyclovir w/onset of varicella infection to prevent complications
• Consider prophylactic antibiotics for those w/recurrent infections, neutropenia, or severe lymphopenia.
• Consider IVIG if immunoglobulin or IgG subclass levels are low, or if vaccine responses are inadequate.
• Treatments for granulomas have included anti-TNF-α therapy & HSCT.
• Consider HSCT in persons w/CHH w/recurrent infections & autoimmune manifestations or bone marrow dysplasia for whom a well-matched donor is available.
• HSCT has resulted in normalization of T lymphocyte numbers & function, resolution of autoimmune manifestations, & catch-up growth, probably due to ↓ infections.
• Overall survival rates have been reported at 63% for unrelated donor transplants & as high as 80% for matched sibs.
• Red blood cell transfusions for severe anemia secondary to depressed erythropoiesis
• HSCT is rarely needed.
• Iron chelation for those requiring recurrent red blood cell transfusions
• Standard treatments for congenital megacolon, Hirschsprung disease, intestinal malabsorption
• Nutrition eval in those w/short bowel syndrome
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders: Recommended Surveillance
Serum concentration of IgG, IgA, IgM
CD3, 4, 8, 19, 16/56
Post-vaccine titers
Other immunologic parameters: T cell subsets, TREC analysis; T cell repertoire; proliferation response to PHA; proliferation response to anti-CD3
At diagnosis in all persons
Frequency of follow-up labs is based on initial results.
Assess for skin changes, enlarged lymph nodes, hepatomegaly, splenomegaly, & other signs of malignancy.
CBC w/differential
LDH & uric acid
Annually in children
In adults, frequency of follow up is determined on individual basis.
Every 1-2 yrs in children
In adults, frequency of follow up is determined on individual basis.
AD = anauxetic dysplasia; CBC = complete blood count; CHH = cartilage-hair hypoplasia; Ig = immunoglobulin; LDH = lactate dehydrogenase; PHA = phytohemagglutinin; TREC = T cell receptor excision circles
No data are available on the likely timing of recurrence of anemia after successful treatment.
Severe anemia in adolescents and adults with CHH can be the presenting symptom of malignancy and may require extensive investigations with bone marrow evaluation and imaging studies.
• Serum concentration of IgG, IgA, IgM
• CD3, 4, 8, 19, 16/56
• Post-vaccine titers
• Other immunologic parameters: T cell subsets, TREC analysis; T cell repertoire; proliferation response to PHA; proliferation response to anti-CD3
• At diagnosis in all persons
• Frequency of follow-up labs is based on initial results.
• Assess for skin changes, enlarged lymph nodes, hepatomegaly, splenomegaly, & other signs of malignancy.
• CBC w/differential
• LDH & uric acid
• Annually in children
• In adults, frequency of follow up is determined on individual basis.
• Every 1-2 yrs in children
• In adults, frequency of follow up is determined on individual basis.
## Agents/Circumstances to Avoid
Immunization with live vaccines should be carefully considered in those with CHH and evidence of abnormal immunologic function and should be avoided in those with CHH and severe combined immunodeficiency [
Note: (1) Routine immunizations with inactivated vaccines are safe in persons with CHH. (2) No serious adverse events have been recorded after immunization with live viral vaccines in individuals of Finnish ancestry with CHH. (3) Individuals with CHH generate humoral and cellular immune response to live viral vaccines. Immunization with live vaccines may be considered in selected individuals with CHH without immunodeficiency or with clinically mild immunodeficiency [
## Evaluation of Relatives at Risk
Early diagnosis of relatives (i.e., sibs) at risk for CHH-AD spectrum disorders is important for early recognition and management of manifestations that can be associated with significant morbidity (e.g., infections, immunization with live vaccines, malignancies). Relatives at risk should be tested if clinical features, especially short stature, are present; completely asymptomatic individuals need not be tested. Evaluations can include:
Molecular genetic testing if the pathogenic variants in the family are known;
Radiographic evaluation and
See
• Molecular genetic testing if the pathogenic variants in the family are known;
• Radiographic evaluation and
## Pregnancy Management
Despite significant short stature in women with CHH and other potential CHH-related effects on pregnancy outcome, most pregnancies lead to a term cesarean section delivery. Fetal growth is generally unaffected; therefore, planned cesarean section should be considered in term pregnancies due to cephalopelvic disproportion [
## Therapies Under Investigation
Search
## Genetic Counseling
The cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are inherited in an autosomal recessive manner.
The parents of an affected individual are presumed to be heterozygous for an
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
According to previous evaluations, heterozygotes (carriers) are not at increased risk for cancer and are asymptomatic [
If both parents are known to be heterozygous for an
The clinical manifestations of the CHH-AD spectrum disorders are variable, even within the same family.
According to previous evaluations, heterozygotes (carriers) are not at increased risk for cancer and are asymptomatic [
Carrier testing for at-risk family members requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing for the reproductive partners of known carriers and for the reproductive partners of individuals affected with a CHH-AD spectrum disorder should be considered, particularly if both partners are of the same ethnic background. A high incidence of CHH has been reported in the Old Order Amish population, with a prevalence of 1-2:1,000 (carrier frequency of 1:10), and in Finland, with an incidence of 1:23,000 (carrier frequency of 1:76) [
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are presumed to be heterozygous for an
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• According to previous evaluations, heterozygotes (carriers) are not at increased risk for cancer and are asymptomatic [
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• The clinical manifestations of the CHH-AD spectrum disorders are variable, even within the same family.
• According to previous evaluations, heterozygotes (carriers) are not at increased risk for cancer and are asymptomatic [
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing for the reproductive partners of known carriers and for the reproductive partners of individuals affected with a CHH-AD spectrum disorder should be considered, particularly if both partners are of the same ethnic background. A high incidence of CHH has been reported in the Old Order Amish population, with a prevalence of 1-2:1,000 (carrier frequency of 1:10), and in Finland, with an incidence of 1:23,000 (carrier frequency of 1:76) [
## Mode of Inheritance
The cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are presumed to be heterozygous for an
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
According to previous evaluations, heterozygotes (carriers) are not at increased risk for cancer and are asymptomatic [
If both parents are known to be heterozygous for an
The clinical manifestations of the CHH-AD spectrum disorders are variable, even within the same family.
According to previous evaluations, heterozygotes (carriers) are not at increased risk for cancer and are asymptomatic [
• The parents of an affected individual are presumed to be heterozygous for an
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• According to previous evaluations, heterozygotes (carriers) are not at increased risk for cancer and are asymptomatic [
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• The clinical manifestations of the CHH-AD spectrum disorders are variable, even within the same family.
• According to previous evaluations, heterozygotes (carriers) are not at increased risk for cancer and are asymptomatic [
## Carrier Detection
Carrier testing for at-risk family members requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing for the reproductive partners of known carriers and for the reproductive partners of individuals affected with a CHH-AD spectrum disorder should be considered, particularly if both partners are of the same ethnic background. A high incidence of CHH has been reported in the Old Order Amish population, with a prevalence of 1-2:1,000 (carrier frequency of 1:10), and in Finland, with an incidence of 1:23,000 (carrier frequency of 1:76) [
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing for the reproductive partners of known carriers and for the reproductive partners of individuals affected with a CHH-AD spectrum disorder should be considered, particularly if both partners are of the same ethnic background. A high incidence of CHH has been reported in the Old Order Amish population, with a prevalence of 1-2:1,000 (carrier frequency of 1:10), and in Finland, with an incidence of 1:23,000 (carrier frequency of 1:76) [
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Finland
•
•
•
• Finland
•
•
•
•
•
## Molecular Genetics
Cartilage-Hair Hypoplasia - Anauxetic Dysplasia Spectrum Disorders : Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Cartilage-Hair Hypoplasia - Anauxetic Dysplasia Spectrum Disorders (
Most pathogenic variants are in conserved regions of the
Occasionally small insertions, duplications, or triplications in the promoter region increase the distance between regulatory elements (e.g., the TATA box and the transcription start site). An increase of 24-26 bps between the regulatory elements leads to promoter inefficiency and reduced
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Most pathogenic variants are in conserved regions of the
Occasionally small insertions, duplications, or triplications in the promoter region increase the distance between regulatory elements (e.g., the TATA box and the transcription start site). An increase of 24-26 bps between the regulatory elements leads to promoter inefficiency and reduced
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
Svetlana (Kostjukovits) Vakkilainen, MD, PhD (2015-present)Outi Mäkitie, MD, PhD (2015-present)Christian T Thiel, MD; Friedrich-Alexander Universität (2011-2015)
7 August 2025 (aa) Revision: ClinGen variant interpretation guidelines
11 May 2023 (sw) Comprehensive update posted live
24 May 2018 (sw) Comprehensive update posted live
13 August 2015 (me) Comprehensive update posted live
15 March 2012 (me) Review posted live
3 February 2011 (ct) Original submission
• 7 August 2025 (aa) Revision: ClinGen variant interpretation guidelines
• 11 May 2023 (sw) Comprehensive update posted live
• 24 May 2018 (sw) Comprehensive update posted live
• 13 August 2015 (me) Comprehensive update posted live
• 15 March 2012 (me) Review posted live
• 3 February 2011 (ct) Original submission
## Author History
Svetlana (Kostjukovits) Vakkilainen, MD, PhD (2015-present)Outi Mäkitie, MD, PhD (2015-present)Christian T Thiel, MD; Friedrich-Alexander Universität (2011-2015)
## Revision History
7 August 2025 (aa) Revision: ClinGen variant interpretation guidelines
11 May 2023 (sw) Comprehensive update posted live
24 May 2018 (sw) Comprehensive update posted live
13 August 2015 (me) Comprehensive update posted live
15 March 2012 (me) Review posted live
3 February 2011 (ct) Original submission
• 7 August 2025 (aa) Revision: ClinGen variant interpretation guidelines
• 11 May 2023 (sw) Comprehensive update posted live
• 24 May 2018 (sw) Comprehensive update posted live
• 13 August 2015 (me) Comprehensive update posted live
• 15 March 2012 (me) Review posted live
• 3 February 2011 (ct) Original submission
## References
## Literature Cited
|
[] |
15/3/2012
|
11/5/2023
|
7/8/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
chkb-md
|
chkb-md
|
[
"Megaconial Congenital Muscular Dystrophy",
"Megaconial Congenital Muscular Dystrophy",
"CHKB-Related Congenital Muscular Dystrophy (CHKB-CMD)",
"CHKB-Related Adolescent-Onset Limb-Girdle Muscular Dystrophy (CHKB-LGMD)",
"Choline/ethanolamine kinase",
"CHKB",
"CHKB-Related Muscular Dystrophy"
] |
Sophelia HS Chan, Ichizo Nishino
|
Summary CMD: All affected children have developmental delay and speech delay; gross motor milestones are delayed with subsequent loss of ambulation over time. Most have intellectual disability of varying severity; some have no speech. Autism spectrum disorder or attention-deficit/hyperactivity disorder is common. Dilated cardiomyopathy, seen in 14 children, resulted in death from heart failure in five and cardiac transplantation in one. Seizures are seen in some individuals. Ichthyosis is common. LGMD: Motor development is normal; all affected children start walking at the usual age. Two affected individuals presented with rhabdomyolysis. One had mild intellectual disability. Behavior abnormalities and dilated cardiomyopathy were not observed. The diagnosis of
|
## GeneReview Scope
Congenital muscular dystrophy (CMD)
Adolescent-onset limb-girdle muscular dystrophy (LGMD)
For other genetic causes of these phenotypes, see
No genotype-phenotype correlations for
• Congenital muscular dystrophy (CMD)
• Adolescent-onset limb-girdle muscular dystrophy (LGMD)
## Diagnosis
No diagnostic criteria have been published for
Onset in infancy / early childhood of
Hypotonia with head lag followed by inability to sit, stand, or walk
Delayed sitting and walking with waddling gait and positive Gower sign
Early loss of ambulation as weakness increases over time
Secondary scoliosis, hip subluxation, and joint contractures
Rarely presents as late-onset recurrent rhabdomyolysis triggered by strenuous exercise
Intellectual disability (absent or mild)
Most commonly, levels are two to nine times the normal range.
Less commonly, levels can be normal [
During episodes of rhabdomyolysis, CK levels can be greater than 10,000 u/L [
Thighs
Earliest involvement is in the posterior compartment [
The adductor longus is relatively spared.
In advanced disease, extensive fatty replacement can occur.
Calves. The extensor digitorum longus is relatively spared.
Although histologic findings on skeletal muscle biopsy are not necessary to consider when establishing the diagnosis of
For information about muscle pathology and respiratory chain enzyme analysis, click
Family history is consistent with autosomal recessive inheritance (affected sibs and/or parental consanguinity). The absence of a known family history does not exclude the diagnosis.
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/ insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/ duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplication.
• Onset in infancy / early childhood of
• Hypotonia with head lag followed by inability to sit, stand, or walk
• Delayed sitting and walking with waddling gait and positive Gower sign
• Early loss of ambulation as weakness increases over time
• Secondary scoliosis, hip subluxation, and joint contractures
• Hypotonia with head lag followed by inability to sit, stand, or walk
• Delayed sitting and walking with waddling gait and positive Gower sign
• Early loss of ambulation as weakness increases over time
• Secondary scoliosis, hip subluxation, and joint contractures
• Hypotonia with head lag followed by inability to sit, stand, or walk
• Delayed sitting and walking with waddling gait and positive Gower sign
• Early loss of ambulation as weakness increases over time
• Secondary scoliosis, hip subluxation, and joint contractures
• Rarely presents as late-onset recurrent rhabdomyolysis triggered by strenuous exercise
• Intellectual disability (absent or mild)
• Most commonly, levels are two to nine times the normal range.
• Less commonly, levels can be normal [
• During episodes of rhabdomyolysis, CK levels can be greater than 10,000 u/L [
• Thighs
• Earliest involvement is in the posterior compartment [
• The adductor longus is relatively spared.
• In advanced disease, extensive fatty replacement can occur.
• Earliest involvement is in the posterior compartment [
• The adductor longus is relatively spared.
• In advanced disease, extensive fatty replacement can occur.
• Calves. The extensor digitorum longus is relatively spared.
• Earliest involvement is in the posterior compartment [
• The adductor longus is relatively spared.
• In advanced disease, extensive fatty replacement can occur.
## Suggestive Findings
Onset in infancy / early childhood of
Hypotonia with head lag followed by inability to sit, stand, or walk
Delayed sitting and walking with waddling gait and positive Gower sign
Early loss of ambulation as weakness increases over time
Secondary scoliosis, hip subluxation, and joint contractures
Rarely presents as late-onset recurrent rhabdomyolysis triggered by strenuous exercise
Intellectual disability (absent or mild)
Most commonly, levels are two to nine times the normal range.
Less commonly, levels can be normal [
During episodes of rhabdomyolysis, CK levels can be greater than 10,000 u/L [
Thighs
Earliest involvement is in the posterior compartment [
The adductor longus is relatively spared.
In advanced disease, extensive fatty replacement can occur.
Calves. The extensor digitorum longus is relatively spared.
Although histologic findings on skeletal muscle biopsy are not necessary to consider when establishing the diagnosis of
For information about muscle pathology and respiratory chain enzyme analysis, click
Family history is consistent with autosomal recessive inheritance (affected sibs and/or parental consanguinity). The absence of a known family history does not exclude the diagnosis.
• Onset in infancy / early childhood of
• Hypotonia with head lag followed by inability to sit, stand, or walk
• Delayed sitting and walking with waddling gait and positive Gower sign
• Early loss of ambulation as weakness increases over time
• Secondary scoliosis, hip subluxation, and joint contractures
• Hypotonia with head lag followed by inability to sit, stand, or walk
• Delayed sitting and walking with waddling gait and positive Gower sign
• Early loss of ambulation as weakness increases over time
• Secondary scoliosis, hip subluxation, and joint contractures
• Hypotonia with head lag followed by inability to sit, stand, or walk
• Delayed sitting and walking with waddling gait and positive Gower sign
• Early loss of ambulation as weakness increases over time
• Secondary scoliosis, hip subluxation, and joint contractures
• Rarely presents as late-onset recurrent rhabdomyolysis triggered by strenuous exercise
• Intellectual disability (absent or mild)
• Most commonly, levels are two to nine times the normal range.
• Less commonly, levels can be normal [
• During episodes of rhabdomyolysis, CK levels can be greater than 10,000 u/L [
• Thighs
• Earliest involvement is in the posterior compartment [
• The adductor longus is relatively spared.
• In advanced disease, extensive fatty replacement can occur.
• Earliest involvement is in the posterior compartment [
• The adductor longus is relatively spared.
• In advanced disease, extensive fatty replacement can occur.
• Calves. The extensor digitorum longus is relatively spared.
• Earliest involvement is in the posterior compartment [
• The adductor longus is relatively spared.
• In advanced disease, extensive fatty replacement can occur.
## Clinical Findings
Onset in infancy / early childhood of
Hypotonia with head lag followed by inability to sit, stand, or walk
Delayed sitting and walking with waddling gait and positive Gower sign
Early loss of ambulation as weakness increases over time
Secondary scoliosis, hip subluxation, and joint contractures
Rarely presents as late-onset recurrent rhabdomyolysis triggered by strenuous exercise
Intellectual disability (absent or mild)
• Onset in infancy / early childhood of
• Hypotonia with head lag followed by inability to sit, stand, or walk
• Delayed sitting and walking with waddling gait and positive Gower sign
• Early loss of ambulation as weakness increases over time
• Secondary scoliosis, hip subluxation, and joint contractures
• Hypotonia with head lag followed by inability to sit, stand, or walk
• Delayed sitting and walking with waddling gait and positive Gower sign
• Early loss of ambulation as weakness increases over time
• Secondary scoliosis, hip subluxation, and joint contractures
• Hypotonia with head lag followed by inability to sit, stand, or walk
• Delayed sitting and walking with waddling gait and positive Gower sign
• Early loss of ambulation as weakness increases over time
• Secondary scoliosis, hip subluxation, and joint contractures
• Rarely presents as late-onset recurrent rhabdomyolysis triggered by strenuous exercise
• Intellectual disability (absent or mild)
## Laboratory Findings
Most commonly, levels are two to nine times the normal range.
Less commonly, levels can be normal [
During episodes of rhabdomyolysis, CK levels can be greater than 10,000 u/L [
• Most commonly, levels are two to nine times the normal range.
• Less commonly, levels can be normal [
• During episodes of rhabdomyolysis, CK levels can be greater than 10,000 u/L [
## Imaging Findings
Thighs
Earliest involvement is in the posterior compartment [
The adductor longus is relatively spared.
In advanced disease, extensive fatty replacement can occur.
Calves. The extensor digitorum longus is relatively spared.
• Thighs
• Earliest involvement is in the posterior compartment [
• The adductor longus is relatively spared.
• In advanced disease, extensive fatty replacement can occur.
• Earliest involvement is in the posterior compartment [
• The adductor longus is relatively spared.
• In advanced disease, extensive fatty replacement can occur.
• Calves. The extensor digitorum longus is relatively spared.
• Earliest involvement is in the posterior compartment [
• The adductor longus is relatively spared.
• In advanced disease, extensive fatty replacement can occur.
## Muscle Histology
Although histologic findings on skeletal muscle biopsy are not necessary to consider when establishing the diagnosis of
For information about muscle pathology and respiratory chain enzyme analysis, click
## Family History
Family history is consistent with autosomal recessive inheritance (affected sibs and/or parental consanguinity). The absence of a known family history does not exclude the diagnosis.
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/ insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/ duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplication.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/ insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/ duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplication.
## Clinical Characteristics
To date, 47 individuals have been identified with
Forty-four had congenital muscular dystrophy and three had adolescent-onset limb-girdle muscular dystrophy. The following description of the phenotypic features associated with
11/44 were able to sit but not walk.
Of the 34 whose walking age was known, 8 walked at usual age & 26 were delayed.
3 eventually lost ambulation.
All started walking at usual age.
2 had presented w/adolescent- or adult-onset rhabdomyolysis.
All 44 had DD/ID.
2 had borderline intellect; 42 had mild, moderate, or severe ID.
14 had dilated cardiomyopathy, 5 of whom died of severe heart failure between ages 25 mos & 23 yrs.
1 had a heart transplant at age 10 yrs & made a good recovery.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disability
A severe anxiety disorder manifesting as inability to speak in certain social situations
Children at the milder end of the spectrum of CMD started walking at the usual age, around age one year, and presented with limb-girdle muscular dystrophy before age three years. The weakness can become more apparent during puberty, causing difficulty with stairs or episodes of weakness during viral infection or intercurrent illness. Typically, Gower sign is present, with difficulty rising from the floor. Assistance is required getting from sitting to standing.
Lower-limb proximal weakness causes a broad-based waddling gait. The proximal and generalized muscle weakness often progresses over time, with some individuals losing independent ambulation. Facial weakness is rare [
Contractures, mostly at the knees and ankles due to the significant lower-limb weakness, are common [
Muscle strength can fluctuate during febrile intercurrent illness or vaccination.
One individual lost ambulation at age 21 years following acute life-threatening pancreatitis complicated by acute respiratory distress syndrome [
Two individuals experienced temporary episodes of increased falling after an infection (upper respiratory tract infection in one and chickenpox in the other) [
Another individual experienced increased weakness (including complete loss of motor skills) after viral or febrile intercurrent illnesses but fully recovered over several weeks [
Some individuals with truncal and limb muscle weakness develop scoliosis [
One boy with dilated cardiomyopathy and severe heart failure was successfully rescued initially by a left ventricular assist device (LVAD), followed by heart transplantation at age 10 years. One year after transplantation, he was stable with normal biventricular function [
The five individuals who died of complications of their cardiomyopathy included:
A boy, diagnosed with dilated cardiomyopathy at age 21 months, who died at age 26 months from heart failure [
A boy who died at age eight years following acute deterioration after gastrostomy surgery from previously undiagnosed dilated cardiomyopathy [
A girl who died at age 10 years [
Two individuals who died at ages 13 years and 23 years, respectively [
One individual had recurrent abdominal pain and failure to gain weight [
The three individuals with this phenotype had normal motor development at a younger age and only presented in adolescence with mild walking difficulty due to limb-girdle muscle weakness [
Though uncommon, two sibs presented with late-onset rhabdomyolysis without prior significant weakness [
Following a febrile upper respiratory tract infection at age 16 years, the older sister presented with generalized myalgia and significantly increased limb weakness that required use of a wheelchair; she eventually recovered and was able to resume walking without assistance. Subsequently she had mild non-progressive limb-girdle muscle weakness; however, when she exercised, she had myalgia. She also had multiple episodes of rhabdomyolysis with myoglobinuria requiring hospitalization followed by extended recovery periods. The episodic worsening of her symptoms was often associated with acute illness.
The younger brother, who also had had no prior significant clinical weakness, had postexercise myalgia starting at age 12 years [
To date, no deaths have been reported this group of individuals.
No genotypic-phenotypic correlations for
Differing phenotypes in individuals of the same ethnicity who were homozygous for the same CHKB variant include the following:
The prevalence of
In 73 individuals from India with congenital muscular dystrophy, pathogenic variants in
• 11/44 were able to sit but not walk.
• Of the 34 whose walking age was known, 8 walked at usual age & 26 were delayed.
• 3 eventually lost ambulation.
• All started walking at usual age.
• 2 had presented w/adolescent- or adult-onset rhabdomyolysis.
• All 44 had DD/ID.
• 2 had borderline intellect; 42 had mild, moderate, or severe ID.
• 14 had dilated cardiomyopathy, 5 of whom died of severe heart failure between ages 25 mos & 23 yrs.
• 1 had a heart transplant at age 10 yrs & made a good recovery.
• One individual lost ambulation at age 21 years following acute life-threatening pancreatitis complicated by acute respiratory distress syndrome [
• Two individuals experienced temporary episodes of increased falling after an infection (upper respiratory tract infection in one and chickenpox in the other) [
• Another individual experienced increased weakness (including complete loss of motor skills) after viral or febrile intercurrent illnesses but fully recovered over several weeks [
• A boy, diagnosed with dilated cardiomyopathy at age 21 months, who died at age 26 months from heart failure [
• A boy who died at age eight years following acute deterioration after gastrostomy surgery from previously undiagnosed dilated cardiomyopathy [
• A girl who died at age 10 years [
• Two individuals who died at ages 13 years and 23 years, respectively [
• One individual had recurrent abdominal pain and failure to gain weight [
• Following a febrile upper respiratory tract infection at age 16 years, the older sister presented with generalized myalgia and significantly increased limb weakness that required use of a wheelchair; she eventually recovered and was able to resume walking without assistance. Subsequently she had mild non-progressive limb-girdle muscle weakness; however, when she exercised, she had myalgia. She also had multiple episodes of rhabdomyolysis with myoglobinuria requiring hospitalization followed by extended recovery periods. The episodic worsening of her symptoms was often associated with acute illness.
• The younger brother, who also had had no prior significant clinical weakness, had postexercise myalgia starting at age 12 years [
## Clinical Description
To date, 47 individuals have been identified with
Forty-four had congenital muscular dystrophy and three had adolescent-onset limb-girdle muscular dystrophy. The following description of the phenotypic features associated with
11/44 were able to sit but not walk.
Of the 34 whose walking age was known, 8 walked at usual age & 26 were delayed.
3 eventually lost ambulation.
All started walking at usual age.
2 had presented w/adolescent- or adult-onset rhabdomyolysis.
All 44 had DD/ID.
2 had borderline intellect; 42 had mild, moderate, or severe ID.
14 had dilated cardiomyopathy, 5 of whom died of severe heart failure between ages 25 mos & 23 yrs.
1 had a heart transplant at age 10 yrs & made a good recovery.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disability
A severe anxiety disorder manifesting as inability to speak in certain social situations
Children at the milder end of the spectrum of CMD started walking at the usual age, around age one year, and presented with limb-girdle muscular dystrophy before age three years. The weakness can become more apparent during puberty, causing difficulty with stairs or episodes of weakness during viral infection or intercurrent illness. Typically, Gower sign is present, with difficulty rising from the floor. Assistance is required getting from sitting to standing.
Lower-limb proximal weakness causes a broad-based waddling gait. The proximal and generalized muscle weakness often progresses over time, with some individuals losing independent ambulation. Facial weakness is rare [
Contractures, mostly at the knees and ankles due to the significant lower-limb weakness, are common [
Muscle strength can fluctuate during febrile intercurrent illness or vaccination.
One individual lost ambulation at age 21 years following acute life-threatening pancreatitis complicated by acute respiratory distress syndrome [
Two individuals experienced temporary episodes of increased falling after an infection (upper respiratory tract infection in one and chickenpox in the other) [
Another individual experienced increased weakness (including complete loss of motor skills) after viral or febrile intercurrent illnesses but fully recovered over several weeks [
Some individuals with truncal and limb muscle weakness develop scoliosis [
One boy with dilated cardiomyopathy and severe heart failure was successfully rescued initially by a left ventricular assist device (LVAD), followed by heart transplantation at age 10 years. One year after transplantation, he was stable with normal biventricular function [
The five individuals who died of complications of their cardiomyopathy included:
A boy, diagnosed with dilated cardiomyopathy at age 21 months, who died at age 26 months from heart failure [
A boy who died at age eight years following acute deterioration after gastrostomy surgery from previously undiagnosed dilated cardiomyopathy [
A girl who died at age 10 years [
Two individuals who died at ages 13 years and 23 years, respectively [
One individual had recurrent abdominal pain and failure to gain weight [
The three individuals with this phenotype had normal motor development at a younger age and only presented in adolescence with mild walking difficulty due to limb-girdle muscle weakness [
Though uncommon, two sibs presented with late-onset rhabdomyolysis without prior significant weakness [
Following a febrile upper respiratory tract infection at age 16 years, the older sister presented with generalized myalgia and significantly increased limb weakness that required use of a wheelchair; she eventually recovered and was able to resume walking without assistance. Subsequently she had mild non-progressive limb-girdle muscle weakness; however, when she exercised, she had myalgia. She also had multiple episodes of rhabdomyolysis with myoglobinuria requiring hospitalization followed by extended recovery periods. The episodic worsening of her symptoms was often associated with acute illness.
The younger brother, who also had had no prior significant clinical weakness, had postexercise myalgia starting at age 12 years [
To date, no deaths have been reported this group of individuals.
• 11/44 were able to sit but not walk.
• Of the 34 whose walking age was known, 8 walked at usual age & 26 were delayed.
• 3 eventually lost ambulation.
• All started walking at usual age.
• 2 had presented w/adolescent- or adult-onset rhabdomyolysis.
• All 44 had DD/ID.
• 2 had borderline intellect; 42 had mild, moderate, or severe ID.
• 14 had dilated cardiomyopathy, 5 of whom died of severe heart failure between ages 25 mos & 23 yrs.
• 1 had a heart transplant at age 10 yrs & made a good recovery.
• One individual lost ambulation at age 21 years following acute life-threatening pancreatitis complicated by acute respiratory distress syndrome [
• Two individuals experienced temporary episodes of increased falling after an infection (upper respiratory tract infection in one and chickenpox in the other) [
• Another individual experienced increased weakness (including complete loss of motor skills) after viral or febrile intercurrent illnesses but fully recovered over several weeks [
• A boy, diagnosed with dilated cardiomyopathy at age 21 months, who died at age 26 months from heart failure [
• A boy who died at age eight years following acute deterioration after gastrostomy surgery from previously undiagnosed dilated cardiomyopathy [
• A girl who died at age 10 years [
• Two individuals who died at ages 13 years and 23 years, respectively [
• One individual had recurrent abdominal pain and failure to gain weight [
• Following a febrile upper respiratory tract infection at age 16 years, the older sister presented with generalized myalgia and significantly increased limb weakness that required use of a wheelchair; she eventually recovered and was able to resume walking without assistance. Subsequently she had mild non-progressive limb-girdle muscle weakness; however, when she exercised, she had myalgia. She also had multiple episodes of rhabdomyolysis with myoglobinuria requiring hospitalization followed by extended recovery periods. The episodic worsening of her symptoms was often associated with acute illness.
• The younger brother, who also had had no prior significant clinical weakness, had postexercise myalgia starting at age 12 years [
## Congenital Muscular Dystrophy (CMD)
Children at the milder end of the spectrum of CMD started walking at the usual age, around age one year, and presented with limb-girdle muscular dystrophy before age three years. The weakness can become more apparent during puberty, causing difficulty with stairs or episodes of weakness during viral infection or intercurrent illness. Typically, Gower sign is present, with difficulty rising from the floor. Assistance is required getting from sitting to standing.
Lower-limb proximal weakness causes a broad-based waddling gait. The proximal and generalized muscle weakness often progresses over time, with some individuals losing independent ambulation. Facial weakness is rare [
Contractures, mostly at the knees and ankles due to the significant lower-limb weakness, are common [
Muscle strength can fluctuate during febrile intercurrent illness or vaccination.
One individual lost ambulation at age 21 years following acute life-threatening pancreatitis complicated by acute respiratory distress syndrome [
Two individuals experienced temporary episodes of increased falling after an infection (upper respiratory tract infection in one and chickenpox in the other) [
Another individual experienced increased weakness (including complete loss of motor skills) after viral or febrile intercurrent illnesses but fully recovered over several weeks [
Some individuals with truncal and limb muscle weakness develop scoliosis [
One boy with dilated cardiomyopathy and severe heart failure was successfully rescued initially by a left ventricular assist device (LVAD), followed by heart transplantation at age 10 years. One year after transplantation, he was stable with normal biventricular function [
The five individuals who died of complications of their cardiomyopathy included:
A boy, diagnosed with dilated cardiomyopathy at age 21 months, who died at age 26 months from heart failure [
A boy who died at age eight years following acute deterioration after gastrostomy surgery from previously undiagnosed dilated cardiomyopathy [
A girl who died at age 10 years [
Two individuals who died at ages 13 years and 23 years, respectively [
One individual had recurrent abdominal pain and failure to gain weight [
• One individual lost ambulation at age 21 years following acute life-threatening pancreatitis complicated by acute respiratory distress syndrome [
• Two individuals experienced temporary episodes of increased falling after an infection (upper respiratory tract infection in one and chickenpox in the other) [
• Another individual experienced increased weakness (including complete loss of motor skills) after viral or febrile intercurrent illnesses but fully recovered over several weeks [
• A boy, diagnosed with dilated cardiomyopathy at age 21 months, who died at age 26 months from heart failure [
• A boy who died at age eight years following acute deterioration after gastrostomy surgery from previously undiagnosed dilated cardiomyopathy [
• A girl who died at age 10 years [
• Two individuals who died at ages 13 years and 23 years, respectively [
• One individual had recurrent abdominal pain and failure to gain weight [
## Adolescent-Onset Limb-Girdle Muscular Dystrophy (LGMD)
The three individuals with this phenotype had normal motor development at a younger age and only presented in adolescence with mild walking difficulty due to limb-girdle muscle weakness [
Though uncommon, two sibs presented with late-onset rhabdomyolysis without prior significant weakness [
Following a febrile upper respiratory tract infection at age 16 years, the older sister presented with generalized myalgia and significantly increased limb weakness that required use of a wheelchair; she eventually recovered and was able to resume walking without assistance. Subsequently she had mild non-progressive limb-girdle muscle weakness; however, when she exercised, she had myalgia. She also had multiple episodes of rhabdomyolysis with myoglobinuria requiring hospitalization followed by extended recovery periods. The episodic worsening of her symptoms was often associated with acute illness.
The younger brother, who also had had no prior significant clinical weakness, had postexercise myalgia starting at age 12 years [
To date, no deaths have been reported this group of individuals.
• Following a febrile upper respiratory tract infection at age 16 years, the older sister presented with generalized myalgia and significantly increased limb weakness that required use of a wheelchair; she eventually recovered and was able to resume walking without assistance. Subsequently she had mild non-progressive limb-girdle muscle weakness; however, when she exercised, she had myalgia. She also had multiple episodes of rhabdomyolysis with myoglobinuria requiring hospitalization followed by extended recovery periods. The episodic worsening of her symptoms was often associated with acute illness.
• The younger brother, who also had had no prior significant clinical weakness, had postexercise myalgia starting at age 12 years [
## Genotype-Phenotype Correlations
No genotypic-phenotypic correlations for
Differing phenotypes in individuals of the same ethnicity who were homozygous for the same CHKB variant include the following:
## Nomenclature
## Prevalence
The prevalence of
In 73 individuals from India with congenital muscular dystrophy, pathogenic variants in
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders of interest in the differential diagnosis of
Of note, none of the disorders listed in
Differential Diagnosis of
Muscle weakness due to muscular dystrophy
ASD, cognitive impairment, & epilepsy are common.
Structural eye & brain malformations
Moderately ↑ CK
Muscle biopsy shows loss of alpha-dystroglycan protein.
Muscle weakness due to muscular dystrophy
Language delay, DD, ASD, & ADHD are common.
Epilepsy can occur.
Dilated cardiomyopathy is common (although onset occurs in adolescence or early adulthood).
Skeletal muscle weakness progresses more rapidly.
Much higher CK levels
Muscle biopsy shows loss of dystrophin protein.
Significant hypotonia w/weakness
ASD & cognitive impairment are common.
AD = autosomal dominant; ADHD = attention-deficit/hyperactivity disorder; AR = autosomal recessive; ASD = autism spectrum disorder; CK = creatine kinase; CMD = congenital muscular dystrophy; DD = developmental delay; DM1 = myotonic dystrophy type 1; MOI = mode of inheritance; XL = X-linked
OMIM
Differential Diagnosis of
Moderately ↑ CK
Cognition is generally spared.
Muscle biopsy shows loss of dystrophin protein.
Moderately ↑ CK.
Abnormal N-glycosylation of serum proteins
Muscle biopsy shows loss of alpha-dystroglycan protein.
Moderately ↑ CK
Muscle biopsy shows absent alpha-dystroglycan protein.
Moderately ↑ CK
White matter changes on brain MRI
Muscle biopsy shows loss of merosin protein.
AD = autosomal dominant; AR = autosomal recessive; LGMD = limb-girdle muscular dystrophy; MOI = mode of inheritance; XL = X-linked
In addition to limb-girdle muscle weakness
See
Differential Diagnosis of
No cardiac involvement
No sign of myopathy between attacks
Prolonged rhabdomyolysis triggered by exercise, fasting, cold exposure, or stress
No cardiac involvement
Exercise-induced rhabdomyolysis
AR = autosomal recessive; MOI = mode of inheritance
In addition to recurrent rhabdomyolysis
• Muscle weakness due to muscular dystrophy
• ASD, cognitive impairment, & epilepsy are common.
• Structural eye & brain malformations
• Moderately ↑ CK
• Muscle biopsy shows loss of alpha-dystroglycan protein.
• Muscle weakness due to muscular dystrophy
• Language delay, DD, ASD, & ADHD are common.
• Epilepsy can occur.
• Dilated cardiomyopathy is common (although onset occurs in adolescence or early adulthood).
• Skeletal muscle weakness progresses more rapidly.
• Much higher CK levels
• Muscle biopsy shows loss of dystrophin protein.
• Significant hypotonia w/weakness
• ASD & cognitive impairment are common.
• Moderately ↑ CK
• Cognition is generally spared.
• Muscle biopsy shows loss of dystrophin protein.
• Moderately ↑ CK.
• Abnormal N-glycosylation of serum proteins
• Muscle biopsy shows loss of alpha-dystroglycan protein.
• Moderately ↑ CK
• Muscle biopsy shows absent alpha-dystroglycan protein.
• Moderately ↑ CK
• White matter changes on brain MRI
• Muscle biopsy shows loss of merosin protein.
• No cardiac involvement
• No sign of myopathy between attacks
• Prolonged rhabdomyolysis triggered by exercise, fasting, cold exposure, or stress
• No cardiac involvement
• Exercise-induced rhabdomyolysis
## Management
No clinical guidelines for
Management should follow the Standard of Care Guidelines for congenital muscular dystrophy [
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
EEG if seizures are a concern
Brain MRI for possible focal epileptic focus
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
PT to improve gross motor skills
OT to improve fine motor skills
Hips & x-ray for subluxation
Spine & x-ray for scoliosis
Joints for contractures
Developmental performance
Adaptive & cognitive eval
Need for early intervention / special education support
To assess degree & nature of hearing loss
To refer to otolaryngologist
For dietary advice
For videofluoroscopic swallowing study
For referral to gastroenterologist
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; PT = physical therapy; OT = occupational therapy
Medical geneticist, certified genetic counseling, certified advanced genetic nurse
There is no cure for
Treatment of Manifestations in Individuals with
Incl stretching & training to avoid contractures & falls
Consider need for positioning & mobility devices, disability parking placard / permit card.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Assess respiratory & cardiac status (w/attention to possible cardiomyopathy).
Malignant hyperthermia precautions given history of rhabdomyolysis in some persons
Assess need for early intervention & referral for multidisciplinary specialists.
Assess need for early referral for special education support.
Dietary plan by dietitian
Feeding plan per treating gastroenterologist or feeding team
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Consider involvement in adaptive sports or Special Olympics.
Ongoing assessment of need for palliative care involvement &/or home nursing
ADL = activities of daily living; ASM = anti-seizure medication
Caregiver education on the disease state and medication use, including possible side effects
Surveillance recommendations – which include evaluations to monitor existing neurologic features and assess for the emergence of new findings/concerns – are intended to promote development, mitigate comorbidities, and optimize function while maximizing quality of life (see
Recommended Surveillance for Individuals with
Every 6 mos, if stable
Every 2-3 mos, if adjusting medications
Physical medicine, OT/PT assessment of mobility, self-help skills
Orthopedics assessment for scoliosis &/or hip subluxation
ADL = activities of daily living
Avoid strenuous exercise and viral infection, as in some affected individuals these may exacerbate muscle weakness.
See
Because of the small number of individuals reported to date with adolescent-onset LGMD, the risk of dilated cardiomyopathy in this milder phenotype is unknown. Nonetheless, it would be advisable for women of childbearing age who are considering pregnancy to undergo cardiac evaluation prior to becoming pregnant and to discuss pregnancy-related risks with her cardiologist and a high-risk obstetrician.
Search
• EEG if seizures are a concern
• Brain MRI for possible focal epileptic focus
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• PT to improve gross motor skills
• OT to improve fine motor skills
• Hips & x-ray for subluxation
• Spine & x-ray for scoliosis
• Joints for contractures
• Developmental performance
• Adaptive & cognitive eval
• Need for early intervention / special education support
• To assess degree & nature of hearing loss
• To refer to otolaryngologist
• For dietary advice
• For videofluoroscopic swallowing study
• For referral to gastroenterologist
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Incl stretching & training to avoid contractures & falls
• Consider need for positioning & mobility devices, disability parking placard / permit card.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Assess respiratory & cardiac status (w/attention to possible cardiomyopathy).
• Malignant hyperthermia precautions given history of rhabdomyolysis in some persons
• Assess need for early intervention & referral for multidisciplinary specialists.
• Assess need for early referral for special education support.
• Dietary plan by dietitian
• Feeding plan per treating gastroenterologist or feeding team
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Consider involvement in adaptive sports or Special Olympics.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Every 6 mos, if stable
• Every 2-3 mos, if adjusting medications
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Orthopedics assessment for scoliosis &/or hip subluxation
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
EEG if seizures are a concern
Brain MRI for possible focal epileptic focus
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
PT to improve gross motor skills
OT to improve fine motor skills
Hips & x-ray for subluxation
Spine & x-ray for scoliosis
Joints for contractures
Developmental performance
Adaptive & cognitive eval
Need for early intervention / special education support
To assess degree & nature of hearing loss
To refer to otolaryngologist
For dietary advice
For videofluoroscopic swallowing study
For referral to gastroenterologist
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; PT = physical therapy; OT = occupational therapy
Medical geneticist, certified genetic counseling, certified advanced genetic nurse
• EEG if seizures are a concern
• Brain MRI for possible focal epileptic focus
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• PT to improve gross motor skills
• OT to improve fine motor skills
• Hips & x-ray for subluxation
• Spine & x-ray for scoliosis
• Joints for contractures
• Developmental performance
• Adaptive & cognitive eval
• Need for early intervention / special education support
• To assess degree & nature of hearing loss
• To refer to otolaryngologist
• For dietary advice
• For videofluoroscopic swallowing study
• For referral to gastroenterologist
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
There is no cure for
Treatment of Manifestations in Individuals with
Incl stretching & training to avoid contractures & falls
Consider need for positioning & mobility devices, disability parking placard / permit card.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Assess respiratory & cardiac status (w/attention to possible cardiomyopathy).
Malignant hyperthermia precautions given history of rhabdomyolysis in some persons
Assess need for early intervention & referral for multidisciplinary specialists.
Assess need for early referral for special education support.
Dietary plan by dietitian
Feeding plan per treating gastroenterologist or feeding team
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Consider involvement in adaptive sports or Special Olympics.
Ongoing assessment of need for palliative care involvement &/or home nursing
ADL = activities of daily living; ASM = anti-seizure medication
Caregiver education on the disease state and medication use, including possible side effects
• Incl stretching & training to avoid contractures & falls
• Consider need for positioning & mobility devices, disability parking placard / permit card.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Assess respiratory & cardiac status (w/attention to possible cardiomyopathy).
• Malignant hyperthermia precautions given history of rhabdomyolysis in some persons
• Assess need for early intervention & referral for multidisciplinary specialists.
• Assess need for early referral for special education support.
• Dietary plan by dietitian
• Feeding plan per treating gastroenterologist or feeding team
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Consider involvement in adaptive sports or Special Olympics.
• Ongoing assessment of need for palliative care involvement &/or home nursing
## Surveillance
Surveillance recommendations – which include evaluations to monitor existing neurologic features and assess for the emergence of new findings/concerns – are intended to promote development, mitigate comorbidities, and optimize function while maximizing quality of life (see
Recommended Surveillance for Individuals with
Every 6 mos, if stable
Every 2-3 mos, if adjusting medications
Physical medicine, OT/PT assessment of mobility, self-help skills
Orthopedics assessment for scoliosis &/or hip subluxation
ADL = activities of daily living
• Every 6 mos, if stable
• Every 2-3 mos, if adjusting medications
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Orthopedics assessment for scoliosis &/or hip subluxation
## Agents/Circumstances to Avoid
Avoid strenuous exercise and viral infection, as in some affected individuals these may exacerbate muscle weakness.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Because of the small number of individuals reported to date with adolescent-onset LGMD, the risk of dilated cardiomyopathy in this milder phenotype is unknown. Nonetheless, it would be advisable for women of childbearing age who are considering pregnancy to undergo cardiac evaluation prior to becoming pregnant and to discuss pregnancy-related risks with her cardiologist and a high-risk obstetrician.
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of an affected individual are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
To date, individuals with
Unless an individual with
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• To date, individuals with
• Unless an individual with
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Mode of Inheritance
## Risk to Family Members
The parents of an affected individual are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
To date, individuals with
Unless an individual with
• The parents of an affected individual are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• To date, individuals with
• Unless an individual with
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
CMDIR/Cure CMD
•
•
•
•
•
• United Kingdom
•
•
•
• CMDIR/Cure CMD
•
•
•
## Molecular Genetics
CHKB-Related Muscular Dystrophy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CHKB-Related Muscular Dystrophy (
Biallelic pathogenic variants in
Notable
Variants listed in the table have been provided by the authors.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (
## Molecular Pathogenesis
Biallelic pathogenic variants in
Notable
Variants listed in the table have been provided by the authors.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (
## Chapter Notes
We would like to thank Prof Bert BA de Vries for including
## Author Notes
## Acknowledgments
We would like to thank Prof Bert BA de Vries for including
## References
## Literature Cited
|
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"S Mitsuhashi, I Nishino. Phospholipid synthetic defect and mitophagy in muscle disease.. Autophagy. 2011;7:1559-61",
"S Mitsuhashi, I Nishino. Megaconial congenital muscular dystrophy due to loss-of-function mutations in choline kinase β.. Curr Opin Neurol. 2013;26:536-43",
"I Nishino, O Kobayashi, Y Goto, M Kurihara, K Kumagai, T Fujita, K Hashimoto, S Horai, I. Nonaka. A new congenital muscular dystrophy with mitochondrial structural abnormalities.. Muscle Nerve. 1998;21:40-7",
"J Oliveira, L Negrão, I Fineza, R Taipa, M Melo-Pires, AM Fortuna, AR Gonçalves, H Froufe, C Egas, R Santos, M Sousa. New splicing mutation in the choline kinase beta (CHKB) gene causing a muscular dystrophy detected by whole-exome sequencing.. J Hum Genet. 2015;60:305-12",
"C Pascual-Morena, I Cavero-Redondo, S Reina-Gutiérrez, A Saz-Lara, JF López-Gil, V Martínez-Vizcaíno. Prevalence of neuropsychiatric disorders in Duchenne and Becker muscular dystrophies: a systematic review and meta-analysis.. Arch Phys Med Rehabil. 2022;103:2444-53",
"R Quinlivan, S Mitsuahashi, C Sewry, S Cirak, C Aoyama, D Mooore, S Abbs, S Robb, T Newton, C Moss, D Birchall, H Sugimoto, K Bushby, M Guglieri, F Muntoni, I Nishino, V Straub. Muscular dystrophy with large mitochondria associated with mutations in the CHKB gene in three British patients: extending the clinical and pathological phenotype.. Neuromuscul Disord. 2013;23:549-56",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"M Tavasoli, S Lahire, S Sokolenko, R Novorolsky, SA Reid, A Lefsay, MOC Otley, K Uaesoontrachoon, J Rowsell, S Srinivassane, M Praest, A MacKinnon, MS Mammoliti, AA Maloney, M Moraca, J Pedro Fernandez-Murray, M McKenna, CJ Sinal, K Nagaraju, GS Robertson, EP Hoffman, CR McMaster. Mechanism of action and therapeutic route for a muscular dystrophy caused by a genetic defect in lipid metabolism.. Nat Commun. 2022;13:1559",
"AV Vanlander, L Muiño Mosquera, J Panzer, T Deconinck, J Smet, S Seneca, J Van Dorpe, L Ferdinande, C Ceuterick-de Groote, P De Jonghe, R Van Coster, J Baets. Megaconial muscular dystrophy caused by mitochondrial membrane homeostasis defect, new insights from skeletal and heart muscle analyses.. Mitochondrion. 2016;27:32-8",
"CH Wang, CG Bonnemann, A Rutkowski, T Sejersen, J Bellini, V Battista, JM Florence, U Schara, PM Schuler, K Wahbi, A Aloysius, RO Bash, C Béroud, E Bertini, K Bushby, RD Cohn, AM Connolly, N Deconinck, I Desguerre, M Eagle, B Estournet-Mathiaud, A Ferreiro, A Fujak, N Goemans, ST Iannaccone, P Jouinot, M Main, P Melacini, W Mueller-Felber, F Muntoni, LL Nelson, J Rahbek, S Quijano-Roy, C Sewry, K Storhaug, A Simonds, B Tseng, J Vajsar, A Vianello, R Zeller. Consensus statement on standard of care for congenital muscular dystrophies.. J Child Neurol. 2010;25:1559-81",
"U Yis, F Baydan, M Karakaya, S Hız Kurul, S. Cirak. Importance of skin changes in the differential diagnosis of congenital muscular dystrophies.. Biomed Res Int. 2016;2016"
] |
30/3/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
chol-liver-ov
|
chol-liver-ov
|
[
"3 beta-hydroxysteroid dehydrogenase type 7",
"Aldo-keto reductase family 1 member D1",
"Alpha-methylacyl-CoA racemase",
"Bile acid receptor",
"Bile acid-CoA:amino acid N-acyltransferase",
"Bile salt export pump",
"Cytochrome P450 7B1",
"Kinesin-like protein KIF12",
"Lipolysis-stimulated lipoprotein receptor",
"Phosphatidylcholine translocator ABCB4",
"Phospholipid-transporting ATPase IC",
"Tight junction protein 2",
"Ubiquitin carboxyl-terminal hydrolase 53",
"Unconventional myosin-Vb",
"ABCB11",
"ABCB4",
"AKR1D1",
"AMACR",
"ATP8B1",
"BAAT",
"CYP7B1",
"HSD3B7",
"KIF12",
"LSR",
"MYO5B",
"NR1H4",
"TJP2",
"USP53",
"Pediatric Genetic Cholestatic Liver Disease",
"Overview"
] |
Pediatric Genetic Cholestatic Liver Disease Overview
|
Maria Amendola, James E Squires
|
Summary The purpose of this overview is to: Briefly describe the common Review the Provide an Review high-level dietary, medical, and surgical Inform Note: Disorders in which cholestasis is a secondary manifestation of the underlying causative pathology are outside the scope of this chapter.
|
## Clinical Characteristics of Genetic Cholestatic Liver Disease
For the purposes of this chapter, the term "primary cholestatic liver disease" is used to designate those inherited disorders in which cholestasis is a primary manifestation of the underlying causative pathology (such as transport of bile acids and phospholipids, bile acid synthesis, and bile acid metabolism or transport). Disorders in which cholestasis is a secondary manifestation of the underlying causative pathology are outside the scope of this chapter.
Jaundice (yellowing of the skin and/or mucous membranes and/or peripheral sclera of the eye – i.e., scleral icterus)
Pruritus or itching (commonly related to the relative elevation of serum bile acids)
Malabsorption of fat-soluble vitamins (i.e., vitamins A, D, E, and K), resulting in:
Poor weight gain
Easy bleeding or bruising (secondary to coagulopathy from vitamin K deficiency)
Hepatosplenomegaly
Discolored and/or pale stools (i.e., acholic stools)
The first episode of cholestasis may occur in infancy in any of the pediatric genetic disorders discussed in this overview, regardless of the natural history of the disorder.
The natural history of many genetic cholestatic disorders is progression to fibrosis (i.e., general scarring of the liver secondary to injury) that can be graded 1-4. Cirrhosis, the most severe form of fibrosis, is generally accompanied by other complications such as portal hypertension, synthetic liver dysfunction, and increased risk for hepatocellular carcinoma.
Conjugated or direct hyperbilirubinemia
Note: (1) While consensus guidelines recommend evaluation of cholestatic disease for conjugated or direct bilirubin concentrations above 1.0 mg/dL (17 µmol/L) [
Gamma-glutamyl transpeptidase (GGTP; also referred to as gamma-glutamyl transferase [GGT]) levels are integral to identifying different causes of cholestatic liver disease, including:
Low-normal GGTP levels in most disorders known as progressive familial intrahepatic cholestasis (see
Elevated GGTP levels in disorders with abnormal biliary duct morphology or cholangiociliopathies/ciliary development (see
Elevated serum bile acids
While the majority of cholestatic conditions have elevated primary serum bile acids (cholic and chenodeoxycholic acids), the family of bile acid synthetic defect disorders may be defined by the absence of primary bile acids and the presence of atypical bile acids specific to each primary defect (see
Elevated alkaline phosphatase is used infrequently to assess children with cholestasis, as it often reflects alternative processes such as bone injury or growth.
Liver ultrasound findings may include [
Coarseness, nodularity, or increased echogenicity
Hepatomegaly
Antegrade portal blood flow on Doppler assessment
Bile duct abnormalities including:
Dilatation with mechanical obstruction
Diminutive extrahepatic ducts and gall bladder abnormalities
Abdominal ultrasound may include:
Splenomegaly
Ascites
• Jaundice (yellowing of the skin and/or mucous membranes and/or peripheral sclera of the eye – i.e., scleral icterus)
• Pruritus or itching (commonly related to the relative elevation of serum bile acids)
• Malabsorption of fat-soluble vitamins (i.e., vitamins A, D, E, and K), resulting in:
• Poor weight gain
• Easy bleeding or bruising (secondary to coagulopathy from vitamin K deficiency)
• Poor weight gain
• Easy bleeding or bruising (secondary to coagulopathy from vitamin K deficiency)
• Hepatosplenomegaly
• Discolored and/or pale stools (i.e., acholic stools)
• Poor weight gain
• Easy bleeding or bruising (secondary to coagulopathy from vitamin K deficiency)
• Conjugated or direct hyperbilirubinemia
• Note: (1) While consensus guidelines recommend evaluation of cholestatic disease for conjugated or direct bilirubin concentrations above 1.0 mg/dL (17 µmol/L) [
• Gamma-glutamyl transpeptidase (GGTP; also referred to as gamma-glutamyl transferase [GGT]) levels are integral to identifying different causes of cholestatic liver disease, including:
• Low-normal GGTP levels in most disorders known as progressive familial intrahepatic cholestasis (see
• Elevated GGTP levels in disorders with abnormal biliary duct morphology or cholangiociliopathies/ciliary development (see
• Low-normal GGTP levels in most disorders known as progressive familial intrahepatic cholestasis (see
• Elevated GGTP levels in disorders with abnormal biliary duct morphology or cholangiociliopathies/ciliary development (see
• Elevated serum bile acids
• While the majority of cholestatic conditions have elevated primary serum bile acids (cholic and chenodeoxycholic acids), the family of bile acid synthetic defect disorders may be defined by the absence of primary bile acids and the presence of atypical bile acids specific to each primary defect (see
• Elevated alkaline phosphatase is used infrequently to assess children with cholestasis, as it often reflects alternative processes such as bone injury or growth.
• While the majority of cholestatic conditions have elevated primary serum bile acids (cholic and chenodeoxycholic acids), the family of bile acid synthetic defect disorders may be defined by the absence of primary bile acids and the presence of atypical bile acids specific to each primary defect (see
• Elevated alkaline phosphatase is used infrequently to assess children with cholestasis, as it often reflects alternative processes such as bone injury or growth.
• Low-normal GGTP levels in most disorders known as progressive familial intrahepatic cholestasis (see
• Elevated GGTP levels in disorders with abnormal biliary duct morphology or cholangiociliopathies/ciliary development (see
• While the majority of cholestatic conditions have elevated primary serum bile acids (cholic and chenodeoxycholic acids), the family of bile acid synthetic defect disorders may be defined by the absence of primary bile acids and the presence of atypical bile acids specific to each primary defect (see
• Elevated alkaline phosphatase is used infrequently to assess children with cholestasis, as it often reflects alternative processes such as bone injury or growth.
• Coarseness, nodularity, or increased echogenicity
• Hepatomegaly
• Antegrade portal blood flow on Doppler assessment
• Bile duct abnormalities including:
• Dilatation with mechanical obstruction
• Diminutive extrahepatic ducts and gall bladder abnormalities
• Dilatation with mechanical obstruction
• Diminutive extrahepatic ducts and gall bladder abnormalities
• Dilatation with mechanical obstruction
• Diminutive extrahepatic ducts and gall bladder abnormalities
• Splenomegaly
• Ascites
## Causes of Genetic Cholestatic Liver Disease
Note: Pathologic cholestasis occurs in one in 2,500 newborns in North America, 40% of which is attributed to biliary atresia, an inflammatory cholangiopathy that requires immediate diagnosis (suggested by liver ultrasound examination and liver biopsy and confirmed with intraoperative cholangiogram) and life-saving surgical intervention [
The subject of this overview is the estimated 25%-50% of pediatric primary genetic cholestasis NOT related to biliary atresia that has an identifiable genetic etiology [
The genetic disorders discussed in
Disorders of transport of bile acids or phospholipids (
Disorders of bile acid synthesis (
Disorders with extrahepatic metabolic or developmental findings (
Note: (1) Although some investigators have proposed the use of gene-based nomenclature (e.g., ATP8B1 deficiency) rather than phenotype-based nomenclature (e.g., PFIC1) to enable gene-specific clinical care and facilitate scientific discovery [
Pediatric Genetic Cholestatic Liver Diseases: Genes and Clinical Features of Defects in Transport of Bile Acids or Phospholipids
Adapted from Tables 1-
AD = autosomal dominant; AFP = alpha-fetoprotein; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AR = autosomal recessive; AST = aspartate aminotransferase; BSEP = bile salt export pump; BRIC = benign recurrent intrahepatic cholestasis; CCA = cholangiocarcinoma; ESLD = end-stage liver disease; GGTP = gamma-glutamyl transpeptidase; HCC = hepatocellular carcinoma; HTN = hypertension; ICP = intrahepatic cholestasis of pregnancy; PFIC = progressive familial intrahepatic cholestasis
Genes are listed alphabetically.
"Byler disease" refers to severe ATP8B1 deficiency in individuals of Amish ancestry; "Greenland childhood cholestasis" or "Greenland familial cholestasis" refers to severe ATP8B1 deficiency in individuals of Inuit ancestry.
There are two main mechanisms by which bile acid synthesis defects can damage the liver:
Defective bile acids affect bile-induced bile flow, resulting in cholestasis.
Buildup of intermediates/metabolites from the process of bile acid synthesis are toxic to hepatocytes.
Note:
Pediatric Genetic Cholestatic Liver Diseases: Genes and Clinical Features of Disorders of Bile Acid Synthesis
Adapted from Tables 1-
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBAS = congenital defect in bile acid synthesis; ESLD = end-stage liver disease; GGTP = gamma-glutamyl transpeptidase; HSM = hepatosplenomegaly; PFIC = progressive familial intrahepatic cholestasis
Genes are listed alphabetically.
Selected references included
Note:
Pediatric Genetic Cholestatic Liver Diseases: Genes and Clinical Features of Disorders with Extrahepatic Metabolic or Developmental Findings
↑ AST/ALT & GGTP for >6 mos
HSM, confirmed on ultrasound
Coarseness, nodularity, ↑ echogenicity or portal HTN on ultrasound
Liver biopsy w/biliary or multilobular cirrhosis
Adapted from Tables 1-
ALF = acute liver failure; ALP = alkaline phosphatase; ALT = alanine aminotransferase; ARPKD = autosomal recessive polycystic kidney disease; AST = aspartate aminotransferase; CAKUT = congenital anomalies of the kidney and urinary tract; CHD = congenital heart disease; DD = developmental delay; ESLD = end-stage liver disease; GGTP = gamma-glutamyl transpeptidase; HCC = hepatocellular carcinoma; HSM = hepatosplenomegaly; HTN = hypertension; INR = international normalized ratio; IUGR = intrauterine growth restriction; MODY5 = maturity-onset diabetes of the young type 5; VLCFA = very long-chain fatty acids
Genes are listed alphabetically.
Link to
• Disorders of transport of bile acids or phospholipids (
• Disorders of bile acid synthesis (
• Disorders with extrahepatic metabolic or developmental findings (
• Defective bile acids affect bile-induced bile flow, resulting in cholestasis.
• Buildup of intermediates/metabolites from the process of bile acid synthesis are toxic to hepatocytes.
• ↑ AST/ALT & GGTP for >6 mos
• HSM, confirmed on ultrasound
• Coarseness, nodularity, ↑ echogenicity or portal HTN on ultrasound
• Liver biopsy w/biliary or multilobular cirrhosis
## Disorders of Transport of Bile Acids or Phospholipids
Note: (1) Although some investigators have proposed the use of gene-based nomenclature (e.g., ATP8B1 deficiency) rather than phenotype-based nomenclature (e.g., PFIC1) to enable gene-specific clinical care and facilitate scientific discovery [
Pediatric Genetic Cholestatic Liver Diseases: Genes and Clinical Features of Defects in Transport of Bile Acids or Phospholipids
Adapted from Tables 1-
AD = autosomal dominant; AFP = alpha-fetoprotein; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AR = autosomal recessive; AST = aspartate aminotransferase; BSEP = bile salt export pump; BRIC = benign recurrent intrahepatic cholestasis; CCA = cholangiocarcinoma; ESLD = end-stage liver disease; GGTP = gamma-glutamyl transpeptidase; HCC = hepatocellular carcinoma; HTN = hypertension; ICP = intrahepatic cholestasis of pregnancy; PFIC = progressive familial intrahepatic cholestasis
Genes are listed alphabetically.
"Byler disease" refers to severe ATP8B1 deficiency in individuals of Amish ancestry; "Greenland childhood cholestasis" or "Greenland familial cholestasis" refers to severe ATP8B1 deficiency in individuals of Inuit ancestry.
## Disorders of Bile Acid Synthesis
There are two main mechanisms by which bile acid synthesis defects can damage the liver:
Defective bile acids affect bile-induced bile flow, resulting in cholestasis.
Buildup of intermediates/metabolites from the process of bile acid synthesis are toxic to hepatocytes.
Note:
Pediatric Genetic Cholestatic Liver Diseases: Genes and Clinical Features of Disorders of Bile Acid Synthesis
Adapted from Tables 1-
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBAS = congenital defect in bile acid synthesis; ESLD = end-stage liver disease; GGTP = gamma-glutamyl transpeptidase; HSM = hepatosplenomegaly; PFIC = progressive familial intrahepatic cholestasis
Genes are listed alphabetically.
Selected references included
• Defective bile acids affect bile-induced bile flow, resulting in cholestasis.
• Buildup of intermediates/metabolites from the process of bile acid synthesis are toxic to hepatocytes.
## Disorders with Cholestatic Liver Disease and Extrahepatic Findings
Note:
Pediatric Genetic Cholestatic Liver Diseases: Genes and Clinical Features of Disorders with Extrahepatic Metabolic or Developmental Findings
↑ AST/ALT & GGTP for >6 mos
HSM, confirmed on ultrasound
Coarseness, nodularity, ↑ echogenicity or portal HTN on ultrasound
Liver biopsy w/biliary or multilobular cirrhosis
Adapted from Tables 1-
ALF = acute liver failure; ALP = alkaline phosphatase; ALT = alanine aminotransferase; ARPKD = autosomal recessive polycystic kidney disease; AST = aspartate aminotransferase; CAKUT = congenital anomalies of the kidney and urinary tract; CHD = congenital heart disease; DD = developmental delay; ESLD = end-stage liver disease; GGTP = gamma-glutamyl transpeptidase; HCC = hepatocellular carcinoma; HSM = hepatosplenomegaly; HTN = hypertension; INR = international normalized ratio; IUGR = intrauterine growth restriction; MODY5 = maturity-onset diabetes of the young type 5; VLCFA = very long-chain fatty acids
Genes are listed alphabetically.
Link to
• ↑ AST/ALT & GGTP for >6 mos
• HSM, confirmed on ultrasound
• Coarseness, nodularity, ↑ echogenicity or portal HTN on ultrasound
• Liver biopsy w/biliary or multilobular cirrhosis
## Evaluation Strategies to Identify the Cause of a Genetic Cholestatic Liver Disease in a Proband
Establishing a specific cause of pediatric genetic cholestatic liver disease:
Can aid in discussions of prognosis (which are beyond the scope of this
Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
• Can aid in discussions of prognosis (which are beyond the scope of this
• Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Management
The interventions discussed here focus on symptomatic treatment of clinical manifestations, surveillance issues, and disease-specific treatments/surveillance.
Standard nutritional approaches for malabsorption of fat and fat-soluble vitamins that benefit growth and development:
Supplementation of the fat-soluble vitamins A, D, E, and K
Use of dietary medium-chain triglycerides (MCTs), as they are absorbed independent of bile acids. MCTs can be provided either as infant formula (e.g., Alimentum
Cholestyramine binds bile acids in the gut and enhances fecal bile acid secretion
Rifaximin is an antibiotic that induces enzymes of drug metabolism to modify and increase excretion of bile salts. Because rifaximin can cause drug-induced hepatitis, its use must be closely monitored [
Ileal bile acid transporter inhibitors (IBAT), such as odevixibat or maralixibat, reduce enterohepatic circulation of bile acids by decreasing their reabsorption in the ileum, thus increasing their excretion. Studies have shown that these agents are as effective in treating pruritus and normalizing bile acid levels in certain cholestatic liver diseases, including PFIC and Alagille syndrome [
Naloxone, hydroxyzine, and sertraline (which have less well-understood mechanisms of action) may lessen pruritus in some affected individuals [
Surgical management by either
Although no studies have demonstrated superiority of either of these surgical interventions, the response to PEBD may be longer lasting than the response to ileal exclusion.
Initially described for children with low-GGTP forms of PFIC, PEBD is associated with an excellent long-term outcome when serum bile acid levels normalize within one year.
Some data suggest that PEBD is effective in PFIC1 (ATP8B1 deficiency) and mild-to-moderate PFIC2 (BSEP deficiency) in which some enzyme function is retained [
When the medical and surgical interventions discussed above fail to provide relief from severe pruritus or prevent progression to end-stage liver disease with cirrhosis, liver transplantation often provides a good outcome.
Note that liver transplantation fails to prevent the extrahepatic complications for any of the disorders described in
UDCA (see
The two indications for liver transplantation in these conditions are disease refractory to medical/surgical supportive treatments and progression to end-stage liver disease [
Additional treatment is summarized in
Pediatric Genetic Cholestatic Liver Diseases: Treatment of Manifestations and Surveillance Issues for Disorders of Transport of Bile Acids or Phospholipids
BSEP = bile salt export pump; ESLD = end-stage liver disease; HCC = hepatocellular carcinoma; PFIC = progressive familial intrahepatic cholestasis; UDCA = ursodeoxycholic acid
Genes are listed alphabetically.
The surgical treatment for pruritus used in most cases is a partial external biliary diversion (PEBD). A partial internal biliary diversion (PIBD) and ileal exclusion have been documented as other methods of surgical treatment of pruritus.
PEBD is associated with an excellent long-term outcome when serum bile acid levels normalize within one year.
Pediatric Genetic Cholestatic Liver Diseases: Treatment of Manifestations and Surveillance Issues for Disorders of Bile Acid Synthesis
CBAS = congenital defect in bile acid synthesis
Genes are listed alphabetically
Management of extrahepatic metabolic or developmental manifestations, which typically persist despite treatment of hepatic manifestations, is outside the scope of this overview.
Pediatric Genetic Cholestatic Liver Diseases: Treatment of Manifestations and Surveillance Issues for Disorders with Extrahepatic Metabolic or Developmental Findings
HCC = hepatocellular carcinoma; HTN = hypertension; UDCA = ursodeoxycholic acid
Genes are listed alphabetically.
For more detailed information about the clinical manifestations of the liver disease in Alagille syndrome and its management, see Childhood Liver Disease Research Network,
For more detailed information about the clinical manifestations of the liver disease in alpha-1 antitrypsin deficiency and its management, see Childhood Liver Disease Research Network,
No specific treatment or management of cholestatic liver disease in arthrogryposis, renal dysfunction, and cholestasis has been recommended.
• Supplementation of the fat-soluble vitamins A, D, E, and K
• Use of dietary medium-chain triglycerides (MCTs), as they are absorbed independent of bile acids. MCTs can be provided either as infant formula (e.g., Alimentum
• Cholestyramine binds bile acids in the gut and enhances fecal bile acid secretion
• Rifaximin is an antibiotic that induces enzymes of drug metabolism to modify and increase excretion of bile salts. Because rifaximin can cause drug-induced hepatitis, its use must be closely monitored [
• Ileal bile acid transporter inhibitors (IBAT), such as odevixibat or maralixibat, reduce enterohepatic circulation of bile acids by decreasing their reabsorption in the ileum, thus increasing their excretion. Studies have shown that these agents are as effective in treating pruritus and normalizing bile acid levels in certain cholestatic liver diseases, including PFIC and Alagille syndrome [
• Naloxone, hydroxyzine, and sertraline (which have less well-understood mechanisms of action) may lessen pruritus in some affected individuals [
## Symptomatic Treatment of Clinical Manifestations
Standard nutritional approaches for malabsorption of fat and fat-soluble vitamins that benefit growth and development:
Supplementation of the fat-soluble vitamins A, D, E, and K
Use of dietary medium-chain triglycerides (MCTs), as they are absorbed independent of bile acids. MCTs can be provided either as infant formula (e.g., Alimentum
Cholestyramine binds bile acids in the gut and enhances fecal bile acid secretion
Rifaximin is an antibiotic that induces enzymes of drug metabolism to modify and increase excretion of bile salts. Because rifaximin can cause drug-induced hepatitis, its use must be closely monitored [
Ileal bile acid transporter inhibitors (IBAT), such as odevixibat or maralixibat, reduce enterohepatic circulation of bile acids by decreasing their reabsorption in the ileum, thus increasing their excretion. Studies have shown that these agents are as effective in treating pruritus and normalizing bile acid levels in certain cholestatic liver diseases, including PFIC and Alagille syndrome [
Naloxone, hydroxyzine, and sertraline (which have less well-understood mechanisms of action) may lessen pruritus in some affected individuals [
Surgical management by either
Although no studies have demonstrated superiority of either of these surgical interventions, the response to PEBD may be longer lasting than the response to ileal exclusion.
Initially described for children with low-GGTP forms of PFIC, PEBD is associated with an excellent long-term outcome when serum bile acid levels normalize within one year.
Some data suggest that PEBD is effective in PFIC1 (ATP8B1 deficiency) and mild-to-moderate PFIC2 (BSEP deficiency) in which some enzyme function is retained [
When the medical and surgical interventions discussed above fail to provide relief from severe pruritus or prevent progression to end-stage liver disease with cirrhosis, liver transplantation often provides a good outcome.
Note that liver transplantation fails to prevent the extrahepatic complications for any of the disorders described in
• Supplementation of the fat-soluble vitamins A, D, E, and K
• Use of dietary medium-chain triglycerides (MCTs), as they are absorbed independent of bile acids. MCTs can be provided either as infant formula (e.g., Alimentum
• Cholestyramine binds bile acids in the gut and enhances fecal bile acid secretion
• Rifaximin is an antibiotic that induces enzymes of drug metabolism to modify and increase excretion of bile salts. Because rifaximin can cause drug-induced hepatitis, its use must be closely monitored [
• Ileal bile acid transporter inhibitors (IBAT), such as odevixibat or maralixibat, reduce enterohepatic circulation of bile acids by decreasing their reabsorption in the ileum, thus increasing their excretion. Studies have shown that these agents are as effective in treating pruritus and normalizing bile acid levels in certain cholestatic liver diseases, including PFIC and Alagille syndrome [
• Naloxone, hydroxyzine, and sertraline (which have less well-understood mechanisms of action) may lessen pruritus in some affected individuals [
## Nutritional Supplements
Standard nutritional approaches for malabsorption of fat and fat-soluble vitamins that benefit growth and development:
Supplementation of the fat-soluble vitamins A, D, E, and K
Use of dietary medium-chain triglycerides (MCTs), as they are absorbed independent of bile acids. MCTs can be provided either as infant formula (e.g., Alimentum
• Supplementation of the fat-soluble vitamins A, D, E, and K
• Use of dietary medium-chain triglycerides (MCTs), as they are absorbed independent of bile acids. MCTs can be provided either as infant formula (e.g., Alimentum
## Pruritus – Medical Management
Cholestyramine binds bile acids in the gut and enhances fecal bile acid secretion
Rifaximin is an antibiotic that induces enzymes of drug metabolism to modify and increase excretion of bile salts. Because rifaximin can cause drug-induced hepatitis, its use must be closely monitored [
Ileal bile acid transporter inhibitors (IBAT), such as odevixibat or maralixibat, reduce enterohepatic circulation of bile acids by decreasing their reabsorption in the ileum, thus increasing their excretion. Studies have shown that these agents are as effective in treating pruritus and normalizing bile acid levels in certain cholestatic liver diseases, including PFIC and Alagille syndrome [
Naloxone, hydroxyzine, and sertraline (which have less well-understood mechanisms of action) may lessen pruritus in some affected individuals [
• Cholestyramine binds bile acids in the gut and enhances fecal bile acid secretion
• Rifaximin is an antibiotic that induces enzymes of drug metabolism to modify and increase excretion of bile salts. Because rifaximin can cause drug-induced hepatitis, its use must be closely monitored [
• Ileal bile acid transporter inhibitors (IBAT), such as odevixibat or maralixibat, reduce enterohepatic circulation of bile acids by decreasing their reabsorption in the ileum, thus increasing their excretion. Studies have shown that these agents are as effective in treating pruritus and normalizing bile acid levels in certain cholestatic liver diseases, including PFIC and Alagille syndrome [
• Naloxone, hydroxyzine, and sertraline (which have less well-understood mechanisms of action) may lessen pruritus in some affected individuals [
## Pruritis – Surgical Management
Surgical management by either
Although no studies have demonstrated superiority of either of these surgical interventions, the response to PEBD may be longer lasting than the response to ileal exclusion.
Initially described for children with low-GGTP forms of PFIC, PEBD is associated with an excellent long-term outcome when serum bile acid levels normalize within one year.
Some data suggest that PEBD is effective in PFIC1 (ATP8B1 deficiency) and mild-to-moderate PFIC2 (BSEP deficiency) in which some enzyme function is retained [
## Liver Transplantation
When the medical and surgical interventions discussed above fail to provide relief from severe pruritus or prevent progression to end-stage liver disease with cirrhosis, liver transplantation often provides a good outcome.
Note that liver transplantation fails to prevent the extrahepatic complications for any of the disorders described in
## Surveillance Issues
## Disease-Specific Treatment of Manifestations
UDCA (see
The two indications for liver transplantation in these conditions are disease refractory to medical/surgical supportive treatments and progression to end-stage liver disease [
Additional treatment is summarized in
Pediatric Genetic Cholestatic Liver Diseases: Treatment of Manifestations and Surveillance Issues for Disorders of Transport of Bile Acids or Phospholipids
BSEP = bile salt export pump; ESLD = end-stage liver disease; HCC = hepatocellular carcinoma; PFIC = progressive familial intrahepatic cholestasis; UDCA = ursodeoxycholic acid
Genes are listed alphabetically.
The surgical treatment for pruritus used in most cases is a partial external biliary diversion (PEBD). A partial internal biliary diversion (PIBD) and ileal exclusion have been documented as other methods of surgical treatment of pruritus.
PEBD is associated with an excellent long-term outcome when serum bile acid levels normalize within one year.
Pediatric Genetic Cholestatic Liver Diseases: Treatment of Manifestations and Surveillance Issues for Disorders of Bile Acid Synthesis
CBAS = congenital defect in bile acid synthesis
Genes are listed alphabetically
Management of extrahepatic metabolic or developmental manifestations, which typically persist despite treatment of hepatic manifestations, is outside the scope of this overview.
Pediatric Genetic Cholestatic Liver Diseases: Treatment of Manifestations and Surveillance Issues for Disorders with Extrahepatic Metabolic or Developmental Findings
HCC = hepatocellular carcinoma; HTN = hypertension; UDCA = ursodeoxycholic acid
Genes are listed alphabetically.
For more detailed information about the clinical manifestations of the liver disease in Alagille syndrome and its management, see Childhood Liver Disease Research Network,
For more detailed information about the clinical manifestations of the liver disease in alpha-1 antitrypsin deficiency and its management, see Childhood Liver Disease Research Network,
No specific treatment or management of cholestatic liver disease in arthrogryposis, renal dysfunction, and cholestasis has been recommended.
## Disorders of Transport of Bile Acids or Phospholipids
UDCA (see
The two indications for liver transplantation in these conditions are disease refractory to medical/surgical supportive treatments and progression to end-stage liver disease [
Additional treatment is summarized in
Pediatric Genetic Cholestatic Liver Diseases: Treatment of Manifestations and Surveillance Issues for Disorders of Transport of Bile Acids or Phospholipids
BSEP = bile salt export pump; ESLD = end-stage liver disease; HCC = hepatocellular carcinoma; PFIC = progressive familial intrahepatic cholestasis; UDCA = ursodeoxycholic acid
Genes are listed alphabetically.
The surgical treatment for pruritus used in most cases is a partial external biliary diversion (PEBD). A partial internal biliary diversion (PIBD) and ileal exclusion have been documented as other methods of surgical treatment of pruritus.
PEBD is associated with an excellent long-term outcome when serum bile acid levels normalize within one year.
## Disorders of Bile Acid Synthesis
Pediatric Genetic Cholestatic Liver Diseases: Treatment of Manifestations and Surveillance Issues for Disorders of Bile Acid Synthesis
CBAS = congenital defect in bile acid synthesis
Genes are listed alphabetically
## Disorders with Cholestatic Liver Disease and Extrahepatic Findings
Management of extrahepatic metabolic or developmental manifestations, which typically persist despite treatment of hepatic manifestations, is outside the scope of this overview.
Pediatric Genetic Cholestatic Liver Diseases: Treatment of Manifestations and Surveillance Issues for Disorders with Extrahepatic Metabolic or Developmental Findings
HCC = hepatocellular carcinoma; HTN = hypertension; UDCA = ursodeoxycholic acid
Genes are listed alphabetically.
For more detailed information about the clinical manifestations of the liver disease in Alagille syndrome and its management, see Childhood Liver Disease Research Network,
For more detailed information about the clinical manifestations of the liver disease in alpha-1 antitrypsin deficiency and its management, see Childhood Liver Disease Research Network,
No specific treatment or management of cholestatic liver disease in arthrogryposis, renal dysfunction, and cholestasis has been recommended.
## Genetic Counseling
The vast majority of pediatric genetic primary cholestatic liver diseases are inherited in an autosomal recessive manner. Exceptions include autosomal dominant inheritance of liver disease associated with
Note: If a proband has a specific genetic disorder or syndrome associated with cholestatic liver disease (e.g.,
The parents of an affected child are presumed to be heterozygous for one of the pathogenic variants identified in the proband.
Once a molecular diagnosis is established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
The heterozygous parents of a proband are typically asymptomatic but may rarely manifest related features. Intrahepatic cholestasis of pregnancy has been reported occasionally in mothers of individuals with progressive familial intrahepatic cholestasis (PFIC).
If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being a heterozygote, and a 25% chance of inheriting neither of the familial pathogenic variants.
Heterozygous sibs may be at increased risk for transient neonatal cholestasis. Female sibs who are heterozygous for a PFIC-associated pathogenic variant may be at risk for intrahepatic cholestasis of pregnancy.
Unless an affected individual's reproductive partner also has autosomal recessive cholestatic liver disease or is a carrier, offspring will be obligate heterozygotes for a pathogenic variant
Offspring of an affected individual and a carrier have a 50% chance of being affected and a 50% chance of being carriers. Higher carrier frequencies have been reported in some populations.
Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and of reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the PFIC-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for one of the pathogenic variants identified in the proband.
• Once a molecular diagnosis is established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• The heterozygous parents of a proband are typically asymptomatic but may rarely manifest related features. Intrahepatic cholestasis of pregnancy has been reported occasionally in mothers of individuals with progressive familial intrahepatic cholestasis (PFIC).
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being a heterozygote, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygous sibs may be at increased risk for transient neonatal cholestasis. Female sibs who are heterozygous for a PFIC-associated pathogenic variant may be at risk for intrahepatic cholestasis of pregnancy.
• Unless an affected individual's reproductive partner also has autosomal recessive cholestatic liver disease or is a carrier, offspring will be obligate heterozygotes for a pathogenic variant
• Offspring of an affected individual and a carrier have a 50% chance of being affected and a 50% chance of being carriers. Higher carrier frequencies have been reported in some populations.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and of reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
The vast majority of pediatric genetic primary cholestatic liver diseases are inherited in an autosomal recessive manner. Exceptions include autosomal dominant inheritance of liver disease associated with
Note: If a proband has a specific genetic disorder or syndrome associated with cholestatic liver disease (e.g.,
## Risk to Family Members (Autosomal Recessive Inheritance)
The parents of an affected child are presumed to be heterozygous for one of the pathogenic variants identified in the proband.
Once a molecular diagnosis is established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
The heterozygous parents of a proband are typically asymptomatic but may rarely manifest related features. Intrahepatic cholestasis of pregnancy has been reported occasionally in mothers of individuals with progressive familial intrahepatic cholestasis (PFIC).
If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being a heterozygote, and a 25% chance of inheriting neither of the familial pathogenic variants.
Heterozygous sibs may be at increased risk for transient neonatal cholestasis. Female sibs who are heterozygous for a PFIC-associated pathogenic variant may be at risk for intrahepatic cholestasis of pregnancy.
Unless an affected individual's reproductive partner also has autosomal recessive cholestatic liver disease or is a carrier, offspring will be obligate heterozygotes for a pathogenic variant
Offspring of an affected individual and a carrier have a 50% chance of being affected and a 50% chance of being carriers. Higher carrier frequencies have been reported in some populations.
• The parents of an affected child are presumed to be heterozygous for one of the pathogenic variants identified in the proband.
• Once a molecular diagnosis is established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• The heterozygous parents of a proband are typically asymptomatic but may rarely manifest related features. Intrahepatic cholestasis of pregnancy has been reported occasionally in mothers of individuals with progressive familial intrahepatic cholestasis (PFIC).
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being a heterozygote, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygous sibs may be at increased risk for transient neonatal cholestasis. Female sibs who are heterozygous for a PFIC-associated pathogenic variant may be at risk for intrahepatic cholestasis of pregnancy.
• Unless an affected individual's reproductive partner also has autosomal recessive cholestatic liver disease or is a carrier, offspring will be obligate heterozygotes for a pathogenic variant
• Offspring of an affected individual and a carrier have a 50% chance of being affected and a 50% chance of being carriers. Higher carrier frequencies have been reported in some populations.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and of reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and of reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the PFIC-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
United Kingdom
•
•
•
•
•
• Canada
•
•
•
•
• United Kingdom
•
•
•
## Chapter Notes
25 May 2023 (aa) Revision:
15 September 2022 (bp) Review posted live
9 December 2021 (js) Original submission
• 25 May 2023 (aa) Revision:
• 15 September 2022 (bp) Review posted live
• 9 December 2021 (js) Original submission
## Author Notes
## Revision History
25 May 2023 (aa) Revision:
15 September 2022 (bp) Review posted live
9 December 2021 (js) Original submission
• 25 May 2023 (aa) Revision:
• 15 September 2022 (bp) Review posted live
• 9 December 2021 (js) Original submission
## References
## Literature Cited
|
[] |
15/9/2022
|
25/5/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
choroid
|
choroid
|
[
"Rab proteins geranylgeranyltransferase component A 1",
"CHM",
"Choroideremia"
] |
Choroideremia
|
Ian M MacDonald, Stacey Hume, Yi Zhai, Manlong Xu
|
Summary Choroideremia (CHM) is characterized by progressive chorioretinal degeneration in affected males and milder signs in heterozygous (carrier) females. Typically, symptoms in affected males evolve from night blindness to peripheral visual field loss, with central vision preserved until late in life. Although carrier females are generally asymptomatic, signs of chorioretinal degeneration can be reliably observed with fundus autofluorescence imaging, and – after age 25 years – with careful fundus examination. The diagnosis of choroideremia is established in a male proband with suggestive findings and a hemizygous pathogenic variant in CHM is inherited in an X-linked manner. Affected males transmit the pathogenic variant to all of their daughters and none of their sons. Heterozygous females have a 50% chance of transmitting the variant in each pregnancy: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be symptomatic. Once the
|
## Diagnosis
Peripapillary atrophy of the RPE occurs early and is progressive [
The function and anatomy of the central macula are preserved until late in the disease process and can be demonstrated with fundus autofluorescence imaging (
The diagnosis of choroideremia
Note: Identification of a hemizygous
Molecular genetic testing approaches can include
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Choroideremia
See
See
Additional individuals with contiguous gene deletions that include CHM (not included in these calculations) have been reported (see
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Copy number variants may represent up to 25% of instances in which Sanger sequencing did not identify a pathogenic variant and/or no REP1 was found with western analysis. These observations are based predominantly on persons of northern European heritage and on separate Chinese cohorts [
• Peripapillary atrophy of the RPE occurs early and is progressive [
• The function and anatomy of the central macula are preserved until late in the disease process and can be demonstrated with fundus autofluorescence imaging (
## Suggestive Findings
Peripapillary atrophy of the RPE occurs early and is progressive [
The function and anatomy of the central macula are preserved until late in the disease process and can be demonstrated with fundus autofluorescence imaging (
• Peripapillary atrophy of the RPE occurs early and is progressive [
• The function and anatomy of the central macula are preserved until late in the disease process and can be demonstrated with fundus autofluorescence imaging (
## Establishing the Diagnosis
The diagnosis of choroideremia
Note: Identification of a hemizygous
Molecular genetic testing approaches can include
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Choroideremia
See
See
Additional individuals with contiguous gene deletions that include CHM (not included in these calculations) have been reported (see
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Copy number variants may represent up to 25% of instances in which Sanger sequencing did not identify a pathogenic variant and/or no REP1 was found with western analysis. These observations are based predominantly on persons of northern European heritage and on separate Chinese cohorts [
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Choroideremia
See
See
Additional individuals with contiguous gene deletions that include CHM (not included in these calculations) have been reported (see
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Copy number variants may represent up to 25% of instances in which Sanger sequencing did not identify a pathogenic variant and/or no REP1 was found with western analysis. These observations are based predominantly on persons of northern European heritage and on separate Chinese cohorts [
## Clinical Characteristics
Posterior subcapsular cataracts are similar to those observed in retinitis pigmentosa.
Cystoid macular edema has been reported.
Symptomatic but mildly affected females are likely underreported in the literature.
Note: The terms "silent carrier" and "manifesting heterozygote" are used in the literature to refer to asymptomatic heterozygous females and symptomatic heterozygous females, respectively. In this
Heterozygous females may or may not show changes with ERG testing, funduscopic examination, fundus autofluorescence (at a young age, <25 years), color vision testing, and visual field testing.
The ERG may be normal or reduced. In seven heterozygous females,
Fundoscopy may reveal pigmentary stippling and distinct chorioretinal atrophy [
Color vision defects can be found using the desaturated panel D15 test [
Visual fields can range from normal in the majority of heterozygous females to distinct field defects that mimic those of affected males [
Fundus autofluorescence imaging will demonstrate patchy areas of lost fluorescence throughout the fundus [
Heterozygous females who demonstrate clinical findings mimicking those of affected males likely have skewed X-chromosome inactivation.
Genotype-phenotype correlations have not been demonstrated for this disorder.
Prevalence is estimated at between 1:50,000 and 1:100,000 [
• The ERG may be normal or reduced. In seven heterozygous females,
• Fundoscopy may reveal pigmentary stippling and distinct chorioretinal atrophy [
• Color vision defects can be found using the desaturated panel D15 test [
• Visual fields can range from normal in the majority of heterozygous females to distinct field defects that mimic those of affected males [
• Fundus autofluorescence imaging will demonstrate patchy areas of lost fluorescence throughout the fundus [
## Clinical Description
Posterior subcapsular cataracts are similar to those observed in retinitis pigmentosa.
Cystoid macular edema has been reported.
Symptomatic but mildly affected females are likely underreported in the literature.
Note: The terms "silent carrier" and "manifesting heterozygote" are used in the literature to refer to asymptomatic heterozygous females and symptomatic heterozygous females, respectively. In this
Heterozygous females may or may not show changes with ERG testing, funduscopic examination, fundus autofluorescence (at a young age, <25 years), color vision testing, and visual field testing.
The ERG may be normal or reduced. In seven heterozygous females,
Fundoscopy may reveal pigmentary stippling and distinct chorioretinal atrophy [
Color vision defects can be found using the desaturated panel D15 test [
Visual fields can range from normal in the majority of heterozygous females to distinct field defects that mimic those of affected males [
Fundus autofluorescence imaging will demonstrate patchy areas of lost fluorescence throughout the fundus [
Heterozygous females who demonstrate clinical findings mimicking those of affected males likely have skewed X-chromosome inactivation.
• The ERG may be normal or reduced. In seven heterozygous females,
• Fundoscopy may reveal pigmentary stippling and distinct chorioretinal atrophy [
• Color vision defects can be found using the desaturated panel D15 test [
• Visual fields can range from normal in the majority of heterozygous females to distinct field defects that mimic those of affected males [
• Fundus autofluorescence imaging will demonstrate patchy areas of lost fluorescence throughout the fundus [
## Genotype-Phenotype Correlations
Genotype-phenotype correlations have not been demonstrated for this disorder.
## Prevalence
Prevalence is estimated at between 1:50,000 and 1:100,000 [
## Genetically Related (Allelic) Disorders
Choroideremia (CHM) is typically an isolated clinical finding; however, it may rarely be part of a contiguous gene deletion involving Xq21.
Males with large interstitial deletions involving Xq21 and additional X chromosome material may have CHM, severe cognitive deficits, and birth defects such as cleft lip and palate and agenesis of the corpus callosum [
Males who have a small deletion involving Xq21 may have CHM, mixed sensorineural and conductive hearing loss (caused by deletion of
A contiguous gene deletion involving Xq21 in a female with premature ovarian failure and mixed conductive and sensorineural deafness resulted from a
• Males with large interstitial deletions involving Xq21 and additional X chromosome material may have CHM, severe cognitive deficits, and birth defects such as cleft lip and palate and agenesis of the corpus callosum [
• Males who have a small deletion involving Xq21 may have CHM, mixed sensorineural and conductive hearing loss (caused by deletion of
• A contiguous gene deletion involving Xq21 in a female with premature ovarian failure and mixed conductive and sensorineural deafness resulted from a
## Differential Diagnosis
Choroideremia (CHM) needs to be distinguished from the inherited retinal dystrophies summarized in
Genes of Interest in the Differential Diagnosis of Choroideremia
AD = autosomal dominant; AR = autosomal recessive; CHM = choroideremia; DiffDx = differential diagnosis; MOI = mode of inheritance; XL = X-linked
See
In RP, abnormalities of the photoreceptors (rods & cones) or the retinal pigment epithelium lead to progressive visual loss.
Very rare digenic forms also occur.
## Management
No clinical practice guidelines for choroideremia have been published.
To establish the extent of disease and needs in an individual diagnosed with choroideremia (CHM), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Ophthalmologic examination including best corrected visual acuity (BCVA), funduscopic examination, and visual field testing for a baseline
Spectral domain optical coherence tomography (SD-OCT) to evaluate and monitor the change of macular structure over time, especially ellipsoid zone (EZ), outer retinal tubulations, and chorioretinal atrophy. It is also helpful in identifying any comorbid maculopathy.
Referral to a low vision specialist or vision rehabilitation clinic may be particularly helpful as central vision declines and/or visual field becomes limited.
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of choroideremia in order to facilitate medical and personal decision making
Retinal detachment, which may occur more commonly in individuals with high myopia (as seen in CHM), is treated by conventional surgical techniques by an ophthalmologist.
Cataract surgery may be required for individuals with a posterior subcapsular cataract.
Rare instances of choroidal neovascularization may be treated with intravitreal bevacizumab [
UV-blocking sunglasses may have a protective role when an affected individual is outdoors.
Low vision services are designed to benefit those whose ability to function is compromised by vision impairment. Low vision specialists, often optometrists, help optimize the use of remaining vision. Services provided vary based on age and needs.
Counseling from organizations or professionals who work with the blind and visually impaired may help the affected individual cope with issues such as depression, loss of independence, fitness for driving, and anxiety over employment issues.
Nutrition and ocular health have become increasingly topical:
For those individuals who do not have access to fresh fruit and leafy green vegetables, a supplement with antioxidant vitamins may be important.
No information is available on the effectiveness of vitamin A supplementation in the treatment of CHM.
A source of omega-3 very-long-chain fatty acids, including docosahexaenoic acid, may be beneficial, as clinical studies suggest that regular intake of fish is important.
Regular ophthalmologic examination to monitor progression of CHM is recommended, as affected individuals need advice regarding their levels of visual function.
Kinetic visual field examinations provide practical information for both the clinician and the affected individual.
SD-OCT imaging is a fundamental clinical tool to evaluate macular structure, especially when central vision is affected and cystoid macular edema is suspected.
Avoid the following:
UV exposure from sunlight reflected from water and snow
Smoking, a major risk factor for macular degeneration
See
Gene replacement therapy using a subretinal delivery of AAV2-REP1 (Nightstar Therapeutics, UK) has been trialed in the UK, Canada, US, and Germany. Reports showed some gain in visual acuity in the treated eye compared to the untreated eye. However, some individuals experienced significant complications such as retinal overstretch and postoperative inflammation. This product is currently in a Phase III trial; results are expected in the coming years [
Another gene augmentation agent that is being trialed uses an intravitreal delivery of 4D-110 (4D Molecular Therapeutics, USA) in individuals with genetically confirmed choroideremia (
Search
• Ophthalmologic examination including best corrected visual acuity (BCVA), funduscopic examination, and visual field testing for a baseline
• Spectral domain optical coherence tomography (SD-OCT) to evaluate and monitor the change of macular structure over time, especially ellipsoid zone (EZ), outer retinal tubulations, and chorioretinal atrophy. It is also helpful in identifying any comorbid maculopathy.
• Referral to a low vision specialist or vision rehabilitation clinic may be particularly helpful as central vision declines and/or visual field becomes limited.
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of choroideremia in order to facilitate medical and personal decision making
• For those individuals who do not have access to fresh fruit and leafy green vegetables, a supplement with antioxidant vitamins may be important.
• No information is available on the effectiveness of vitamin A supplementation in the treatment of CHM.
• A source of omega-3 very-long-chain fatty acids, including docosahexaenoic acid, may be beneficial, as clinical studies suggest that regular intake of fish is important.
• UV exposure from sunlight reflected from water and snow
• Smoking, a major risk factor for macular degeneration
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with choroideremia (CHM), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Ophthalmologic examination including best corrected visual acuity (BCVA), funduscopic examination, and visual field testing for a baseline
Spectral domain optical coherence tomography (SD-OCT) to evaluate and monitor the change of macular structure over time, especially ellipsoid zone (EZ), outer retinal tubulations, and chorioretinal atrophy. It is also helpful in identifying any comorbid maculopathy.
Referral to a low vision specialist or vision rehabilitation clinic may be particularly helpful as central vision declines and/or visual field becomes limited.
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of choroideremia in order to facilitate medical and personal decision making
• Ophthalmologic examination including best corrected visual acuity (BCVA), funduscopic examination, and visual field testing for a baseline
• Spectral domain optical coherence tomography (SD-OCT) to evaluate and monitor the change of macular structure over time, especially ellipsoid zone (EZ), outer retinal tubulations, and chorioretinal atrophy. It is also helpful in identifying any comorbid maculopathy.
• Referral to a low vision specialist or vision rehabilitation clinic may be particularly helpful as central vision declines and/or visual field becomes limited.
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of choroideremia in order to facilitate medical and personal decision making
## Treatment of Manifestations
Retinal detachment, which may occur more commonly in individuals with high myopia (as seen in CHM), is treated by conventional surgical techniques by an ophthalmologist.
Cataract surgery may be required for individuals with a posterior subcapsular cataract.
Rare instances of choroidal neovascularization may be treated with intravitreal bevacizumab [
UV-blocking sunglasses may have a protective role when an affected individual is outdoors.
Low vision services are designed to benefit those whose ability to function is compromised by vision impairment. Low vision specialists, often optometrists, help optimize the use of remaining vision. Services provided vary based on age and needs.
Counseling from organizations or professionals who work with the blind and visually impaired may help the affected individual cope with issues such as depression, loss of independence, fitness for driving, and anxiety over employment issues.
Nutrition and ocular health have become increasingly topical:
For those individuals who do not have access to fresh fruit and leafy green vegetables, a supplement with antioxidant vitamins may be important.
No information is available on the effectiveness of vitamin A supplementation in the treatment of CHM.
A source of omega-3 very-long-chain fatty acids, including docosahexaenoic acid, may be beneficial, as clinical studies suggest that regular intake of fish is important.
• For those individuals who do not have access to fresh fruit and leafy green vegetables, a supplement with antioxidant vitamins may be important.
• No information is available on the effectiveness of vitamin A supplementation in the treatment of CHM.
• A source of omega-3 very-long-chain fatty acids, including docosahexaenoic acid, may be beneficial, as clinical studies suggest that regular intake of fish is important.
## Surveillance
Regular ophthalmologic examination to monitor progression of CHM is recommended, as affected individuals need advice regarding their levels of visual function.
Kinetic visual field examinations provide practical information for both the clinician and the affected individual.
SD-OCT imaging is a fundamental clinical tool to evaluate macular structure, especially when central vision is affected and cystoid macular edema is suspected.
## Agents/Circumstances to Avoid
Avoid the following:
UV exposure from sunlight reflected from water and snow
Smoking, a major risk factor for macular degeneration
• UV exposure from sunlight reflected from water and snow
• Smoking, a major risk factor for macular degeneration
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Gene replacement therapy using a subretinal delivery of AAV2-REP1 (Nightstar Therapeutics, UK) has been trialed in the UK, Canada, US, and Germany. Reports showed some gain in visual acuity in the treated eye compared to the untreated eye. However, some individuals experienced significant complications such as retinal overstretch and postoperative inflammation. This product is currently in a Phase III trial; results are expected in the coming years [
Another gene augmentation agent that is being trialed uses an intravitreal delivery of 4D-110 (4D Molecular Therapeutics, USA) in individuals with genetically confirmed choroideremia (
Search
## Genetic Counseling
Choroideremia (CHM) is inherited in an X-linked manner.
The father of an affected male will not have CHM nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
Evaluation of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Evaluations of the mother include:
Molecular genetic testing for the
Examination of the retina through a dilated pupil to determine if she has signs of chorioretinal degeneration; however, a normal fundus examination at a young age (<25 years) may not be sufficient to exclude carrier status (see
If the mother of the proband has a
Males who inherit the pathogenic variant will be affected; it is not possible to predict at what age an affected male will start to experience vision problems and how quickly the disease will progress.
Females who inherit the pathogenic variant will be heterozygotes and may or may not initially show changes with ERG testing, funduscopic examination, color vision testing, and/or visual field testing; however, with time, areas of decreased fundus autofluorescence will be seen (see
It is not possible to predict if a heterozygous female will manifest any vision loss. At one time, consensus held that heterozygous females experienced only mild vision disturbances later in life; however, heterozygous females may have vision loss similar to that of affected males because of skewed X-chromosome inactivation.
If the proband represents a simplex case (i.e., a single occurrence in a family), if the mother has a normal fundus examination, and if the
Note: Molecular genetic testing may be able to identify the family member in whom a
Note: Females who are heterozygous for this X-linked disorder may not have manifestations of CHM at a young age, but most definitely will have signs after age 25 years (see
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The father of an affected male will not have CHM nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
• Evaluation of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Evaluations of the mother include:
• Molecular genetic testing for the
• Examination of the retina through a dilated pupil to determine if she has signs of chorioretinal degeneration; however, a normal fundus examination at a young age (<25 years) may not be sufficient to exclude carrier status (see
• Molecular genetic testing for the
• Examination of the retina through a dilated pupil to determine if she has signs of chorioretinal degeneration; however, a normal fundus examination at a young age (<25 years) may not be sufficient to exclude carrier status (see
• Molecular genetic testing for the
• Examination of the retina through a dilated pupil to determine if she has signs of chorioretinal degeneration; however, a normal fundus examination at a young age (<25 years) may not be sufficient to exclude carrier status (see
• If the mother of the proband has a
• Males who inherit the pathogenic variant will be affected; it is not possible to predict at what age an affected male will start to experience vision problems and how quickly the disease will progress.
• Females who inherit the pathogenic variant will be heterozygotes and may or may not initially show changes with ERG testing, funduscopic examination, color vision testing, and/or visual field testing; however, with time, areas of decreased fundus autofluorescence will be seen (see
• It is not possible to predict if a heterozygous female will manifest any vision loss. At one time, consensus held that heterozygous females experienced only mild vision disturbances later in life; however, heterozygous females may have vision loss similar to that of affected males because of skewed X-chromosome inactivation.
• Males who inherit the pathogenic variant will be affected; it is not possible to predict at what age an affected male will start to experience vision problems and how quickly the disease will progress.
• Females who inherit the pathogenic variant will be heterozygotes and may or may not initially show changes with ERG testing, funduscopic examination, color vision testing, and/or visual field testing; however, with time, areas of decreased fundus autofluorescence will be seen (see
• It is not possible to predict if a heterozygous female will manifest any vision loss. At one time, consensus held that heterozygous females experienced only mild vision disturbances later in life; however, heterozygous females may have vision loss similar to that of affected males because of skewed X-chromosome inactivation.
• If the proband represents a simplex case (i.e., a single occurrence in a family), if the mother has a normal fundus examination, and if the
• Males who inherit the pathogenic variant will be affected; it is not possible to predict at what age an affected male will start to experience vision problems and how quickly the disease will progress.
• Females who inherit the pathogenic variant will be heterozygotes and may or may not initially show changes with ERG testing, funduscopic examination, color vision testing, and/or visual field testing; however, with time, areas of decreased fundus autofluorescence will be seen (see
• It is not possible to predict if a heterozygous female will manifest any vision loss. At one time, consensus held that heterozygous females experienced only mild vision disturbances later in life; however, heterozygous females may have vision loss similar to that of affected males because of skewed X-chromosome inactivation.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
## Mode of Inheritance
Choroideremia (CHM) is inherited in an X-linked manner.
## Risk to Family Members
The father of an affected male will not have CHM nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
Evaluation of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Evaluations of the mother include:
Molecular genetic testing for the
Examination of the retina through a dilated pupil to determine if she has signs of chorioretinal degeneration; however, a normal fundus examination at a young age (<25 years) may not be sufficient to exclude carrier status (see
If the mother of the proband has a
Males who inherit the pathogenic variant will be affected; it is not possible to predict at what age an affected male will start to experience vision problems and how quickly the disease will progress.
Females who inherit the pathogenic variant will be heterozygotes and may or may not initially show changes with ERG testing, funduscopic examination, color vision testing, and/or visual field testing; however, with time, areas of decreased fundus autofluorescence will be seen (see
It is not possible to predict if a heterozygous female will manifest any vision loss. At one time, consensus held that heterozygous females experienced only mild vision disturbances later in life; however, heterozygous females may have vision loss similar to that of affected males because of skewed X-chromosome inactivation.
If the proband represents a simplex case (i.e., a single occurrence in a family), if the mother has a normal fundus examination, and if the
Note: Molecular genetic testing may be able to identify the family member in whom a
• The father of an affected male will not have CHM nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
• Evaluation of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Evaluations of the mother include:
• Molecular genetic testing for the
• Examination of the retina through a dilated pupil to determine if she has signs of chorioretinal degeneration; however, a normal fundus examination at a young age (<25 years) may not be sufficient to exclude carrier status (see
• Molecular genetic testing for the
• Examination of the retina through a dilated pupil to determine if she has signs of chorioretinal degeneration; however, a normal fundus examination at a young age (<25 years) may not be sufficient to exclude carrier status (see
• Molecular genetic testing for the
• Examination of the retina through a dilated pupil to determine if she has signs of chorioretinal degeneration; however, a normal fundus examination at a young age (<25 years) may not be sufficient to exclude carrier status (see
• If the mother of the proband has a
• Males who inherit the pathogenic variant will be affected; it is not possible to predict at what age an affected male will start to experience vision problems and how quickly the disease will progress.
• Females who inherit the pathogenic variant will be heterozygotes and may or may not initially show changes with ERG testing, funduscopic examination, color vision testing, and/or visual field testing; however, with time, areas of decreased fundus autofluorescence will be seen (see
• It is not possible to predict if a heterozygous female will manifest any vision loss. At one time, consensus held that heterozygous females experienced only mild vision disturbances later in life; however, heterozygous females may have vision loss similar to that of affected males because of skewed X-chromosome inactivation.
• Males who inherit the pathogenic variant will be affected; it is not possible to predict at what age an affected male will start to experience vision problems and how quickly the disease will progress.
• Females who inherit the pathogenic variant will be heterozygotes and may or may not initially show changes with ERG testing, funduscopic examination, color vision testing, and/or visual field testing; however, with time, areas of decreased fundus autofluorescence will be seen (see
• It is not possible to predict if a heterozygous female will manifest any vision loss. At one time, consensus held that heterozygous females experienced only mild vision disturbances later in life; however, heterozygous females may have vision loss similar to that of affected males because of skewed X-chromosome inactivation.
• If the proband represents a simplex case (i.e., a single occurrence in a family), if the mother has a normal fundus examination, and if the
• Males who inherit the pathogenic variant will be affected; it is not possible to predict at what age an affected male will start to experience vision problems and how quickly the disease will progress.
• Females who inherit the pathogenic variant will be heterozygotes and may or may not initially show changes with ERG testing, funduscopic examination, color vision testing, and/or visual field testing; however, with time, areas of decreased fundus autofluorescence will be seen (see
• It is not possible to predict if a heterozygous female will manifest any vision loss. At one time, consensus held that heterozygous females experienced only mild vision disturbances later in life; however, heterozygous females may have vision loss similar to that of affected males because of skewed X-chromosome inactivation.
## Heterozygote Detection
Note: Females who are heterozygous for this X-linked disorder may not have manifestations of CHM at a young age, but most definitely will have signs after age 25 years (see
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
23 East Brundreth Street
Springfield MA 01109-2110
7168 Columbia Gateway Drive
Suite 100
Columbia MD 21046
•
• 23 East Brundreth Street
• Springfield MA 01109-2110
•
•
• 7168 Columbia Gateway Drive
• Suite 100
• Columbia MD 21046
•
•
•
•
•
## Molecular Genetics
Choroideremia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Choroideremia (
REP-1, the protein encoded by
An exception is the
Most Cited
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
REP-1, the protein encoded by
An exception is the
Most Cited
Variants listed in the table have been provided by the authors.
## Chapter Notes
Ian M MacDonald, MSc, MD, CM, is Professor Emeritus in the Department of Ophthalmology and Visual Sciences, University of Alberta, and past Chair of the department for 20 years. Prior to becoming Chair in Edmonton, he was a career scientist of the Ontario Ministry of Health at the University of Ottawa. From 2007 to 2008, he served as Branch Chief of Ophthalmic Genetics and Visual Function at the National Eye Institute of the National Institutes of Health. Dr MacDonald trained in genetics as an undergraduate and postgraduate student at McGill University, Montreal. His ophthalmology residency and clinical genetics fellowship training occurred at the University of Ottawa, Queen's University, Kingston, and the Hospital for Sick Children, Toronto.
Dr MacDonald's areas of interest are inherited ocular disorders, in particular maculopathies and choroideremia. In 2009, in recognition of his work in Canada to foster the development of academic ophthalmology, he was elected as a Fellow of the Canadian Academy of Health Sciences. The Canadian College of Medical Geneticists honored him with a Lifetime Achievement Award.
CHM Gene Therapy at University of Alberta website:
Grant funding from Fighting Blindness Canada is gratefully acknowledged. Past grant funding: CIHR, Alberta Innovates, Choroideremia Research Foundation Inc. Dr Yi Zhai received a fellowship award from the Choroideremia Research Foundation. Dr Manlong Xu received fellowship support from a grateful patient, Pat Krawchuk.
Natural History of the Progression of Choroideremia (NIGHT NCT03359551) and SOLSTICE NCT03584165 was supported by Nightstar Therapeutics and Biogen Study Group.
The choroideremia natural history study (NCT02994368) was supported by funding from 4D Molecular Therapeutics, Inc (Emeryville, CA as sponsor) and Roche Pharma AG.
Stephanie Hoang, MSc, CGC, CCGC; University of Alberta Hospital (2015-2021)Stacey Hume, PhD (2015-present)Ian M MacDonald, MD, CM (2003-present) Kerry McTaggart, MSc; University of Alberta (2003-2007) Meira R Meltzer, MA, MS, CGC; National Eye Institute (2007-2010) Miguel C Seabra, MD, PhD; Imperial College School of Medicine (2003-2021) Christina Sereda, MSc; University of Alberta (2003-2007) Nizar Smaoui, MD; GeneDx (2007-2015)Manlong Xu, MD, PhD (2021-present)Yi Zhai, MD, PhD (2021-present)
4 March 2021 (bp) Comprehensive update posted live
26 February 2015 (me) Comprehensive update posted live
3 June 2010 (me) Comprehensive update posted live
28 May 2008 (cd) Revision: duplication/deletion analysis available clinically
3 May 2007 (me) Comprehensive update posted live
29 December 2004 (me) Comprehensive update posted live
2 January 2004 (im) Revision: testing
7 May 2003 (im) Revision: Molecular genetic testing; prenatal diagnosis
21 February 2003 (me) Review posted live
2 December 2002 (im) Original submission
• 4 March 2021 (bp) Comprehensive update posted live
• 26 February 2015 (me) Comprehensive update posted live
• 3 June 2010 (me) Comprehensive update posted live
• 28 May 2008 (cd) Revision: duplication/deletion analysis available clinically
• 3 May 2007 (me) Comprehensive update posted live
• 29 December 2004 (me) Comprehensive update posted live
• 2 January 2004 (im) Revision: testing
• 7 May 2003 (im) Revision: Molecular genetic testing; prenatal diagnosis
• 21 February 2003 (me) Review posted live
• 2 December 2002 (im) Original submission
## Author Notes
Ian M MacDonald, MSc, MD, CM, is Professor Emeritus in the Department of Ophthalmology and Visual Sciences, University of Alberta, and past Chair of the department for 20 years. Prior to becoming Chair in Edmonton, he was a career scientist of the Ontario Ministry of Health at the University of Ottawa. From 2007 to 2008, he served as Branch Chief of Ophthalmic Genetics and Visual Function at the National Eye Institute of the National Institutes of Health. Dr MacDonald trained in genetics as an undergraduate and postgraduate student at McGill University, Montreal. His ophthalmology residency and clinical genetics fellowship training occurred at the University of Ottawa, Queen's University, Kingston, and the Hospital for Sick Children, Toronto.
Dr MacDonald's areas of interest are inherited ocular disorders, in particular maculopathies and choroideremia. In 2009, in recognition of his work in Canada to foster the development of academic ophthalmology, he was elected as a Fellow of the Canadian Academy of Health Sciences. The Canadian College of Medical Geneticists honored him with a Lifetime Achievement Award.
CHM Gene Therapy at University of Alberta website:
## Acknowledgments
Grant funding from Fighting Blindness Canada is gratefully acknowledged. Past grant funding: CIHR, Alberta Innovates, Choroideremia Research Foundation Inc. Dr Yi Zhai received a fellowship award from the Choroideremia Research Foundation. Dr Manlong Xu received fellowship support from a grateful patient, Pat Krawchuk.
Natural History of the Progression of Choroideremia (NIGHT NCT03359551) and SOLSTICE NCT03584165 was supported by Nightstar Therapeutics and Biogen Study Group.
The choroideremia natural history study (NCT02994368) was supported by funding from 4D Molecular Therapeutics, Inc (Emeryville, CA as sponsor) and Roche Pharma AG.
## Author History
Stephanie Hoang, MSc, CGC, CCGC; University of Alberta Hospital (2015-2021)Stacey Hume, PhD (2015-present)Ian M MacDonald, MD, CM (2003-present) Kerry McTaggart, MSc; University of Alberta (2003-2007) Meira R Meltzer, MA, MS, CGC; National Eye Institute (2007-2010) Miguel C Seabra, MD, PhD; Imperial College School of Medicine (2003-2021) Christina Sereda, MSc; University of Alberta (2003-2007) Nizar Smaoui, MD; GeneDx (2007-2015)Manlong Xu, MD, PhD (2021-present)Yi Zhai, MD, PhD (2021-present)
## Revision History
4 March 2021 (bp) Comprehensive update posted live
26 February 2015 (me) Comprehensive update posted live
3 June 2010 (me) Comprehensive update posted live
28 May 2008 (cd) Revision: duplication/deletion analysis available clinically
3 May 2007 (me) Comprehensive update posted live
29 December 2004 (me) Comprehensive update posted live
2 January 2004 (im) Revision: testing
7 May 2003 (im) Revision: Molecular genetic testing; prenatal diagnosis
21 February 2003 (me) Review posted live
2 December 2002 (im) Original submission
• 4 March 2021 (bp) Comprehensive update posted live
• 26 February 2015 (me) Comprehensive update posted live
• 3 June 2010 (me) Comprehensive update posted live
• 28 May 2008 (cd) Revision: duplication/deletion analysis available clinically
• 3 May 2007 (me) Comprehensive update posted live
• 29 December 2004 (me) Comprehensive update posted live
• 2 January 2004 (im) Revision: testing
• 7 May 2003 (im) Revision: Molecular genetic testing; prenatal diagnosis
• 21 February 2003 (me) Review posted live
• 2 December 2002 (im) Original submission
## References
## Published Guidelines / Consensus Statements
## Literature Cited
Fundus collage image from the left eye of an affected male with light pigmentation age 36 years
Fundus collage image from the left eye an affected male with dark pigmentation age 35 years
Fundus autofluorescence image from the left eye of an affected male age 35 years.
Fundus autofluorescence image from the right eye of a female carrier age 30 years
|
[] |
21/2/2003
|
4/3/2021
|
28/5/2008
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
christianson
|
christianson
|
[
"Sodium/hydrogen exchanger 6",
"SLC9A6",
"Christianson Syndrome"
] |
Christianson Syndrome
|
Eric M Morrow, Matthew F Pescosolido
|
Summary Christianson syndrome (referred to as CS in this The diagnosis of CS is established in a male proband by identification of a hemizygous pathogenic variant in Measurement of weight and height (and calculation of body mass index) Assessment for scoliosis/kyphoscoliosis Detailed history and related assessments in adolescents and young adults for evidence of possible loss of any of the following skills: feeding, fine/gross motor skills, ambulation, and use of words/sounds CS is inherited in an X-linked manner. The risk to sibs depends on the genetic status of the mother. Heterozygous (carrier) females have a 50% chance of transmitting the
|
## Diagnosis
Christianson syndrome (referred to as CS in this
Developmental delay / intellectual disability (usually severe to profound)
Absent to minimal language development
Hyperkinesis
Epilepsy (onset usually before age three years)
Truncal ataxia
Postnatal-onset microcephaly
Nondysmorphic facial features
The diagnosis of CS
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas
For an introduction to multigene panels click
Comprehensive genomic testing (when clinically available) typically includes exome sequencing and genome sequencing.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Christianson Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Some probands were detected by screening large cohorts.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Developmental delay / intellectual disability (usually severe to profound)
• Absent to minimal language development
• Hyperkinesis
• Epilepsy (onset usually before age three years)
• Truncal ataxia
• Postnatal-onset microcephaly
• Nondysmorphic facial features
## Suggestive Findings
Christianson syndrome (referred to as CS in this
Developmental delay / intellectual disability (usually severe to profound)
Absent to minimal language development
Hyperkinesis
Epilepsy (onset usually before age three years)
Truncal ataxia
Postnatal-onset microcephaly
Nondysmorphic facial features
• Developmental delay / intellectual disability (usually severe to profound)
• Absent to minimal language development
• Hyperkinesis
• Epilepsy (onset usually before age three years)
• Truncal ataxia
• Postnatal-onset microcephaly
• Nondysmorphic facial features
## Establishing the Diagnosis
The diagnosis of CS
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas
For an introduction to multigene panels click
Comprehensive genomic testing (when clinically available) typically includes exome sequencing and genome sequencing.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Christianson Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Some probands were detected by screening large cohorts.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Gene-Targeted Testing
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas
For an introduction to multigene panels click
## Comprehensive Genomic Testing
Comprehensive genomic testing (when clinically available) typically includes exome sequencing and genome sequencing.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Christianson Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Some probands were detected by screening large cohorts.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
Christianson syndrome (CS), an X-linked disorder, typically manifests in males in the first few years of life with delayed developmental milestones and seizures. Additional findings in affected males include intellectual disability (ID), absent-to-limited speech, postnatal microcephaly, truncal ataxia, hyperkinesis, and nondysmorphic facial features. Affected males may also manifest signs of autism spectrum disorder (ASD) and behaviors typically associated with
The phenotypic spectrum in females heterozygous for a
Gross motor milestones are delayed. Independent ambulation is achieved approximately one to two years later than average.
Speech is generally absent. Very limited receptive language and use of a few single words may emerge in the first years of life; however, these words may subsequently be lost. To date, speech was unaffected in one adult male [
IQ is generally well below 35-40.
EEG findings include abnormalities in both background (e.g., generalized slowing) and epileptiform activity (e.g., frequent generalized spike-wave complexes, irregular generalized spike-wave pattern, and multifocal independent and sometimes synchronous spikes). One individual had generalized discharges in more than 85% of slow-wave sleep recordings, a pattern associated with electrographic status epilepticus of sleep [
Clinical and EEG findings suggestive of Lennox-Gastaut syndrome, a syndromic epileptic encephalopathy, have been reported [
Epileptic encephalopathy (childhood-onset epilepsies characterized by severe, intractable, multiform seizures associated with cognitive impairments) has been reported [
In one family, an affected boy and his maternal uncle did not have ataxia [
Progressive cerebellar atrophy, particularly affecting the vermis, is one of the most common neuroimaging findings [
Of note, birth weight (when reported) was normal in the majority of affected males.
Medical illness and/or severe or worsening seizure episodes usually precede regressions [
The risk for regression appears to increase after the first decade of life as regression has been reported in males in their 40s-50s [
Sleep disturbances, including frequent nighttime waking, an inability to fall asleep, and, in two males, no discernable sleep pattern [
Scoliosis and one individual with severe kyphoscoliosis [
High pain threshold resulting in serious injury [
Osteoporosis observed in some cases [
To date, 43 heterozygous females in 17 families have been reported [
Manifestations range from no reported abnormal neurologic or psychological findings [
The most common findings:
Mild developmental delay (especially with speech/language) and/or mild intellectual disability [
In some, a notable discrepancy on neuropsychological testing between verbal and performance IQ, with verbal IQ being much lower [
Speech disorder/dysphasia [
Dyslexia [
Behavior problems including aggression [
Hyperactivity/hyperkinesia [
To date, no genotype-phenotype correlations have been identified.
The estimated prevalence of CS is between 1:16,000 and 1:100,000 [
CS may be among the most common X-linked neurodevelopmental disorders based on X-chromosome sequencing of approximately 200 families with suspected X-linked intellectual disability [
• Gross motor milestones are delayed. Independent ambulation is achieved approximately one to two years later than average.
• Speech is generally absent. Very limited receptive language and use of a few single words may emerge in the first years of life; however, these words may subsequently be lost. To date, speech was unaffected in one adult male [
• IQ is generally well below 35-40.
• Gross motor milestones are delayed. Independent ambulation is achieved approximately one to two years later than average.
• Speech is generally absent. Very limited receptive language and use of a few single words may emerge in the first years of life; however, these words may subsequently be lost. To date, speech was unaffected in one adult male [
• IQ is generally well below 35-40.
• EEG findings include abnormalities in both background (e.g., generalized slowing) and epileptiform activity (e.g., frequent generalized spike-wave complexes, irregular generalized spike-wave pattern, and multifocal independent and sometimes synchronous spikes). One individual had generalized discharges in more than 85% of slow-wave sleep recordings, a pattern associated with electrographic status epilepticus of sleep [
• Clinical and EEG findings suggestive of Lennox-Gastaut syndrome, a syndromic epileptic encephalopathy, have been reported [
• Epileptic encephalopathy (childhood-onset epilepsies characterized by severe, intractable, multiform seizures associated with cognitive impairments) has been reported [
• In one family, an affected boy and his maternal uncle did not have ataxia [
• Progressive cerebellar atrophy, particularly affecting the vermis, is one of the most common neuroimaging findings [
• Gross motor milestones are delayed. Independent ambulation is achieved approximately one to two years later than average.
• Speech is generally absent. Very limited receptive language and use of a few single words may emerge in the first years of life; however, these words may subsequently be lost. To date, speech was unaffected in one adult male [
• IQ is generally well below 35-40.
• Of note, birth weight (when reported) was normal in the majority of affected males.
• Medical illness and/or severe or worsening seizure episodes usually precede regressions [
• The risk for regression appears to increase after the first decade of life as regression has been reported in males in their 40s-50s [
• Sleep disturbances, including frequent nighttime waking, an inability to fall asleep, and, in two males, no discernable sleep pattern [
• Scoliosis and one individual with severe kyphoscoliosis [
• High pain threshold resulting in serious injury [
• Osteoporosis observed in some cases [
• Mild developmental delay (especially with speech/language) and/or mild intellectual disability [
• In some, a notable discrepancy on neuropsychological testing between verbal and performance IQ, with verbal IQ being much lower [
• Speech disorder/dysphasia [
• Dyslexia [
• Behavior problems including aggression [
• Hyperactivity/hyperkinesia [
## Clinical Description
Christianson syndrome (CS), an X-linked disorder, typically manifests in males in the first few years of life with delayed developmental milestones and seizures. Additional findings in affected males include intellectual disability (ID), absent-to-limited speech, postnatal microcephaly, truncal ataxia, hyperkinesis, and nondysmorphic facial features. Affected males may also manifest signs of autism spectrum disorder (ASD) and behaviors typically associated with
The phenotypic spectrum in females heterozygous for a
Gross motor milestones are delayed. Independent ambulation is achieved approximately one to two years later than average.
Speech is generally absent. Very limited receptive language and use of a few single words may emerge in the first years of life; however, these words may subsequently be lost. To date, speech was unaffected in one adult male [
IQ is generally well below 35-40.
EEG findings include abnormalities in both background (e.g., generalized slowing) and epileptiform activity (e.g., frequent generalized spike-wave complexes, irregular generalized spike-wave pattern, and multifocal independent and sometimes synchronous spikes). One individual had generalized discharges in more than 85% of slow-wave sleep recordings, a pattern associated with electrographic status epilepticus of sleep [
Clinical and EEG findings suggestive of Lennox-Gastaut syndrome, a syndromic epileptic encephalopathy, have been reported [
Epileptic encephalopathy (childhood-onset epilepsies characterized by severe, intractable, multiform seizures associated with cognitive impairments) has been reported [
In one family, an affected boy and his maternal uncle did not have ataxia [
Progressive cerebellar atrophy, particularly affecting the vermis, is one of the most common neuroimaging findings [
Of note, birth weight (when reported) was normal in the majority of affected males.
Medical illness and/or severe or worsening seizure episodes usually precede regressions [
The risk for regression appears to increase after the first decade of life as regression has been reported in males in their 40s-50s [
Sleep disturbances, including frequent nighttime waking, an inability to fall asleep, and, in two males, no discernable sleep pattern [
Scoliosis and one individual with severe kyphoscoliosis [
High pain threshold resulting in serious injury [
Osteoporosis observed in some cases [
To date, 43 heterozygous females in 17 families have been reported [
Manifestations range from no reported abnormal neurologic or psychological findings [
The most common findings:
Mild developmental delay (especially with speech/language) and/or mild intellectual disability [
In some, a notable discrepancy on neuropsychological testing between verbal and performance IQ, with verbal IQ being much lower [
Speech disorder/dysphasia [
Dyslexia [
Behavior problems including aggression [
Hyperactivity/hyperkinesia [
• Gross motor milestones are delayed. Independent ambulation is achieved approximately one to two years later than average.
• Speech is generally absent. Very limited receptive language and use of a few single words may emerge in the first years of life; however, these words may subsequently be lost. To date, speech was unaffected in one adult male [
• IQ is generally well below 35-40.
• Gross motor milestones are delayed. Independent ambulation is achieved approximately one to two years later than average.
• Speech is generally absent. Very limited receptive language and use of a few single words may emerge in the first years of life; however, these words may subsequently be lost. To date, speech was unaffected in one adult male [
• IQ is generally well below 35-40.
• EEG findings include abnormalities in both background (e.g., generalized slowing) and epileptiform activity (e.g., frequent generalized spike-wave complexes, irregular generalized spike-wave pattern, and multifocal independent and sometimes synchronous spikes). One individual had generalized discharges in more than 85% of slow-wave sleep recordings, a pattern associated with electrographic status epilepticus of sleep [
• Clinical and EEG findings suggestive of Lennox-Gastaut syndrome, a syndromic epileptic encephalopathy, have been reported [
• Epileptic encephalopathy (childhood-onset epilepsies characterized by severe, intractable, multiform seizures associated with cognitive impairments) has been reported [
• In one family, an affected boy and his maternal uncle did not have ataxia [
• Progressive cerebellar atrophy, particularly affecting the vermis, is one of the most common neuroimaging findings [
• Gross motor milestones are delayed. Independent ambulation is achieved approximately one to two years later than average.
• Speech is generally absent. Very limited receptive language and use of a few single words may emerge in the first years of life; however, these words may subsequently be lost. To date, speech was unaffected in one adult male [
• IQ is generally well below 35-40.
• Of note, birth weight (when reported) was normal in the majority of affected males.
• Medical illness and/or severe or worsening seizure episodes usually precede regressions [
• The risk for regression appears to increase after the first decade of life as regression has been reported in males in their 40s-50s [
• Sleep disturbances, including frequent nighttime waking, an inability to fall asleep, and, in two males, no discernable sleep pattern [
• Scoliosis and one individual with severe kyphoscoliosis [
• High pain threshold resulting in serious injury [
• Osteoporosis observed in some cases [
• Mild developmental delay (especially with speech/language) and/or mild intellectual disability [
• In some, a notable discrepancy on neuropsychological testing between verbal and performance IQ, with verbal IQ being much lower [
• Speech disorder/dysphasia [
• Dyslexia [
• Behavior problems including aggression [
• Hyperactivity/hyperkinesia [
## Affected Males
Gross motor milestones are delayed. Independent ambulation is achieved approximately one to two years later than average.
Speech is generally absent. Very limited receptive language and use of a few single words may emerge in the first years of life; however, these words may subsequently be lost. To date, speech was unaffected in one adult male [
IQ is generally well below 35-40.
EEG findings include abnormalities in both background (e.g., generalized slowing) and epileptiform activity (e.g., frequent generalized spike-wave complexes, irregular generalized spike-wave pattern, and multifocal independent and sometimes synchronous spikes). One individual had generalized discharges in more than 85% of slow-wave sleep recordings, a pattern associated with electrographic status epilepticus of sleep [
Clinical and EEG findings suggestive of Lennox-Gastaut syndrome, a syndromic epileptic encephalopathy, have been reported [
Epileptic encephalopathy (childhood-onset epilepsies characterized by severe, intractable, multiform seizures associated with cognitive impairments) has been reported [
In one family, an affected boy and his maternal uncle did not have ataxia [
Progressive cerebellar atrophy, particularly affecting the vermis, is one of the most common neuroimaging findings [
Of note, birth weight (when reported) was normal in the majority of affected males.
Medical illness and/or severe or worsening seizure episodes usually precede regressions [
The risk for regression appears to increase after the first decade of life as regression has been reported in males in their 40s-50s [
Sleep disturbances, including frequent nighttime waking, an inability to fall asleep, and, in two males, no discernable sleep pattern [
Scoliosis and one individual with severe kyphoscoliosis [
High pain threshold resulting in serious injury [
Osteoporosis observed in some cases [
• Gross motor milestones are delayed. Independent ambulation is achieved approximately one to two years later than average.
• Speech is generally absent. Very limited receptive language and use of a few single words may emerge in the first years of life; however, these words may subsequently be lost. To date, speech was unaffected in one adult male [
• IQ is generally well below 35-40.
• Gross motor milestones are delayed. Independent ambulation is achieved approximately one to two years later than average.
• Speech is generally absent. Very limited receptive language and use of a few single words may emerge in the first years of life; however, these words may subsequently be lost. To date, speech was unaffected in one adult male [
• IQ is generally well below 35-40.
• EEG findings include abnormalities in both background (e.g., generalized slowing) and epileptiform activity (e.g., frequent generalized spike-wave complexes, irregular generalized spike-wave pattern, and multifocal independent and sometimes synchronous spikes). One individual had generalized discharges in more than 85% of slow-wave sleep recordings, a pattern associated with electrographic status epilepticus of sleep [
• Clinical and EEG findings suggestive of Lennox-Gastaut syndrome, a syndromic epileptic encephalopathy, have been reported [
• Epileptic encephalopathy (childhood-onset epilepsies characterized by severe, intractable, multiform seizures associated with cognitive impairments) has been reported [
• In one family, an affected boy and his maternal uncle did not have ataxia [
• Progressive cerebellar atrophy, particularly affecting the vermis, is one of the most common neuroimaging findings [
• Gross motor milestones are delayed. Independent ambulation is achieved approximately one to two years later than average.
• Speech is generally absent. Very limited receptive language and use of a few single words may emerge in the first years of life; however, these words may subsequently be lost. To date, speech was unaffected in one adult male [
• IQ is generally well below 35-40.
• Of note, birth weight (when reported) was normal in the majority of affected males.
• Medical illness and/or severe or worsening seizure episodes usually precede regressions [
• The risk for regression appears to increase after the first decade of life as regression has been reported in males in their 40s-50s [
• Sleep disturbances, including frequent nighttime waking, an inability to fall asleep, and, in two males, no discernable sleep pattern [
• Scoliosis and one individual with severe kyphoscoliosis [
• High pain threshold resulting in serious injury [
• Osteoporosis observed in some cases [
## Heterozygous Females (i.e., Carriers)
To date, 43 heterozygous females in 17 families have been reported [
Manifestations range from no reported abnormal neurologic or psychological findings [
The most common findings:
Mild developmental delay (especially with speech/language) and/or mild intellectual disability [
In some, a notable discrepancy on neuropsychological testing between verbal and performance IQ, with verbal IQ being much lower [
Speech disorder/dysphasia [
Dyslexia [
Behavior problems including aggression [
Hyperactivity/hyperkinesia [
• Mild developmental delay (especially with speech/language) and/or mild intellectual disability [
• In some, a notable discrepancy on neuropsychological testing between verbal and performance IQ, with verbal IQ being much lower [
• Speech disorder/dysphasia [
• Dyslexia [
• Behavior problems including aggression [
• Hyperactivity/hyperkinesia [
## Genotype-Phenotype Correlations
To date, no genotype-phenotype correlations have been identified.
## Prevalence
The estimated prevalence of CS is between 1:16,000 and 1:100,000 [
CS may be among the most common X-linked neurodevelopmental disorders based on X-chromosome sequencing of approximately 200 families with suspected X-linked intellectual disability [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Christianson syndrome (CS) can be clinically distinguished from AS in the following ways:
The presence of progressive cerebellar atrophy in CS [
Lifelong problems with weight gain with a low body mass index in individuals with CS. Those with AS may have poor weight gain in early childhood with later normal weight gain or even obesity in young adulthood.
All genes known to be associated with intellectual disability should be included in the differential diagnosis of Christianson syndrome. More than 180 have been identified; see OMIM Phenotypic Series – Intellectual disability:
• The presence of progressive cerebellar atrophy in CS [
• Lifelong problems with weight gain with a low body mass index in individuals with CS. Those with AS may have poor weight gain in early childhood with later normal weight gain or even obesity in young adulthood.
•
•
•
•
## Management
To establish the extent of disease and needs in an individual diagnosed with Christianson syndrome (CS), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Establishment of baseline neurologic functioning with:
Assessment of adaptive functioning (e.g., Vineland, Bayley Scales of Infant Development)
Occupational therapy and physical therapy assessment regarding fine motor and gross motor functioning
Speech/language/communication assessment
Assessment of behavioral issues, as needed, using such evaluation tools as Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview-Revised (ADI-R)]
Neurologic examination
EEG
Brain MRI (based on the clinician's judgment) to determine if any structural brain abnormalities are present, especially cerebellar / brain stem atrophy
Evaluation of swallowing function, feeding, and nutrition as needed
Ophthalmologic assessment, including evaluation for eye movement abnormalities and visual acuity, when warranted
Consultation with a clinical geneticist and/or genetic counselor
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the United States, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion regarding transition plans and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary.
At the time of follow-up clinical examinations, the following are recommended:
Measurement of weight and height (and calculation of BMI) because of the increased age-related risk for poor weight gain despite normal or even high caloric intake
Assessment for scoliosis/kyphoscoliosis
In adolescents / young adults regarding possible regression:
Evaluation for loss of any of the following: feeding skills, fine/gross motor skills, ambulation, use of words/sounds
Repeat neuropsychologic assessments (as needed)
Assessment using an ataxia rating scale
See
Search
• Establishment of baseline neurologic functioning with:
• Assessment of adaptive functioning (e.g., Vineland, Bayley Scales of Infant Development)
• Occupational therapy and physical therapy assessment regarding fine motor and gross motor functioning
• Speech/language/communication assessment
• Assessment of behavioral issues, as needed, using such evaluation tools as Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview-Revised (ADI-R)]
• Neurologic examination
• EEG
• Brain MRI (based on the clinician's judgment) to determine if any structural brain abnormalities are present, especially cerebellar / brain stem atrophy
• Assessment of adaptive functioning (e.g., Vineland, Bayley Scales of Infant Development)
• Occupational therapy and physical therapy assessment regarding fine motor and gross motor functioning
• Speech/language/communication assessment
• Assessment of behavioral issues, as needed, using such evaluation tools as Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview-Revised (ADI-R)]
• Neurologic examination
• EEG
• Brain MRI (based on the clinician's judgment) to determine if any structural brain abnormalities are present, especially cerebellar / brain stem atrophy
• Evaluation of swallowing function, feeding, and nutrition as needed
• Ophthalmologic assessment, including evaluation for eye movement abnormalities and visual acuity, when warranted
• Consultation with a clinical geneticist and/or genetic counselor
• Assessment of adaptive functioning (e.g., Vineland, Bayley Scales of Infant Development)
• Occupational therapy and physical therapy assessment regarding fine motor and gross motor functioning
• Speech/language/communication assessment
• Assessment of behavioral issues, as needed, using such evaluation tools as Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview-Revised (ADI-R)]
• Neurologic examination
• EEG
• Brain MRI (based on the clinician's judgment) to determine if any structural brain abnormalities are present, especially cerebellar / brain stem atrophy
• In the United States, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion regarding transition plans and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Measurement of weight and height (and calculation of BMI) because of the increased age-related risk for poor weight gain despite normal or even high caloric intake
• Assessment for scoliosis/kyphoscoliosis
• In adolescents / young adults regarding possible regression:
• Evaluation for loss of any of the following: feeding skills, fine/gross motor skills, ambulation, use of words/sounds
• Repeat neuropsychologic assessments (as needed)
• Assessment using an ataxia rating scale
• Evaluation for loss of any of the following: feeding skills, fine/gross motor skills, ambulation, use of words/sounds
• Repeat neuropsychologic assessments (as needed)
• Assessment using an ataxia rating scale
• Evaluation for loss of any of the following: feeding skills, fine/gross motor skills, ambulation, use of words/sounds
• Repeat neuropsychologic assessments (as needed)
• Assessment using an ataxia rating scale
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Christianson syndrome (CS), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Establishment of baseline neurologic functioning with:
Assessment of adaptive functioning (e.g., Vineland, Bayley Scales of Infant Development)
Occupational therapy and physical therapy assessment regarding fine motor and gross motor functioning
Speech/language/communication assessment
Assessment of behavioral issues, as needed, using such evaluation tools as Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview-Revised (ADI-R)]
Neurologic examination
EEG
Brain MRI (based on the clinician's judgment) to determine if any structural brain abnormalities are present, especially cerebellar / brain stem atrophy
Evaluation of swallowing function, feeding, and nutrition as needed
Ophthalmologic assessment, including evaluation for eye movement abnormalities and visual acuity, when warranted
Consultation with a clinical geneticist and/or genetic counselor
• Establishment of baseline neurologic functioning with:
• Assessment of adaptive functioning (e.g., Vineland, Bayley Scales of Infant Development)
• Occupational therapy and physical therapy assessment regarding fine motor and gross motor functioning
• Speech/language/communication assessment
• Assessment of behavioral issues, as needed, using such evaluation tools as Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview-Revised (ADI-R)]
• Neurologic examination
• EEG
• Brain MRI (based on the clinician's judgment) to determine if any structural brain abnormalities are present, especially cerebellar / brain stem atrophy
• Assessment of adaptive functioning (e.g., Vineland, Bayley Scales of Infant Development)
• Occupational therapy and physical therapy assessment regarding fine motor and gross motor functioning
• Speech/language/communication assessment
• Assessment of behavioral issues, as needed, using such evaluation tools as Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview-Revised (ADI-R)]
• Neurologic examination
• EEG
• Brain MRI (based on the clinician's judgment) to determine if any structural brain abnormalities are present, especially cerebellar / brain stem atrophy
• Evaluation of swallowing function, feeding, and nutrition as needed
• Ophthalmologic assessment, including evaluation for eye movement abnormalities and visual acuity, when warranted
• Consultation with a clinical geneticist and/or genetic counselor
• Assessment of adaptive functioning (e.g., Vineland, Bayley Scales of Infant Development)
• Occupational therapy and physical therapy assessment regarding fine motor and gross motor functioning
• Speech/language/communication assessment
• Assessment of behavioral issues, as needed, using such evaluation tools as Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview-Revised (ADI-R)]
• Neurologic examination
• EEG
• Brain MRI (based on the clinician's judgment) to determine if any structural brain abnormalities are present, especially cerebellar / brain stem atrophy
## Treatment of Manifestations
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the United States, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion regarding transition plans and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary.
• In the United States, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion regarding transition plans and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the United States, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion regarding transition plans and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• In the United States, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion regarding transition plans and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary.
## Other
## Surveillance
At the time of follow-up clinical examinations, the following are recommended:
Measurement of weight and height (and calculation of BMI) because of the increased age-related risk for poor weight gain despite normal or even high caloric intake
Assessment for scoliosis/kyphoscoliosis
In adolescents / young adults regarding possible regression:
Evaluation for loss of any of the following: feeding skills, fine/gross motor skills, ambulation, use of words/sounds
Repeat neuropsychologic assessments (as needed)
Assessment using an ataxia rating scale
• Measurement of weight and height (and calculation of BMI) because of the increased age-related risk for poor weight gain despite normal or even high caloric intake
• Assessment for scoliosis/kyphoscoliosis
• In adolescents / young adults regarding possible regression:
• Evaluation for loss of any of the following: feeding skills, fine/gross motor skills, ambulation, use of words/sounds
• Repeat neuropsychologic assessments (as needed)
• Assessment using an ataxia rating scale
• Evaluation for loss of any of the following: feeding skills, fine/gross motor skills, ambulation, use of words/sounds
• Repeat neuropsychologic assessments (as needed)
• Assessment using an ataxia rating scale
• Evaluation for loss of any of the following: feeding skills, fine/gross motor skills, ambulation, use of words/sounds
• Repeat neuropsychologic assessments (as needed)
• Assessment using an ataxia rating scale
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Christianson syndrome (CS) is inherited in an X-linked manner.
The father of an affected male will not have CS nor will he be hemizygous for the
In a family with more than one affected male, the mother is an obligate carrier. Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a
Molecular genetic testing of the mother can determine if the
If the mother of the proband has an
If a male represents a simplex case (i.e., a single occurrence in a family), and if the
Note: Molecular genetic testing may be able to identify the family member in whom a
Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the pathogenic variant in the family.
Note: Females who are heterozygous for this X-linked disorder may have a range of clinical manifestations (see Clinical Description,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Once the
• The father of an affected male will not have CS nor will he be hemizygous for the
• In a family with more than one affected male, the mother is an obligate carrier. Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a
• Molecular genetic testing of the mother can determine if the
• If the mother of the proband has an
• If a male represents a simplex case (i.e., a single occurrence in a family), and if the
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Mode of Inheritance
Christianson syndrome (CS) is inherited in an X-linked manner.
## Risk to Family Members
The father of an affected male will not have CS nor will he be hemizygous for the
In a family with more than one affected male, the mother is an obligate carrier. Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a
Molecular genetic testing of the mother can determine if the
If the mother of the proband has an
If a male represents a simplex case (i.e., a single occurrence in a family), and if the
Note: Molecular genetic testing may be able to identify the family member in whom a
• The father of an affected male will not have CS nor will he be hemizygous for the
• In a family with more than one affected male, the mother is an obligate carrier. Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a
• Molecular genetic testing of the mother can determine if the
• If the mother of the proband has an
• If a male represents a simplex case (i.e., a single occurrence in a family), and if the
## Heterozygote Detection
Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the pathogenic variant in the family.
Note: Females who are heterozygous for this X-linked disorder may have a range of clinical manifestations (see Clinical Description,
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
## Resources
15201 Mason Road
Suite 1000 #173
Cypress TX 77433
•
• 15201 Mason Road
• Suite 1000 #173
• Cypress TX 77433
•
•
•
•
•
•
•
## Molecular Genetics
Christianson Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Christianson Syndrome (
Studies have implicated defects in brain-derived neurotrophic factor (BDNF) endosomal signaling in a mouse model of Christianson syndrome [
## Molecular Pathogenesis
Studies have implicated defects in brain-derived neurotrophic factor (BDNF) endosomal signaling in a mouse model of Christianson syndrome [
## References
## Literature Cited
## Chapter Notes
Dr Eric Morrow's research interests in understanding the genetic and molecular mechanisms of neurodevelopmental disorders, including intellectual disability and autism. His research program has a focus in Christianson syndrome and related neurologic conditions. People interested in learning more about ongoing research studies involving Christianson syndrome may contact him at [email protected].
We would like to thank the families of individuals diagnosed with Christianson syndrome for their support and participation in research. This work has been supported by the Hassenfeld Child Health Innovation Institute at Brown University, the Angelman Syndrome Foundation general research grant and National Institutes of Health/National Institute of Mental Health grants R01MH105442, R01MH102418, and R21MH115392 (to EMM); and National Institutes of Health/National Institute of Neurological Disorders and Stroke grant F31NS093880 (to MFP).
11 January 2018 (bp) Review posted live
19 January 2015 (emm) Original submission
• 11 January 2018 (bp) Review posted live
• 19 January 2015 (emm) Original submission
## Author Notes
Dr Eric Morrow's research interests in understanding the genetic and molecular mechanisms of neurodevelopmental disorders, including intellectual disability and autism. His research program has a focus in Christianson syndrome and related neurologic conditions. People interested in learning more about ongoing research studies involving Christianson syndrome may contact him at [email protected].
## Acknowledgments
We would like to thank the families of individuals diagnosed with Christianson syndrome for their support and participation in research. This work has been supported by the Hassenfeld Child Health Innovation Institute at Brown University, the Angelman Syndrome Foundation general research grant and National Institutes of Health/National Institute of Mental Health grants R01MH105442, R01MH102418, and R21MH115392 (to EMM); and National Institutes of Health/National Institute of Neurological Disorders and Stroke grant F31NS093880 (to MFP).
## Revision History
11 January 2018 (bp) Review posted live
19 January 2015 (emm) Original submission
• 11 January 2018 (bp) Review posted live
• 19 January 2015 (emm) Original submission
|
[
"AL Christianson, RE Stevenson, CH van der Meyden, J Pelser, FW Theron, PL van Rensburg, M Chandler, CE Schwartz. X linked severe mental retardation, craniofacial dysmorphology, epilepsy, ophthalmoplegia, and cerebellar atrophy in a large South African kindred is localised to Xq24-q27.. J Med Genet 1999;36:759-66",
"R Coorg, JL Weisenberg. Successful treatment of electrographic status epilepticus of sleep with felbamate in a patient with SLC9A6 mutation.. Pediatr Neurol 2015;53:527-31",
"Y Fichou, N Bahi-Buisson, J Nectoux, J Chelly, D Héron, L Cuisset, T Bienvenu. Mutation in the SLC9A6 gene is not a frequent cause of sporadic Angelman-like syndrome.. Eur J Hum Genet. 2009;17:1378-80",
"JY Garbern, M Neumann, JQ Trojanowski, VM Lee, G Feldman, JW Norris, MJ Friez, CE Schwartz, R Stevenson, AA Sima. A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition.. Brain 2010;133:1391-402",
"GD Gilfillan, KK Selmer, I Roxrud, R Smith, M Kyllerman, K Eiklid, M Kroken, M Mattingsdal, T Egeland, H Stenmark, H Sjøholm, A Server, L Samuelsson, A Christianson, P Tarpey, A Whibley, MR Stratton, PA Futreal, J Teague, S Edkins, J Gecz, G Turner, FL Raymond, C Schwartz, RE Stevenson, DE Undlien, P Strømme. SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome.. Am J Hum Genet 2008;82:1003-10",
"A Masurel-Paulet, A Piton, S Chancenotte, C Redin, C Thauvin-Robinet, Y Henrenger, D Minot, A Creppy, M Ruffier-Bourdet, J Thevenon, P Kuentz, D Lehalle, A Curie, G Blanchard, E Ghosn, M Bonnet, M Archimbaud-Devilliers, F Huet, O Perret, N Philip, JL Mandel, L Faivre. A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome.. Am J Med Genet A. 2016;170:2103-10",
"C Mignot, D Héron, J Bursztyn, M Momtchilova, M Mayer, S Whalen, A Legall, T Billette de Villemeur, L. Burglen. Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum.. Brain Dev 2013;35:172-6",
"N Nakamura, S Tanaka, Y Teko, K Mitsui, H Kanazawa. Four Na+/H+ exchanger isoforms are distributed to Golgi and post-Golgi compartments and are involved in organelle pH regulation.. J Biol Chem 2005;280:1561-72",
"R Ohgaki, SC van IJzendoorn, M Matsushita, D Hoekstra, H Kanazawa. Organellar Na+/H+ exchangers: novel players in organelle pH regulation and their emerging functions.. Biochemistry 2011;50:443-50",
"Q Ouyang, SB Lizarraga, M Schmidt, U Yang, J Gong, D Ellisor, JA Kauer, EM Morrow. Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development.. Neuron 2013;80:97-112",
"MF Pescosolido, DM Stein, M Schmidt, CM El Achkar, M Sabbagh, JM Rogg, U Tantravahi, RL McLean, JS Liu, A Poduri, EM Morrow. Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.. Ann Neurol 2014;76:581-93",
"A Riess, E Rossier, R Krüger, A Dufke, S Beck-Woedl, V Horber, M Alber, D Gläser, O Riess, A Tzschach. Novel SLC9A6 mutations in two families with Christianson syndrome.. Clin Genet 2013;83:596-7",
"RJ Schroer, KR Holden, PS Tarpey, MG Matheus, DA Griesemer, MJ Friez, JZ Fan, RJ Simensen, P Strømme, RE Stevenson, MR Stratton, CE Schwartz. Natural history of Christianson syndrome.. Am J Med Genet A 2010;152A:2775-83",
"P Sinajon, D Verbaan, J So. The expanding phenotypic spectrum of female SLC9A6 mutation carriers: a case series and review of the literature.. Hum Genet. 2016;135:841-50",
"Y Takahashi, K Hosoki, M Matsushita, M Funatsuka, K Saito, H Kanazawa, Y Goto, S Saitoh. A loss-of-function mutation in the SLC9A6 gene causes X-linked mental retardation resembling Angelman syndrome.. Am J Med Genet B Neuropsychiatr Genet 2011;156B:799-807",
"PS Tarpey, R Smith, E Pleasance, A Whibley, S Edkins, C Hardy, S O'Meara, C Latimer, E Dicks, A Menzies, P Stephens, M Blow, C Greenman, Y Xue, C Tyler-Smith, D Thompson, K Gray, J Andrews, S Barthorpe, G Buck, J Cole, R Dunmore, D Jones, M Maddison, T Mironenko, R Turner, K Turrell, J Varian, S West, S Widaa, P Wray, J Teague, A Butler, A Jenkinson, M Jia, D Richardson, R Shepherd, R Wooster, MI Tejada, F Martinez, G Carvill, R Goliath, AP de Brouwer, H van Bokhoven, H Van Esch, J Chelly, M Raynaud, HH Ropers, FE Abidi, AK Srivastava, J Cox, Y Luo, U Mallya, J Moon, J Parnau, S Mohammed, JL Tolmie, C Shoubridge, M Corbett, A Gardner, E Haan, S Rujirabanjerd, M Shaw, L Vandeleur, T Fullston, DF Easton, J Boyle, M Partington, A Hackett, M Field, C Skinner, RE Stevenson, M Bobrow, G Turner, CE Schwartz, J Gecz, FL Raymond, PA Futreal, MR Stratton. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.. Nat Genet 2009;41:535-43",
"N Trump, A McTague, H Brittain, A Papandreou, E Meyer, A Ngoh, R Palmer, D Morrogh, C Boustred, JA Hurst, L Jenkins, MA Kurian, RH Scott. Improving diagnosis and broadening the phenotypes in early-onset seizure and severe developmental delay disorders through gene panel analysis.. J Med Genet 2016;53:310-7",
"A Tzschach, R Ullmann, A Ahmed, T Martin, G Weber, O Decker-Schwering, F Pauly, MG Shamdeen, W Reith, B Oehl-Jaschkowitz. Christianson syndrome in a patient with an interstitial Xq26.3 deletion.. Am J Med Genet A 2011;155A:2771-4",
"A Tzschach, U Grasshoff, S Beck-Woedl, C Dufke, C Bauer, M Kehrer, C Evers, U Moog, B Oehl-Jaschkowitz, N Di Donato, R Maiwald, C Jung, A Kuechler, S Schulz, P Meinecke, S Spranger, J Kohlhase, J Seidel, S Reif, M Rieger, A Riess, M Sturm, J Bickmann, C Schroeder, A Dufke, O Riess, P. Bauer. Next-generation sequencing in X-linked intellectual disability.. Eur J Hum Genet 2015;23:1513-8",
"L Xinhan, M Matsushita, M Numaza, A Taguchi, K Mitsui, H Kanazawa. Na+/H+ exchanger isoform 6 (NHE6/SLC9A6) is involved in clathrin-dependent endocytosis of transferrin.. Am J Physiol Cell Physiol 2011;301:C1431-44",
"G Zanni, S Barresi, R Cohen, N Specchio, L Basel-Vanagaite, EM Valente, A Shuper, F Vigevano, E Bertini. A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES).. Epilepsy Res. 2014;108:811-5"
] |
11/1/2018
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
chrom17-lis
|
chrom17-lis
|
[
"LIS1-Related Lissencephaly / Subcortical Band Heterotopia",
"LIS1-Related Lissencephaly/Subcortical Band Heterotopia",
"PAFAH1B1-Related Subcortical Band Heterotopia (SBH)",
"PAFAH1B1-Related Isolated Lissencephaly Sequence (ILS)",
"Platelet-activating factor acetylhydrolase IB subunit beta",
"PAFAH1B1",
"PAFAH1B1-Related Lissencephaly/Subcortical Band Heterotopia"
] |
Stefanie Brock, William B Dobyns, Anna Jansen
|
Summary The diagnosis of Individuals diagnosed with isolated
|
Isolated lissencephaly sequence (ILS)
Subcortical band heterotopia (SBH)
For other genetic causes of these phenotypes, see
• Isolated lissencephaly sequence (ILS)
• Subcortical band heterotopia (SBH)
## Diagnosis
Note: This chapter on
Generalized hypotonia
Abnormal arching (opisthotonus) in infants transitioning to bilateral spastic cerebral palsy in older individuals
Central visual impairment
Developmental delay, intellectual disability, psychomotor delay, speech and language delay
Behavioral difficulties
Epilepsy ranging from infantile spasms to severe drug-resistant epilepsy
Nonspecific dysmorphic features (See
Note: Dysmorphic features are rare in individuals with intragenic pathogenic variants or intragenic deletions of
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
If CMA is not diagnostic, molecular genetic testing approaches can include a combination of
Gene-targeted testing requires clinical suspicion of a particular genetic cause, based on the clinical and imaging phenotype. This also implies that the clinician is familiar with rare disorders such as lissencephaly/SBH. In contrast, genomic testing can be used when clinical findings are nonspecific, as this does not require preliminary suspicion of a defined genetic cause. Because the phenotype of lissencephaly/SBH is broad, individuals with the distinctive MRI findings described in
When the phenotypic and imaging findings suggest the diagnosis of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by lissencephaly,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
As currently defined, Miller-Dieker syndrome (MDS) is associated with deletions that include both
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Rarely, affected individuals have a balanced reciprocal translocation disrupting
• Generalized hypotonia
• Abnormal arching (opisthotonus) in infants transitioning to bilateral spastic cerebral palsy in older individuals
• Central visual impairment
• Developmental delay, intellectual disability, psychomotor delay, speech and language delay
• Behavioral difficulties
• Epilepsy ranging from infantile spasms to severe drug-resistant epilepsy
• Nonspecific dysmorphic features (See
• Note: Dysmorphic features are rare in individuals with intragenic pathogenic variants or intragenic deletions of
• For an introduction to multigene panels click
## Suggestive Findings
Generalized hypotonia
Abnormal arching (opisthotonus) in infants transitioning to bilateral spastic cerebral palsy in older individuals
Central visual impairment
Developmental delay, intellectual disability, psychomotor delay, speech and language delay
Behavioral difficulties
Epilepsy ranging from infantile spasms to severe drug-resistant epilepsy
Nonspecific dysmorphic features (See
Note: Dysmorphic features are rare in individuals with intragenic pathogenic variants or intragenic deletions of
• Generalized hypotonia
• Abnormal arching (opisthotonus) in infants transitioning to bilateral spastic cerebral palsy in older individuals
• Central visual impairment
• Developmental delay, intellectual disability, psychomotor delay, speech and language delay
• Behavioral difficulties
• Epilepsy ranging from infantile spasms to severe drug-resistant epilepsy
• Nonspecific dysmorphic features (See
• Note: Dysmorphic features are rare in individuals with intragenic pathogenic variants or intragenic deletions of
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
If CMA is not diagnostic, molecular genetic testing approaches can include a combination of
Gene-targeted testing requires clinical suspicion of a particular genetic cause, based on the clinical and imaging phenotype. This also implies that the clinician is familiar with rare disorders such as lissencephaly/SBH. In contrast, genomic testing can be used when clinical findings are nonspecific, as this does not require preliminary suspicion of a defined genetic cause. Because the phenotype of lissencephaly/SBH is broad, individuals with the distinctive MRI findings described in
When the phenotypic and imaging findings suggest the diagnosis of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by lissencephaly,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
As currently defined, Miller-Dieker syndrome (MDS) is associated with deletions that include both
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Rarely, affected individuals have a balanced reciprocal translocation disrupting
• For an introduction to multigene panels click
## Option 1
When the phenotypic and imaging findings suggest the diagnosis of
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by lissencephaly,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
As currently defined, Miller-Dieker syndrome (MDS) is associated with deletions that include both
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Rarely, affected individuals have a balanced reciprocal translocation disrupting
## Clinical Characteristics
Together, isolated lissencephaly sequence (ILS) and subcortical band heterotopia (SBH) comprise the "agyria-pachygyria-band" spectrum of cortical malformations that are caused by deficient neuronal migration during embryogenesis. The term lissencephaly refers to a "smooth brain" with absent (agyria) or abnormally wide gyri (pachygyria).
To date, almost 200 individuals have been identified with an intragenic pathogenic variant in
Affected newborns may appear normal or may have mild-to-moderate hypotonia, feeding difficulties, and poor head control. During the first years, neurologic examination typically demonstrates poor visual tracking and response to sounds, axial hypotonia, and mild distal spasticity. Infants often demonstrate abnormal arching (opisthotonus). Later, distal spasticity becomes more prominent, although axial hypotonia remains. Affected individuals may develop moderate spastic quadriplegia and scoliosis.
Epileptic encephalopathies typically evolve from infantile spasms (West syndrome) to Lennox-Gastaut syndrome of mixed epilepsy with a slow spike-and-wave pattern on EEG.
Some children with ILS have characteristic EEG changes, including diffuse high-amplitude fast rhythms that are considered to be highly specific for this malformation [
After the first months of life, most children have mixed seizure disorders including persisting infantile spasms, focal motor and generalized tonic seizures, and atypical absence, atonic, and myoclonic seizures [
Seizures are drug resistant in more than 65% of affected individuals. While polytherapy with lamotrigine and valproic acid can reduce the number of daily seizures effectively, two thirds of affected individuals continue to experience daily seizures [
Prior to the onset of seizures, most infants have mild delay in development and mild hypotonia.
The developmental prognosis is poor for most individuals with ILS.
Even with good seizure control, the best developmental level achieved (excluding the few individuals with partial lissencephaly) is the equivalent of about age three to five months.
Affected individuals may achieve rolling over, limited creeping, and, very rarely, sitting. Few individuals have been reported to be able to walk with support.
Visual tracking is variable among affected individuals, with a subset achieving normal visual interactions while other do not achieve visual tracking.
With poor seizure control, children with ILS may function at or below the level of a newborn. Regression of acquired functioning due to poor seizure control has been reported [
A few individuals with less severe (grade 4) lissencephaly (see
At birth, the occipitofrontal circumference is typically normal (between the mean and -2 SD). However, postnatal head growth is slow; most children develop microcephaly by age one year. The remainder of the growth parameters are often normal.
Some have difficulty with feeding, and transient elevations in bilirubin in neonates are likely related to feeding difficulties. Feeding often improves during the first few months of life, but typically worsens again with seizure onset during the first year of life, and then again at several years of age for various reasons.
Poor feeding in newborns is usually managed by nasogastric tube feedings, as the feeding problems often improve during the first weeks of life (see Management,
However, feeding often worsens again with intercurrent illnesses and with advancing age and size. At least 50% of children with
Individuals with low central tone frequently develop constipation; this is not specific to those with
Children with lissencephaly have poor control of their airway, which predisposes them to aspiration pneumonia, the most common terminal event. This is not typically seen in those with SBH.
Poor or absent visual interaction and limited visual-perceptual and eye-hand abilities have been reported in a subset of affected individuals, likely secondary to the severe cortical malformations [
In 2017, the imaging criteria for lissencephaly/SBH with a defined monogenic cause were revised. This classification system subdivides lissencephaly/SBH into 21 recurring patterns in order to aid clinicians in predicting the most likely genetic cause based on imaging features. Criteria to stratify lissencephaly/SBH are based on the anteroposterior gradient, grade of severity, cortical thickness and appearance, and associated non-cortical brain malformations [
Gradient of gyral malformation:
Diffuse
Anterior more severe than posterior (a>p)
Posterior more severe than anterior (p>a)
Temporal more severe than posterior and p>a
Grade of gyral malformation:
SBH partial
SBH diffuse
LIS partial pachygyria
LIS diffuse pachygyria
LIS agyria-pachygyria
LIS diffuse agyria
Cortical thickness & appearance:
Simplified gyration overlying SBH
Thin undulating
Thin variable dysgyria
Thin w/enlarged lateral ventricles & thin mantle
Thick classic
Non-cortical brain malformations:
Basal ganglia dysgenesis
Complete or partial agenesis (dysgenesis) of corpus callosum
Tectal hyperplasia
Brain stem hypoplasia & dysgenesis
Cerebellar hypoplasia (either diffuse or vermis predominant)
Applying the above
Clinical Severity of Lissencephaly and Subcortical Brain Heterotopia in General
a = anterior; ID = intellectual disability; LIS = lissencephaly; p = posterior; SBH = subcortical band heterotopia
Enlarged lateral ventricles, especially posteriorly
Mild hypoplasia of the corpus callosum (the anterior portion often appears flattened)
Cavum septi pellucidi et vergae
Normal brain stem and cerebellum in most individuals, mild cerebellar vermis hypoplasia in a few
In
The gyral pattern is normal or demonstrates mildly simplified shallow sulci; a normal cortical ribbon is present.
In general, life expectancy in individuals with lissencephaly due to any cause is related to the severity of the malformation on neuroimaging [
These estimates apply only to individuals with typical lissencephaly affecting the entire brain (the large majority of those with lissencephaly);
Most individuals with a telomeric deletion including the 5' end of
The vast majority of individuals with intragenic deletions and duplications of
Most individuals with a deletion of the 3' end of
Intragenic pathogenic variants in
Intragenic pathogenic variants that predict premature termination of the PAFAH1B1 protein tend to result in a more severe lissencephaly phenotype than missense variants in
Pathogenic variants near the beginning of the gene in the coiled-coil domain that result in truncation/deletion may cause a more severe lissencephaly phenotype than similar variants that occur in other downstream regions of the gene [
Note: These generalizations notwithstanding, severity of the phenotype does not always appear to correspond to location and type of pathogenic variant, as a more severe phenotype has been observed in some individuals with pathogenic missense variants and more severe grades (2 and 3) of lissencephaly have been observed in individuals with truncation/deletion variants in the coiled-coil domain toward the 3' end of
Two
Somatic mosaicism for a
Seizures are intractable in most affected individuals and can cause regression of the developmental stage.
Classic lissencephaly from any cause is rare. Birth prevalence is estimated to range from 11.7 to 40 per million births [personal communication with Metropolitan Atlanta Congenital Defects Program Personnel, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, 2002]. Even the latter is likely to be an underestimate, as the CDC program ascertains only hospitalized children in the first several years of life.
• Epileptic encephalopathies typically evolve from infantile spasms (West syndrome) to Lennox-Gastaut syndrome of mixed epilepsy with a slow spike-and-wave pattern on EEG.
• Some children with ILS have characteristic EEG changes, including diffuse high-amplitude fast rhythms that are considered to be highly specific for this malformation [
• The developmental prognosis is poor for most individuals with ILS.
• Even with good seizure control, the best developmental level achieved (excluding the few individuals with partial lissencephaly) is the equivalent of about age three to five months.
• Affected individuals may achieve rolling over, limited creeping, and, very rarely, sitting. Few individuals have been reported to be able to walk with support.
• Visual tracking is variable among affected individuals, with a subset achieving normal visual interactions while other do not achieve visual tracking.
• With poor seizure control, children with ILS may function at or below the level of a newborn. Regression of acquired functioning due to poor seizure control has been reported [
• A few individuals with less severe (grade 4) lissencephaly (see
• Poor feeding in newborns is usually managed by nasogastric tube feedings, as the feeding problems often improve during the first weeks of life (see Management,
• However, feeding often worsens again with intercurrent illnesses and with advancing age and size. At least 50% of children with
• Individuals with low central tone frequently develop constipation; this is not specific to those with
• Diffuse
• Anterior more severe than posterior (a>p)
• Posterior more severe than anterior (p>a)
• Temporal more severe than posterior and p>a
• SBH partial
• SBH diffuse
• LIS partial pachygyria
• LIS diffuse pachygyria
• LIS agyria-pachygyria
• LIS diffuse agyria
• Simplified gyration overlying SBH
• Thin undulating
• Thin variable dysgyria
• Thin w/enlarged lateral ventricles & thin mantle
• Thick classic
• Basal ganglia dysgenesis
• Complete or partial agenesis (dysgenesis) of corpus callosum
• Tectal hyperplasia
• Brain stem hypoplasia & dysgenesis
• Cerebellar hypoplasia (either diffuse or vermis predominant)
• Enlarged lateral ventricles, especially posteriorly
• Mild hypoplasia of the corpus callosum (the anterior portion often appears flattened)
• Cavum septi pellucidi et vergae
• Normal brain stem and cerebellum in most individuals, mild cerebellar vermis hypoplasia in a few
• In
• The gyral pattern is normal or demonstrates mildly simplified shallow sulci; a normal cortical ribbon is present.
• These estimates apply only to individuals with typical lissencephaly affecting the entire brain (the large majority of those with lissencephaly);
• Most individuals with a telomeric deletion including the 5' end of
• The vast majority of individuals with intragenic deletions and duplications of
• Most individuals with a deletion of the 3' end of
• Intragenic pathogenic variants in
• Intragenic pathogenic variants that predict premature termination of the PAFAH1B1 protein tend to result in a more severe lissencephaly phenotype than missense variants in
• Pathogenic variants near the beginning of the gene in the coiled-coil domain that result in truncation/deletion may cause a more severe lissencephaly phenotype than similar variants that occur in other downstream regions of the gene [
• Intragenic pathogenic variants that predict premature termination of the PAFAH1B1 protein tend to result in a more severe lissencephaly phenotype than missense variants in
• Pathogenic variants near the beginning of the gene in the coiled-coil domain that result in truncation/deletion may cause a more severe lissencephaly phenotype than similar variants that occur in other downstream regions of the gene [
• Intragenic pathogenic variants that predict premature termination of the PAFAH1B1 protein tend to result in a more severe lissencephaly phenotype than missense variants in
• Pathogenic variants near the beginning of the gene in the coiled-coil domain that result in truncation/deletion may cause a more severe lissencephaly phenotype than similar variants that occur in other downstream regions of the gene [
• Two
• Somatic mosaicism for a
• Seizures are intractable in most affected individuals and can cause regression of the developmental stage.
## Clinical Description
Together, isolated lissencephaly sequence (ILS) and subcortical band heterotopia (SBH) comprise the "agyria-pachygyria-band" spectrum of cortical malformations that are caused by deficient neuronal migration during embryogenesis. The term lissencephaly refers to a "smooth brain" with absent (agyria) or abnormally wide gyri (pachygyria).
To date, almost 200 individuals have been identified with an intragenic pathogenic variant in
Affected newborns may appear normal or may have mild-to-moderate hypotonia, feeding difficulties, and poor head control. During the first years, neurologic examination typically demonstrates poor visual tracking and response to sounds, axial hypotonia, and mild distal spasticity. Infants often demonstrate abnormal arching (opisthotonus). Later, distal spasticity becomes more prominent, although axial hypotonia remains. Affected individuals may develop moderate spastic quadriplegia and scoliosis.
Epileptic encephalopathies typically evolve from infantile spasms (West syndrome) to Lennox-Gastaut syndrome of mixed epilepsy with a slow spike-and-wave pattern on EEG.
Some children with ILS have characteristic EEG changes, including diffuse high-amplitude fast rhythms that are considered to be highly specific for this malformation [
After the first months of life, most children have mixed seizure disorders including persisting infantile spasms, focal motor and generalized tonic seizures, and atypical absence, atonic, and myoclonic seizures [
Seizures are drug resistant in more than 65% of affected individuals. While polytherapy with lamotrigine and valproic acid can reduce the number of daily seizures effectively, two thirds of affected individuals continue to experience daily seizures [
Prior to the onset of seizures, most infants have mild delay in development and mild hypotonia.
The developmental prognosis is poor for most individuals with ILS.
Even with good seizure control, the best developmental level achieved (excluding the few individuals with partial lissencephaly) is the equivalent of about age three to five months.
Affected individuals may achieve rolling over, limited creeping, and, very rarely, sitting. Few individuals have been reported to be able to walk with support.
Visual tracking is variable among affected individuals, with a subset achieving normal visual interactions while other do not achieve visual tracking.
With poor seizure control, children with ILS may function at or below the level of a newborn. Regression of acquired functioning due to poor seizure control has been reported [
A few individuals with less severe (grade 4) lissencephaly (see
At birth, the occipitofrontal circumference is typically normal (between the mean and -2 SD). However, postnatal head growth is slow; most children develop microcephaly by age one year. The remainder of the growth parameters are often normal.
Some have difficulty with feeding, and transient elevations in bilirubin in neonates are likely related to feeding difficulties. Feeding often improves during the first few months of life, but typically worsens again with seizure onset during the first year of life, and then again at several years of age for various reasons.
Poor feeding in newborns is usually managed by nasogastric tube feedings, as the feeding problems often improve during the first weeks of life (see Management,
However, feeding often worsens again with intercurrent illnesses and with advancing age and size. At least 50% of children with
Individuals with low central tone frequently develop constipation; this is not specific to those with
Children with lissencephaly have poor control of their airway, which predisposes them to aspiration pneumonia, the most common terminal event. This is not typically seen in those with SBH.
Poor or absent visual interaction and limited visual-perceptual and eye-hand abilities have been reported in a subset of affected individuals, likely secondary to the severe cortical malformations [
In 2017, the imaging criteria for lissencephaly/SBH with a defined monogenic cause were revised. This classification system subdivides lissencephaly/SBH into 21 recurring patterns in order to aid clinicians in predicting the most likely genetic cause based on imaging features. Criteria to stratify lissencephaly/SBH are based on the anteroposterior gradient, grade of severity, cortical thickness and appearance, and associated non-cortical brain malformations [
Gradient of gyral malformation:
Diffuse
Anterior more severe than posterior (a>p)
Posterior more severe than anterior (p>a)
Temporal more severe than posterior and p>a
Grade of gyral malformation:
SBH partial
SBH diffuse
LIS partial pachygyria
LIS diffuse pachygyria
LIS agyria-pachygyria
LIS diffuse agyria
Cortical thickness & appearance:
Simplified gyration overlying SBH
Thin undulating
Thin variable dysgyria
Thin w/enlarged lateral ventricles & thin mantle
Thick classic
Non-cortical brain malformations:
Basal ganglia dysgenesis
Complete or partial agenesis (dysgenesis) of corpus callosum
Tectal hyperplasia
Brain stem hypoplasia & dysgenesis
Cerebellar hypoplasia (either diffuse or vermis predominant)
Applying the above
Clinical Severity of Lissencephaly and Subcortical Brain Heterotopia in General
a = anterior; ID = intellectual disability; LIS = lissencephaly; p = posterior; SBH = subcortical band heterotopia
Enlarged lateral ventricles, especially posteriorly
Mild hypoplasia of the corpus callosum (the anterior portion often appears flattened)
Cavum septi pellucidi et vergae
Normal brain stem and cerebellum in most individuals, mild cerebellar vermis hypoplasia in a few
In
The gyral pattern is normal or demonstrates mildly simplified shallow sulci; a normal cortical ribbon is present.
In general, life expectancy in individuals with lissencephaly due to any cause is related to the severity of the malformation on neuroimaging [
These estimates apply only to individuals with typical lissencephaly affecting the entire brain (the large majority of those with lissencephaly);
• Epileptic encephalopathies typically evolve from infantile spasms (West syndrome) to Lennox-Gastaut syndrome of mixed epilepsy with a slow spike-and-wave pattern on EEG.
• Some children with ILS have characteristic EEG changes, including diffuse high-amplitude fast rhythms that are considered to be highly specific for this malformation [
• The developmental prognosis is poor for most individuals with ILS.
• Even with good seizure control, the best developmental level achieved (excluding the few individuals with partial lissencephaly) is the equivalent of about age three to five months.
• Affected individuals may achieve rolling over, limited creeping, and, very rarely, sitting. Few individuals have been reported to be able to walk with support.
• Visual tracking is variable among affected individuals, with a subset achieving normal visual interactions while other do not achieve visual tracking.
• With poor seizure control, children with ILS may function at or below the level of a newborn. Regression of acquired functioning due to poor seizure control has been reported [
• A few individuals with less severe (grade 4) lissencephaly (see
• Poor feeding in newborns is usually managed by nasogastric tube feedings, as the feeding problems often improve during the first weeks of life (see Management,
• However, feeding often worsens again with intercurrent illnesses and with advancing age and size. At least 50% of children with
• Individuals with low central tone frequently develop constipation; this is not specific to those with
• Diffuse
• Anterior more severe than posterior (a>p)
• Posterior more severe than anterior (p>a)
• Temporal more severe than posterior and p>a
• SBH partial
• SBH diffuse
• LIS partial pachygyria
• LIS diffuse pachygyria
• LIS agyria-pachygyria
• LIS diffuse agyria
• Simplified gyration overlying SBH
• Thin undulating
• Thin variable dysgyria
• Thin w/enlarged lateral ventricles & thin mantle
• Thick classic
• Basal ganglia dysgenesis
• Complete or partial agenesis (dysgenesis) of corpus callosum
• Tectal hyperplasia
• Brain stem hypoplasia & dysgenesis
• Cerebellar hypoplasia (either diffuse or vermis predominant)
• Enlarged lateral ventricles, especially posteriorly
• Mild hypoplasia of the corpus callosum (the anterior portion often appears flattened)
• Cavum septi pellucidi et vergae
• Normal brain stem and cerebellum in most individuals, mild cerebellar vermis hypoplasia in a few
• In
• The gyral pattern is normal or demonstrates mildly simplified shallow sulci; a normal cortical ribbon is present.
• These estimates apply only to individuals with typical lissencephaly affecting the entire brain (the large majority of those with lissencephaly);
## Neurologic
Affected newborns may appear normal or may have mild-to-moderate hypotonia, feeding difficulties, and poor head control. During the first years, neurologic examination typically demonstrates poor visual tracking and response to sounds, axial hypotonia, and mild distal spasticity. Infants often demonstrate abnormal arching (opisthotonus). Later, distal spasticity becomes more prominent, although axial hypotonia remains. Affected individuals may develop moderate spastic quadriplegia and scoliosis.
Epileptic encephalopathies typically evolve from infantile spasms (West syndrome) to Lennox-Gastaut syndrome of mixed epilepsy with a slow spike-and-wave pattern on EEG.
Some children with ILS have characteristic EEG changes, including diffuse high-amplitude fast rhythms that are considered to be highly specific for this malformation [
After the first months of life, most children have mixed seizure disorders including persisting infantile spasms, focal motor and generalized tonic seizures, and atypical absence, atonic, and myoclonic seizures [
Seizures are drug resistant in more than 65% of affected individuals. While polytherapy with lamotrigine and valproic acid can reduce the number of daily seizures effectively, two thirds of affected individuals continue to experience daily seizures [
• Epileptic encephalopathies typically evolve from infantile spasms (West syndrome) to Lennox-Gastaut syndrome of mixed epilepsy with a slow spike-and-wave pattern on EEG.
• Some children with ILS have characteristic EEG changes, including diffuse high-amplitude fast rhythms that are considered to be highly specific for this malformation [
## Neurodevelopment
Prior to the onset of seizures, most infants have mild delay in development and mild hypotonia.
The developmental prognosis is poor for most individuals with ILS.
Even with good seizure control, the best developmental level achieved (excluding the few individuals with partial lissencephaly) is the equivalent of about age three to five months.
Affected individuals may achieve rolling over, limited creeping, and, very rarely, sitting. Few individuals have been reported to be able to walk with support.
Visual tracking is variable among affected individuals, with a subset achieving normal visual interactions while other do not achieve visual tracking.
With poor seizure control, children with ILS may function at or below the level of a newborn. Regression of acquired functioning due to poor seizure control has been reported [
A few individuals with less severe (grade 4) lissencephaly (see
• The developmental prognosis is poor for most individuals with ILS.
• Even with good seizure control, the best developmental level achieved (excluding the few individuals with partial lissencephaly) is the equivalent of about age three to five months.
• Affected individuals may achieve rolling over, limited creeping, and, very rarely, sitting. Few individuals have been reported to be able to walk with support.
• Visual tracking is variable among affected individuals, with a subset achieving normal visual interactions while other do not achieve visual tracking.
• With poor seizure control, children with ILS may function at or below the level of a newborn. Regression of acquired functioning due to poor seizure control has been reported [
• A few individuals with less severe (grade 4) lissencephaly (see
## Growth
At birth, the occipitofrontal circumference is typically normal (between the mean and -2 SD). However, postnatal head growth is slow; most children develop microcephaly by age one year. The remainder of the growth parameters are often normal.
## Feeding
Some have difficulty with feeding, and transient elevations in bilirubin in neonates are likely related to feeding difficulties. Feeding often improves during the first few months of life, but typically worsens again with seizure onset during the first year of life, and then again at several years of age for various reasons.
Poor feeding in newborns is usually managed by nasogastric tube feedings, as the feeding problems often improve during the first weeks of life (see Management,
However, feeding often worsens again with intercurrent illnesses and with advancing age and size. At least 50% of children with
Individuals with low central tone frequently develop constipation; this is not specific to those with
• Poor feeding in newborns is usually managed by nasogastric tube feedings, as the feeding problems often improve during the first weeks of life (see Management,
• However, feeding often worsens again with intercurrent illnesses and with advancing age and size. At least 50% of children with
• Individuals with low central tone frequently develop constipation; this is not specific to those with
## Respiratory
Children with lissencephaly have poor control of their airway, which predisposes them to aspiration pneumonia, the most common terminal event. This is not typically seen in those with SBH.
## Visual Impairment
Poor or absent visual interaction and limited visual-perceptual and eye-hand abilities have been reported in a subset of affected individuals, likely secondary to the severe cortical malformations [
## Neuroimaging
In 2017, the imaging criteria for lissencephaly/SBH with a defined monogenic cause were revised. This classification system subdivides lissencephaly/SBH into 21 recurring patterns in order to aid clinicians in predicting the most likely genetic cause based on imaging features. Criteria to stratify lissencephaly/SBH are based on the anteroposterior gradient, grade of severity, cortical thickness and appearance, and associated non-cortical brain malformations [
Gradient of gyral malformation:
Diffuse
Anterior more severe than posterior (a>p)
Posterior more severe than anterior (p>a)
Temporal more severe than posterior and p>a
Grade of gyral malformation:
SBH partial
SBH diffuse
LIS partial pachygyria
LIS diffuse pachygyria
LIS agyria-pachygyria
LIS diffuse agyria
Cortical thickness & appearance:
Simplified gyration overlying SBH
Thin undulating
Thin variable dysgyria
Thin w/enlarged lateral ventricles & thin mantle
Thick classic
Non-cortical brain malformations:
Basal ganglia dysgenesis
Complete or partial agenesis (dysgenesis) of corpus callosum
Tectal hyperplasia
Brain stem hypoplasia & dysgenesis
Cerebellar hypoplasia (either diffuse or vermis predominant)
Applying the above
Clinical Severity of Lissencephaly and Subcortical Brain Heterotopia in General
a = anterior; ID = intellectual disability; LIS = lissencephaly; p = posterior; SBH = subcortical band heterotopia
Enlarged lateral ventricles, especially posteriorly
Mild hypoplasia of the corpus callosum (the anterior portion often appears flattened)
Cavum septi pellucidi et vergae
Normal brain stem and cerebellum in most individuals, mild cerebellar vermis hypoplasia in a few
In
The gyral pattern is normal or demonstrates mildly simplified shallow sulci; a normal cortical ribbon is present.
• Diffuse
• Anterior more severe than posterior (a>p)
• Posterior more severe than anterior (p>a)
• Temporal more severe than posterior and p>a
• SBH partial
• SBH diffuse
• LIS partial pachygyria
• LIS diffuse pachygyria
• LIS agyria-pachygyria
• LIS diffuse agyria
• Simplified gyration overlying SBH
• Thin undulating
• Thin variable dysgyria
• Thin w/enlarged lateral ventricles & thin mantle
• Thick classic
• Basal ganglia dysgenesis
• Complete or partial agenesis (dysgenesis) of corpus callosum
• Tectal hyperplasia
• Brain stem hypoplasia & dysgenesis
• Cerebellar hypoplasia (either diffuse or vermis predominant)
• Enlarged lateral ventricles, especially posteriorly
• Mild hypoplasia of the corpus callosum (the anterior portion often appears flattened)
• Cavum septi pellucidi et vergae
• Normal brain stem and cerebellum in most individuals, mild cerebellar vermis hypoplasia in a few
• In
• The gyral pattern is normal or demonstrates mildly simplified shallow sulci; a normal cortical ribbon is present.
## Prognosis
In general, life expectancy in individuals with lissencephaly due to any cause is related to the severity of the malformation on neuroimaging [
These estimates apply only to individuals with typical lissencephaly affecting the entire brain (the large majority of those with lissencephaly);
• These estimates apply only to individuals with typical lissencephaly affecting the entire brain (the large majority of those with lissencephaly);
## Genotype-Phenotype Correlations
Most individuals with a telomeric deletion including the 5' end of
The vast majority of individuals with intragenic deletions and duplications of
Most individuals with a deletion of the 3' end of
Intragenic pathogenic variants in
Intragenic pathogenic variants that predict premature termination of the PAFAH1B1 protein tend to result in a more severe lissencephaly phenotype than missense variants in
Pathogenic variants near the beginning of the gene in the coiled-coil domain that result in truncation/deletion may cause a more severe lissencephaly phenotype than similar variants that occur in other downstream regions of the gene [
Note: These generalizations notwithstanding, severity of the phenotype does not always appear to correspond to location and type of pathogenic variant, as a more severe phenotype has been observed in some individuals with pathogenic missense variants and more severe grades (2 and 3) of lissencephaly have been observed in individuals with truncation/deletion variants in the coiled-coil domain toward the 3' end of
Two
Somatic mosaicism for a
Seizures are intractable in most affected individuals and can cause regression of the developmental stage.
• Most individuals with a telomeric deletion including the 5' end of
• The vast majority of individuals with intragenic deletions and duplications of
• Most individuals with a deletion of the 3' end of
• Intragenic pathogenic variants in
• Intragenic pathogenic variants that predict premature termination of the PAFAH1B1 protein tend to result in a more severe lissencephaly phenotype than missense variants in
• Pathogenic variants near the beginning of the gene in the coiled-coil domain that result in truncation/deletion may cause a more severe lissencephaly phenotype than similar variants that occur in other downstream regions of the gene [
• Intragenic pathogenic variants that predict premature termination of the PAFAH1B1 protein tend to result in a more severe lissencephaly phenotype than missense variants in
• Pathogenic variants near the beginning of the gene in the coiled-coil domain that result in truncation/deletion may cause a more severe lissencephaly phenotype than similar variants that occur in other downstream regions of the gene [
• Intragenic pathogenic variants that predict premature termination of the PAFAH1B1 protein tend to result in a more severe lissencephaly phenotype than missense variants in
• Pathogenic variants near the beginning of the gene in the coiled-coil domain that result in truncation/deletion may cause a more severe lissencephaly phenotype than similar variants that occur in other downstream regions of the gene [
• Two
• Somatic mosaicism for a
• Seizures are intractable in most affected individuals and can cause regression of the developmental stage.
## Prevalence
Classic lissencephaly from any cause is rare. Birth prevalence is estimated to range from 11.7 to 40 per million births [personal communication with Metropolitan Atlanta Congenital Defects Program Personnel, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, 2002]. Even the latter is likely to be an underestimate, as the CDC program ascertains only hospitalized children in the first several years of life.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Affected individuals typically have severe lissencephaly (grade 1-2) (see
The developmental prognosis is poor for all children with MDS. Death occurs within the first two years in many children, and only a few reach age ten years. The oldest known individual with MDS died at age 17 years.
## Differential Diagnosis
The greatest difficulty in the diagnosis of lissencephaly and subcortical band heterotopia (SBH) is recognizing the malformation. Lissencephaly is subdivided into several types depending on gradient and grade of gyral malformation and cortical thickness [
Several different cortical malformations that are sometimes mistaken for lissencephaly have been described, including severe congenital microcephaly with reduced number of gyri, cobblestone malformations as seen in Walker-Warburg and other syndromes, polymicrogyria, and polymicrogyria-like variants associated with pathogenic variants of tubulin genes. This leads to inefficient molecular testing and incorrect diagnosis and counseling.
Clinical features can help distinguish children who have lissencephaly from those who have other brain malformations. Children with lissencephaly usually have normal or slightly small OFC at birth (>-3 SD) and diffuse hypotonia except for mildly increased tone at the wrists and ankles. Children with severe congenital (i.e., primary) microcephaly and gyral abnormalities have smaller birth OFC (≤-3 SD) and may be hypotonic or spastic. Infants with polymicrogyria, especially when the frontal lobes are involved, frequently have spastic quadriparesis. Brain imaging (preferably by MRI) and/or neuropathologic examination during autopsy is necessary to confirm a diagnosis of lissencephaly.
The differential diagnosis of classic lissencephaly is summarized in
Genes of Interest in the Differential Diagnosis of Classic Lissencephaly
a = anterior; AD = autosomal dominant; AR = autosomal recessive; CC = corpus callosum, DD = developmental delay; ID = intellectual disability; LIS = lissencephaly; MOI = mode of inheritance; NA = not available; p = posterior; SBH = subcortical band heterotopia; SGP = simplified gyral pattern
See Clinical Description,
In severe classic lissencephaly or SBH the gradient may be difficult to discern.
Topic of this
Lissencephaly with agenesis of the corpus callosum is typically associated with pathogenic variants in
Females who are heterozygous for an
Cortical malformations resembling lissencephaly and caused by mutation of an α-tubulin (
The cobblestone cortical malformation (lissencephaly) syndromes (Walker-Warburg syndrome, muscle-eye-brain disease, and
## Classic Lissencephaly
The differential diagnosis of classic lissencephaly is summarized in
Genes of Interest in the Differential Diagnosis of Classic Lissencephaly
a = anterior; AD = autosomal dominant; AR = autosomal recessive; CC = corpus callosum, DD = developmental delay; ID = intellectual disability; LIS = lissencephaly; MOI = mode of inheritance; NA = not available; p = posterior; SBH = subcortical band heterotopia; SGP = simplified gyral pattern
See Clinical Description,
In severe classic lissencephaly or SBH the gradient may be difficult to discern.
Topic of this
## Lissencephaly with Agenesis of the Corpus Callosum
Lissencephaly with agenesis of the corpus callosum is typically associated with pathogenic variants in
Females who are heterozygous for an
## Tubulin-Related Dysgyria
Cortical malformations resembling lissencephaly and caused by mutation of an α-tubulin (
## Cobblestone Cortical Malformation (Lissencephaly) Syndromes
The cobblestone cortical malformation (lissencephaly) syndromes (Walker-Warburg syndrome, muscle-eye-brain disease, and
## Management
No consensus management recommendations for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
To incl brain MRI
Consider EEG if seizures are a concern.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Community or online
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; EEG = electroencephalogram; OT = occupational therapy; PT = physical therapy
Brain MRI should be interpreted carefully to provide as much prognostic information as possible. Although most affected individuals have severe-to-profound intellectual disability, a minority have less extensive lissencephaly that results in moderate intellectual disability, and a few have limited malformations that allow near-normal development. In the latter, the lissencephaly or SBH is typically less severe and less extensive on MRI. The resolution of brain CT scan is usually not sufficient to make this distinction.
Although ophthalmologic issues are not a primary feature of
Although hearing loss is not a primary feature of
Parents seem best able to deal with this severe disorder when accurate information regarding the prognosis is given as soon as possible after the diagnosis is recognized. For those with severe lissencephaly, it is usually appropriate to discuss limitations of care, such as "do not resuscitate" orders, in the event of severe illnesses.
Treatment of Manifestations in Individuals with
A large majority of affected persons have seizures, incl frequent infantile spasms, which can be difficult to control.
Polytherapy w/valproic acid & lamotrigine appears most effective in ↓ drug-resistant seizures, but 2/3 of affected persons continue to have daily seizures.
Treat seizures promptly & aggressively, as poor seizure control frequently results in ↓ in function & health.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding &/or respiratory issues.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ASM = anti-seizure medication; DD = developmental delay; FTT = failure to thrive; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
Poor seizure control worsens feeding (increasing the likelihood that a gastrostomy tube will be needed) and increases the risk for pneumonia. Overall development can be delayed or impaired through uncontrolled seizures.
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Recommended Surveillance for Individuals with
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations incl unusual spells or developmental regression.
OT = occupational therapy; PT = physical therapy
If present, a neurology consultation should be performed and an EEG considered.
See
Search
• To incl brain MRI
• Consider EEG if seizures are a concern.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Community or online
• Social work involvement for parental support;
• Home nursing referral.
• A large majority of affected persons have seizures, incl frequent infantile spasms, which can be difficult to control.
• Polytherapy w/valproic acid & lamotrigine appears most effective in ↓ drug-resistant seizures, but 2/3 of affected persons continue to have daily seizures.
• Treat seizures promptly & aggressively, as poor seizure control frequently results in ↓ in function & health.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding &/or respiratory issues.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations incl unusual spells or developmental regression.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
To incl brain MRI
Consider EEG if seizures are a concern.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Community or online
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; EEG = electroencephalogram; OT = occupational therapy; PT = physical therapy
Brain MRI should be interpreted carefully to provide as much prognostic information as possible. Although most affected individuals have severe-to-profound intellectual disability, a minority have less extensive lissencephaly that results in moderate intellectual disability, and a few have limited malformations that allow near-normal development. In the latter, the lissencephaly or SBH is typically less severe and less extensive on MRI. The resolution of brain CT scan is usually not sufficient to make this distinction.
Although ophthalmologic issues are not a primary feature of
Although hearing loss is not a primary feature of
• To incl brain MRI
• Consider EEG if seizures are a concern.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Community or online
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Parents seem best able to deal with this severe disorder when accurate information regarding the prognosis is given as soon as possible after the diagnosis is recognized. For those with severe lissencephaly, it is usually appropriate to discuss limitations of care, such as "do not resuscitate" orders, in the event of severe illnesses.
Treatment of Manifestations in Individuals with
A large majority of affected persons have seizures, incl frequent infantile spasms, which can be difficult to control.
Polytherapy w/valproic acid & lamotrigine appears most effective in ↓ drug-resistant seizures, but 2/3 of affected persons continue to have daily seizures.
Treat seizures promptly & aggressively, as poor seizure control frequently results in ↓ in function & health.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding &/or respiratory issues.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ASM = anti-seizure medication; DD = developmental delay; FTT = failure to thrive; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
Poor seizure control worsens feeding (increasing the likelihood that a gastrostomy tube will be needed) and increases the risk for pneumonia. Overall development can be delayed or impaired through uncontrolled seizures.
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• A large majority of affected persons have seizures, incl frequent infantile spasms, which can be difficult to control.
• Polytherapy w/valproic acid & lamotrigine appears most effective in ↓ drug-resistant seizures, but 2/3 of affected persons continue to have daily seizures.
• Treat seizures promptly & aggressively, as poor seizure control frequently results in ↓ in function & health.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding &/or respiratory issues.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Surveillance
Recommended Surveillance for Individuals with
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations incl unusual spells or developmental regression.
OT = occupational therapy; PT = physical therapy
If present, a neurology consultation should be performed and an EEG considered.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations incl unusual spells or developmental regression.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Note: Genetic counseling for the families of individuals diagnosed with Miller-Dieker syndrome is not addressed in this section (see
Individuals diagnosed with isolated
In rare families, an individual with
A boy with ILS (with posterior more severe than anterior gradient) and epilepsy inherited a
Two girls with severe intellectual disability, epilepsy, and anterior-predominant lissencephaly and calcifications of the basal ganglia were born to a mother also presenting with anterior-predominant lissencephaly (the affected daughters and their mother were all heterozygous for the same missense variant in
A boy who presented with ILS/SBH inherited a
Molecular genetic testing for the intragenic
If the genetic alteration identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
* If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic and germline mosaicism for the variant and may be mildly affected [
If a parent of the proband is known to have the intragenic
If a parent of the proband has a structural chromosome rearrangement involving
If the proband has a known
If the parents have not been tested for the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Individuals diagnosed with isolated
• In rare families, an individual with
• A boy with ILS (with posterior more severe than anterior gradient) and epilepsy inherited a
• Two girls with severe intellectual disability, epilepsy, and anterior-predominant lissencephaly and calcifications of the basal ganglia were born to a mother also presenting with anterior-predominant lissencephaly (the affected daughters and their mother were all heterozygous for the same missense variant in
• A boy who presented with ILS/SBH inherited a
• A boy with ILS (with posterior more severe than anterior gradient) and epilepsy inherited a
• Two girls with severe intellectual disability, epilepsy, and anterior-predominant lissencephaly and calcifications of the basal ganglia were born to a mother also presenting with anterior-predominant lissencephaly (the affected daughters and their mother were all heterozygous for the same missense variant in
• A boy who presented with ILS/SBH inherited a
• Molecular genetic testing for the intragenic
• If the genetic alteration identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic and germline mosaicism for the variant and may be mildly affected [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic and germline mosaicism for the variant and may be mildly affected [
• A boy with ILS (with posterior more severe than anterior gradient) and epilepsy inherited a
• Two girls with severe intellectual disability, epilepsy, and anterior-predominant lissencephaly and calcifications of the basal ganglia were born to a mother also presenting with anterior-predominant lissencephaly (the affected daughters and their mother were all heterozygous for the same missense variant in
• A boy who presented with ILS/SBH inherited a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic and germline mosaicism for the variant and may be mildly affected [
• If a parent of the proband is known to have the intragenic
• If a parent of the proband has a structural chromosome rearrangement involving
• If the proband has a known
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Note: Genetic counseling for the families of individuals diagnosed with Miller-Dieker syndrome is not addressed in this section (see
## Risk to Family Members
Individuals diagnosed with isolated
In rare families, an individual with
A boy with ILS (with posterior more severe than anterior gradient) and epilepsy inherited a
Two girls with severe intellectual disability, epilepsy, and anterior-predominant lissencephaly and calcifications of the basal ganglia were born to a mother also presenting with anterior-predominant lissencephaly (the affected daughters and their mother were all heterozygous for the same missense variant in
A boy who presented with ILS/SBH inherited a
Molecular genetic testing for the intragenic
If the genetic alteration identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
* If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic and germline mosaicism for the variant and may be mildly affected [
If a parent of the proband is known to have the intragenic
If a parent of the proband has a structural chromosome rearrangement involving
If the proband has a known
If the parents have not been tested for the
• Individuals diagnosed with isolated
• In rare families, an individual with
• A boy with ILS (with posterior more severe than anterior gradient) and epilepsy inherited a
• Two girls with severe intellectual disability, epilepsy, and anterior-predominant lissencephaly and calcifications of the basal ganglia were born to a mother also presenting with anterior-predominant lissencephaly (the affected daughters and their mother were all heterozygous for the same missense variant in
• A boy who presented with ILS/SBH inherited a
• A boy with ILS (with posterior more severe than anterior gradient) and epilepsy inherited a
• Two girls with severe intellectual disability, epilepsy, and anterior-predominant lissencephaly and calcifications of the basal ganglia were born to a mother also presenting with anterior-predominant lissencephaly (the affected daughters and their mother were all heterozygous for the same missense variant in
• A boy who presented with ILS/SBH inherited a
• Molecular genetic testing for the intragenic
• If the genetic alteration identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic and germline mosaicism for the variant and may be mildly affected [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic and germline mosaicism for the variant and may be mildly affected [
• A boy with ILS (with posterior more severe than anterior gradient) and epilepsy inherited a
• Two girls with severe intellectual disability, epilepsy, and anterior-predominant lissencephaly and calcifications of the basal ganglia were born to a mother also presenting with anterior-predominant lissencephaly (the affected daughters and their mother were all heterozygous for the same missense variant in
• A boy who presented with ILS/SBH inherited a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic and germline mosaicism for the variant and may be mildly affected [
• If a parent of the proband is known to have the intragenic
• If a parent of the proband has a structural chromosome rearrangement involving
• If the proband has a known
• If the parents have not been tested for the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
PO Box 5801
Bethesda MD 20824
•
• PO Box 5801
• Bethesda MD 20824
•
•
•
•
•
## Molecular Genetics
PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia (
Platelet-activating factor acetylhydrolase IB subunit alpha (PAFAH1B1) is highly conserved among species. The main functional domains of this protein are a LisH motif at the N terminus and a coiled-coil region, which are important for protein dimerization. Seven WD40 repeats at the C terminus are necessary for protein-protein interactions [
The PAFAH1B1 protein has several functions. PAFAH1B1 forms a trimeric complex with the PAFAH1B2 and PAFAH1B3 proteins to regulate the level of platelet-activating factor in the brain [
Proliferation of neuronal progenitors and astrocytes has been shown to be impaired in individuals with pathogenic variants in
## Molecular Pathogenesis
Platelet-activating factor acetylhydrolase IB subunit alpha (PAFAH1B1) is highly conserved among species. The main functional domains of this protein are a LisH motif at the N terminus and a coiled-coil region, which are important for protein dimerization. Seven WD40 repeats at the C terminus are necessary for protein-protein interactions [
The PAFAH1B1 protein has several functions. PAFAH1B1 forms a trimeric complex with the PAFAH1B2 and PAFAH1B3 proteins to regulate the level of platelet-activating factor in the brain [
Proliferation of neuronal progenitors and astrocytes has been shown to be impaired in individuals with pathogenic variants in
## Chapter Notes
Stefanie Brock:
William B Dobyns:
Anna Jansen:
Stefanie Brock, MD (2021-present)Soma Das, PhD; University of Chicago (2009-2021)William B Dobyns, MD (2009-present)Anna Jansen, MD, PhD (2021-present)
25 March 2021 (ma) Comprehensive update posted live
14 August 2014 (me) Comprehensive update posted live
3 March 2009 (me) Review posted live
22 August 2008 (wd) Original submission
• 25 March 2021 (ma) Comprehensive update posted live
• 14 August 2014 (me) Comprehensive update posted live
• 3 March 2009 (me) Review posted live
• 22 August 2008 (wd) Original submission
## Author Notes
Stefanie Brock:
William B Dobyns:
Anna Jansen:
## Author History
Stefanie Brock, MD (2021-present)Soma Das, PhD; University of Chicago (2009-2021)William B Dobyns, MD (2009-present)Anna Jansen, MD, PhD (2021-present)
## Revision History
25 March 2021 (ma) Comprehensive update posted live
14 August 2014 (me) Comprehensive update posted live
3 March 2009 (me) Review posted live
22 August 2008 (wd) Original submission
• 25 March 2021 (ma) Comprehensive update posted live
• 14 August 2014 (me) Comprehensive update posted live
• 3 March 2009 (me) Review posted live
• 22 August 2008 (wd) Original submission
## References
## Literature Cited
Left panel – axial T
|
[] |
3/3/2009
|
25/3/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
cip-overview
|
cip-overview
|
[
"Beta-nerve growth factor",
"Clathrin heavy chain 2",
"High affinity nerve growth factor receptor",
"PR domain zinc finger protein 12",
"Sodium channel protein type 11 subunit alpha",
"Sodium channel protein type 9 subunit alpha",
"Zinc finger homeobox protein 2",
"CLTCL1",
"NGF",
"NTRK1",
"PRDM12",
"SCN11A",
"SCN9A",
"ZFHX2",
"Congenital Insensitivity to Pain Overview",
"Overview"
] |
Congenital Insensitivity to Pain Overview
|
Katherine Rose Schon, Alasdair Patrick John Parker, Christopher Geoffrey Woods
|
Summary The purpose of this overview is to: Describe the Review the Provide an Provide a brief summary of Inform
|
## Clinical Characteristics of Congenital Insensitivity to Pain
Inability to feel pain leads to repeated injuries and prevents normal healing.
Self-mutilating injuries of the fingers (biting off fingertips) and oral cavity such as loss of the tongue tip, injuries to the inside of the teeth/gums, and avulsion of teeth are common (
Cuts and bruises may be present.
Burns due to impaired temperature sensation [
Recurrent otitis media may be due to selectively reduced immunity to
Note: (1) Affected individuals may be able to differentiate large temperature changes, but are unable to sense if something is too hot or too cold. (2) A significant number of parents of affected children are suspected of physically abusing their child due to the nature of these injuries [Author, personal observation].
Painless fractures and joint damage frequently occur and can lead to permanent damage.
Bony deformities due to past fractures can occur.
Charcot joints (neuropathic arthropathy), most commonly of the ankles, hips, and lumbar spine, are almost universal (
Charcot spine may present with progressive deformity or new motor and/or sensory deficits [
All affected individuals are at risk for corneal injuries due to absent corneal reflexes.
Permanent corneal scarring can develop and is best assessed through a slit-lamp examination. It has been observed clinically that corneal transplants have an increased risk of failure, presumably due to the lack of nociceptive innervation of the new cornea and the continuing lack of nociceptive innervation of the conjunctiva.
Emotional tearing, as opposed to pain induced tearing, is likely to be present [
Apparent selectively reduced immunity to
Some individuals have anhidrosis (lack of sweating), which disturbs thermoregulation and can lead to recurrent episodes of unexplained fever [
Marked hyperhidrosis may be seen in those affected individuals who have a heterozygous pathogenic c.2432T>C (p.Leu811Pro) variant in
Hyperpyrexia can be fatal if untreated [
Hypothermia can occur in cold conditions.
Development and intellect may be normal or delayed/disabled (see
Individuals with CIP caused by biallelic pathogenic variants in
Individuals with CIP caused by biallelic pathogenic variants in
Hyperactivity, impulsivity, and attention deficit are common in children with biallelic pathogenic variants in
Chronic anemia of unknown cause was observed in 22/28 Israeli affected individuals with congenital insensitivity to pain and anhidrosis [
A few individuals have neuropathic pain, although this does not limit activities [
There are no consensus clinical diagnostic criteria for CIP. However, a diagnosis requires visible proof of lack of nociception in a conscious individual of normal intellectual ability. In those with intellectual disability CIP may be more difficult to diagnose clinically.
Nociception is assessed by applying painful stimuli, which in people with normal nociception would be so difficult to bear that they would move the part of the body away from the stimulus and/or express discomfort. The authors have experience of children being incorrectly judged to have insensitivity to pain after an inadequately painful stimulus.
The technique should not damage/scar prior to significant pain (e.g., sternal rub, which bruises before significant pain).
Application of 5-10 kg pressure with a pen pressed onto the nail bed (the nail bed blanches for a few seconds afterward) is reliable (see
Assessment of the remainder of the peripheral and central nervous system is typically normal (touch, vibration and position sense, motor functions, and deep tendon reflexes).
Routine nerve conduction studies and electromyogram are typically normal [
For more information about autonomic function testing for
Nerve biopsy is not routinely performed in clinical practice. Skin biopsy to determine intra-epidermal nerve fiber density and autonomic innervation is performed in adults in some centers.
• Self-mutilating injuries of the fingers (biting off fingertips) and oral cavity such as loss of the tongue tip, injuries to the inside of the teeth/gums, and avulsion of teeth are common (
• Cuts and bruises may be present.
• Burns due to impaired temperature sensation [
• Recurrent otitis media may be due to selectively reduced immunity to
• Painless fractures and joint damage frequently occur and can lead to permanent damage.
• Bony deformities due to past fractures can occur.
• Charcot joints (neuropathic arthropathy), most commonly of the ankles, hips, and lumbar spine, are almost universal (
• Charcot spine may present with progressive deformity or new motor and/or sensory deficits [
• Charcot joints (neuropathic arthropathy), most commonly of the ankles, hips, and lumbar spine, are almost universal (
• Charcot spine may present with progressive deformity or new motor and/or sensory deficits [
• Charcot joints (neuropathic arthropathy), most commonly of the ankles, hips, and lumbar spine, are almost universal (
• Charcot spine may present with progressive deformity or new motor and/or sensory deficits [
• Permanent corneal scarring can develop and is best assessed through a slit-lamp examination. It has been observed clinically that corneal transplants have an increased risk of failure, presumably due to the lack of nociceptive innervation of the new cornea and the continuing lack of nociceptive innervation of the conjunctiva.
• Emotional tearing, as opposed to pain induced tearing, is likely to be present [
• Individuals with CIP caused by biallelic pathogenic variants in
• Individuals with CIP caused by biallelic pathogenic variants in
• Hyperactivity, impulsivity, and attention deficit are common in children with biallelic pathogenic variants in
• Chronic anemia of unknown cause was observed in 22/28 Israeli affected individuals with congenital insensitivity to pain and anhidrosis [
• A few individuals have neuropathic pain, although this does not limit activities [
• The technique should not damage/scar prior to significant pain (e.g., sternal rub, which bruises before significant pain).
• Application of 5-10 kg pressure with a pen pressed onto the nail bed (the nail bed blanches for a few seconds afterward) is reliable (see
## Characteristic Findings
Self-mutilating injuries of the fingers (biting off fingertips) and oral cavity such as loss of the tongue tip, injuries to the inside of the teeth/gums, and avulsion of teeth are common (
Cuts and bruises may be present.
Burns due to impaired temperature sensation [
Recurrent otitis media may be due to selectively reduced immunity to
Note: (1) Affected individuals may be able to differentiate large temperature changes, but are unable to sense if something is too hot or too cold. (2) A significant number of parents of affected children are suspected of physically abusing their child due to the nature of these injuries [Author, personal observation].
Painless fractures and joint damage frequently occur and can lead to permanent damage.
Bony deformities due to past fractures can occur.
Charcot joints (neuropathic arthropathy), most commonly of the ankles, hips, and lumbar spine, are almost universal (
Charcot spine may present with progressive deformity or new motor and/or sensory deficits [
All affected individuals are at risk for corneal injuries due to absent corneal reflexes.
Permanent corneal scarring can develop and is best assessed through a slit-lamp examination. It has been observed clinically that corneal transplants have an increased risk of failure, presumably due to the lack of nociceptive innervation of the new cornea and the continuing lack of nociceptive innervation of the conjunctiva.
Emotional tearing, as opposed to pain induced tearing, is likely to be present [
Apparent selectively reduced immunity to
Some individuals have anhidrosis (lack of sweating), which disturbs thermoregulation and can lead to recurrent episodes of unexplained fever [
Marked hyperhidrosis may be seen in those affected individuals who have a heterozygous pathogenic c.2432T>C (p.Leu811Pro) variant in
Hyperpyrexia can be fatal if untreated [
Hypothermia can occur in cold conditions.
Development and intellect may be normal or delayed/disabled (see
Individuals with CIP caused by biallelic pathogenic variants in
Individuals with CIP caused by biallelic pathogenic variants in
Hyperactivity, impulsivity, and attention deficit are common in children with biallelic pathogenic variants in
Chronic anemia of unknown cause was observed in 22/28 Israeli affected individuals with congenital insensitivity to pain and anhidrosis [
A few individuals have neuropathic pain, although this does not limit activities [
• Self-mutilating injuries of the fingers (biting off fingertips) and oral cavity such as loss of the tongue tip, injuries to the inside of the teeth/gums, and avulsion of teeth are common (
• Cuts and bruises may be present.
• Burns due to impaired temperature sensation [
• Recurrent otitis media may be due to selectively reduced immunity to
• Painless fractures and joint damage frequently occur and can lead to permanent damage.
• Bony deformities due to past fractures can occur.
• Charcot joints (neuropathic arthropathy), most commonly of the ankles, hips, and lumbar spine, are almost universal (
• Charcot spine may present with progressive deformity or new motor and/or sensory deficits [
• Charcot joints (neuropathic arthropathy), most commonly of the ankles, hips, and lumbar spine, are almost universal (
• Charcot spine may present with progressive deformity or new motor and/or sensory deficits [
• Charcot joints (neuropathic arthropathy), most commonly of the ankles, hips, and lumbar spine, are almost universal (
• Charcot spine may present with progressive deformity or new motor and/or sensory deficits [
• Permanent corneal scarring can develop and is best assessed through a slit-lamp examination. It has been observed clinically that corneal transplants have an increased risk of failure, presumably due to the lack of nociceptive innervation of the new cornea and the continuing lack of nociceptive innervation of the conjunctiva.
• Emotional tearing, as opposed to pain induced tearing, is likely to be present [
• Individuals with CIP caused by biallelic pathogenic variants in
• Individuals with CIP caused by biallelic pathogenic variants in
• Hyperactivity, impulsivity, and attention deficit are common in children with biallelic pathogenic variants in
• Chronic anemia of unknown cause was observed in 22/28 Israeli affected individuals with congenital insensitivity to pain and anhidrosis [
• A few individuals have neuropathic pain, although this does not limit activities [
## Age-Related
Self-mutilating injuries of the fingers (biting off fingertips) and oral cavity such as loss of the tongue tip, injuries to the inside of the teeth/gums, and avulsion of teeth are common (
Cuts and bruises may be present.
Burns due to impaired temperature sensation [
Recurrent otitis media may be due to selectively reduced immunity to
Note: (1) Affected individuals may be able to differentiate large temperature changes, but are unable to sense if something is too hot or too cold. (2) A significant number of parents of affected children are suspected of physically abusing their child due to the nature of these injuries [Author, personal observation].
Painless fractures and joint damage frequently occur and can lead to permanent damage.
Bony deformities due to past fractures can occur.
Charcot joints (neuropathic arthropathy), most commonly of the ankles, hips, and lumbar spine, are almost universal (
Charcot spine may present with progressive deformity or new motor and/or sensory deficits [
• Self-mutilating injuries of the fingers (biting off fingertips) and oral cavity such as loss of the tongue tip, injuries to the inside of the teeth/gums, and avulsion of teeth are common (
• Cuts and bruises may be present.
• Burns due to impaired temperature sensation [
• Recurrent otitis media may be due to selectively reduced immunity to
• Painless fractures and joint damage frequently occur and can lead to permanent damage.
• Bony deformities due to past fractures can occur.
• Charcot joints (neuropathic arthropathy), most commonly of the ankles, hips, and lumbar spine, are almost universal (
• Charcot spine may present with progressive deformity or new motor and/or sensory deficits [
• Charcot joints (neuropathic arthropathy), most commonly of the ankles, hips, and lumbar spine, are almost universal (
• Charcot spine may present with progressive deformity or new motor and/or sensory deficits [
• Charcot joints (neuropathic arthropathy), most commonly of the ankles, hips, and lumbar spine, are almost universal (
• Charcot spine may present with progressive deformity or new motor and/or sensory deficits [
## Eyes
All affected individuals are at risk for corneal injuries due to absent corneal reflexes.
Permanent corneal scarring can develop and is best assessed through a slit-lamp examination. It has been observed clinically that corneal transplants have an increased risk of failure, presumably due to the lack of nociceptive innervation of the new cornea and the continuing lack of nociceptive innervation of the conjunctiva.
Emotional tearing, as opposed to pain induced tearing, is likely to be present [
• Permanent corneal scarring can develop and is best assessed through a slit-lamp examination. It has been observed clinically that corneal transplants have an increased risk of failure, presumably due to the lack of nociceptive innervation of the new cornea and the continuing lack of nociceptive innervation of the conjunctiva.
• Emotional tearing, as opposed to pain induced tearing, is likely to be present [
## Infections
Apparent selectively reduced immunity to
## Temperature Regulation, Anhidrosis, and Hyperhidrosis
Some individuals have anhidrosis (lack of sweating), which disturbs thermoregulation and can lead to recurrent episodes of unexplained fever [
Marked hyperhidrosis may be seen in those affected individuals who have a heterozygous pathogenic c.2432T>C (p.Leu811Pro) variant in
Hyperpyrexia can be fatal if untreated [
Hypothermia can occur in cold conditions.
## Development and Intellect
Development and intellect may be normal or delayed/disabled (see
Individuals with CIP caused by biallelic pathogenic variants in
Individuals with CIP caused by biallelic pathogenic variants in
Hyperactivity, impulsivity, and attention deficit are common in children with biallelic pathogenic variants in
• Individuals with CIP caused by biallelic pathogenic variants in
• Individuals with CIP caused by biallelic pathogenic variants in
• Hyperactivity, impulsivity, and attention deficit are common in children with biallelic pathogenic variants in
## Other
Chronic anemia of unknown cause was observed in 22/28 Israeli affected individuals with congenital insensitivity to pain and anhidrosis [
A few individuals have neuropathic pain, although this does not limit activities [
• Chronic anemia of unknown cause was observed in 22/28 Israeli affected individuals with congenital insensitivity to pain and anhidrosis [
• A few individuals have neuropathic pain, although this does not limit activities [
## Establishing the Clinical Diagnosis of Congenital Insensitivity to Pain
There are no consensus clinical diagnostic criteria for CIP. However, a diagnosis requires visible proof of lack of nociception in a conscious individual of normal intellectual ability. In those with intellectual disability CIP may be more difficult to diagnose clinically.
Nociception is assessed by applying painful stimuli, which in people with normal nociception would be so difficult to bear that they would move the part of the body away from the stimulus and/or express discomfort. The authors have experience of children being incorrectly judged to have insensitivity to pain after an inadequately painful stimulus.
The technique should not damage/scar prior to significant pain (e.g., sternal rub, which bruises before significant pain).
Application of 5-10 kg pressure with a pen pressed onto the nail bed (the nail bed blanches for a few seconds afterward) is reliable (see
Assessment of the remainder of the peripheral and central nervous system is typically normal (touch, vibration and position sense, motor functions, and deep tendon reflexes).
Routine nerve conduction studies and electromyogram are typically normal [
For more information about autonomic function testing for
Nerve biopsy is not routinely performed in clinical practice. Skin biopsy to determine intra-epidermal nerve fiber density and autonomic innervation is performed in adults in some centers.
• The technique should not damage/scar prior to significant pain (e.g., sternal rub, which bruises before significant pain).
• Application of 5-10 kg pressure with a pen pressed onto the nail bed (the nail bed blanches for a few seconds afterward) is reliable (see
## Clinical Examination
Nociception is assessed by applying painful stimuli, which in people with normal nociception would be so difficult to bear that they would move the part of the body away from the stimulus and/or express discomfort. The authors have experience of children being incorrectly judged to have insensitivity to pain after an inadequately painful stimulus.
The technique should not damage/scar prior to significant pain (e.g., sternal rub, which bruises before significant pain).
Application of 5-10 kg pressure with a pen pressed onto the nail bed (the nail bed blanches for a few seconds afterward) is reliable (see
Assessment of the remainder of the peripheral and central nervous system is typically normal (touch, vibration and position sense, motor functions, and deep tendon reflexes).
• The technique should not damage/scar prior to significant pain (e.g., sternal rub, which bruises before significant pain).
• Application of 5-10 kg pressure with a pen pressed onto the nail bed (the nail bed blanches for a few seconds afterward) is reliable (see
## Supportive Laboratory Findings
Routine nerve conduction studies and electromyogram are typically normal [
For more information about autonomic function testing for
Nerve biopsy is not routinely performed in clinical practice. Skin biopsy to determine intra-epidermal nerve fiber density and autonomic innervation is performed in adults in some centers.
## Causes of Congenital Insensitivity to Pain
All causes of CIP affect nociceptors (specialized peripheral sensory neurons) and either cause nonfunctional nociceptors or failure of nociceptor neurodevelopment [
Genes Associated with Congenital Insensitivity to Pain (CIP)
Severe non-progressive learning disability
Delay in central nervous system myelination
One family reported
Variable phenotype
Individuals w/biallelic null variants may have anhidrosis, mild/moderate ID, prematurely aged appearance, ↑
Individuals w/a homozygous missense variant had impairment of pain/temperature sensation & Charcot joints, normal intellect & normal sweating.
Anhidrosis
Tendency to develop corneal ulcers that heal poorly
ID in a majority; always less intellectually able than unaffected family members
Predisposition to
Charcot joints
Dry skin w/lichenification
Also known as
Non-global pain insensitivity in some
Absent corneal reflex & impaired tear production
No Charcot joints
Difficulties w/temperature regulation in some
Usually normal neurologic exam, development, intellect, & olfaction
Known as HSAN VIII
Anosmia
Charcot joints
Normal corneal reflex & tear production
Delayed motor development
Mild muscle weakness
Joint hypermobility
Gastrointestinal dysfunction (intestinal hypoperistalsis or diarrhea)
Pruritis
Hyperhidrosis in those w/c.2432T>C (p.Leu811Pro) variant
1 family reported
Non-global pain insensitivity w/lower back pain, headaches, & pain during childbirth perceived
Normal intelligence
Scarce or absent sweating
Variably reduced sensitivity to heat and cold
Low sensitivity to capsaicin – able to eat large amount of hot pepper w/out discomfort
Some autonomic features such as fainting & vomiting
AD = autosomal dominant; AR = autosomal recessive; HSAN = hereditary sensory and autonomic neuropathy; ID = intellectual disability; MOI = mode of inheritance
Three individuals from a large northern Swedish family who were homozygous for the
See
Pathogenic variants are typically truncating, although one missense variant and one in-frame deletion have been described [
Recurrent
Other Disorders to Consider in the Differential Diagnosis of Congenital Insensitivity to Pain (CIP)
Lack of sweating (overlap w/
Risk of hyperthermia
Hyperuricemia
Progressive, severe DD/ID
Abnormal involuntary movements
Fractures cause pain
Fractures occur w/minimal or absent trauma
Assoc w/other features incl blue sclera, short stature, joint hypermobility, deafness
Absent pain responses from birth
DD (can be seen in
Infantile-onset liver dysfunction typically → liver failure
Failure to thrive, lactic acidosis, & hypoglycemia
More severe neurologic involvement; may incl white matter abnormalities on MRI & seizures
Insensitivity to pain
Painless injuries
Skin lesions (hypopigmented macules, nodules, plaques, or diffuse skin infiltration)
Enlargement of peripheral nerves
Localized (not universal) insensitivity to pain
Normal response to pain (although caregivers may deny this)
Different pattern of injuries (proportionate to size & development of child)
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; HSAN = hereditary sensory and autonomic neuropathy; ID = intellectual disability; MOI = mode of inheritance; NA = not applicable; XL = X-linked
The prevalence of the CIP phenotype is unknown. Consideration of this diagnosis has increased considerably due to the identification of more causative genes and increased awareness from medical/scientific publications and media stories. Fewer than 30 cases are known in the UK [Authors, personal observation], giving an estimated prevalence of one in a million.
• Severe non-progressive learning disability
• Delay in central nervous system myelination
• One family reported
• Variable phenotype
• Individuals w/biallelic null variants may have anhidrosis, mild/moderate ID, prematurely aged appearance, ↑
• Individuals w/a homozygous missense variant had impairment of pain/temperature sensation & Charcot joints, normal intellect & normal sweating.
• Anhidrosis
• Tendency to develop corneal ulcers that heal poorly
• ID in a majority; always less intellectually able than unaffected family members
• Predisposition to
• Charcot joints
• Dry skin w/lichenification
• Also known as
• Non-global pain insensitivity in some
• Absent corneal reflex & impaired tear production
• No Charcot joints
• Difficulties w/temperature regulation in some
• Usually normal neurologic exam, development, intellect, & olfaction
• Known as HSAN VIII
• Anosmia
• Charcot joints
• Normal corneal reflex & tear production
• Delayed motor development
• Mild muscle weakness
• Joint hypermobility
• Gastrointestinal dysfunction (intestinal hypoperistalsis or diarrhea)
• Pruritis
• Hyperhidrosis in those w/c.2432T>C (p.Leu811Pro) variant
• 1 family reported
• Non-global pain insensitivity w/lower back pain, headaches, & pain during childbirth perceived
• Normal intelligence
• Scarce or absent sweating
• Variably reduced sensitivity to heat and cold
• Low sensitivity to capsaicin – able to eat large amount of hot pepper w/out discomfort
• Some autonomic features such as fainting & vomiting
• Lack of sweating (overlap w/
• Risk of hyperthermia
• Hyperuricemia
• Progressive, severe DD/ID
• Abnormal involuntary movements
• Fractures cause pain
• Fractures occur w/minimal or absent trauma
• Assoc w/other features incl blue sclera, short stature, joint hypermobility, deafness
• Absent pain responses from birth
• DD (can be seen in
• Infantile-onset liver dysfunction typically → liver failure
• Failure to thrive, lactic acidosis, & hypoglycemia
• More severe neurologic involvement; may incl white matter abnormalities on MRI & seizures
• Insensitivity to pain
• Painless injuries
• Skin lesions (hypopigmented macules, nodules, plaques, or diffuse skin infiltration)
• Enlargement of peripheral nerves
• Localized (not universal) insensitivity to pain
• Normal response to pain (although caregivers may deny this)
• Different pattern of injuries (proportionate to size & development of child)
## Prevalence
The prevalence of the CIP phenotype is unknown. Consideration of this diagnosis has increased considerably due to the identification of more causative genes and increased awareness from medical/scientific publications and media stories. Fewer than 30 cases are known in the UK [Authors, personal observation], giving an estimated prevalence of one in a million.
## Evaluation Strategy to Identify the Genetic Cause of Congenital Insensitivity to Pain
The diagnosis of a specific Mendelian form of congenital insensitivity to pain
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Targeted gene testing requires the clinician to develop a hypothesis as to which specific gene(s) are likely to be involved, whereas genomic testing does not. Targeted testing is feasible based on phenotype in anyone older than approximately age five years (because of the difficulties of assessing subtle problems of intellectual developmental, sweating, temperature sensing, and autonomic features in infants and young children), with the exception of
Because some individuals with
If no pathogenic variant is found in
Note: Whole-gene deletions have been reported in individuals with
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
• Because some individuals with
## Management
To establish the extent of disease and needs in an individual diagnosed with congenital insensitivity to pain (CIPA), the evaluations summarized
Recommended Evaluations Following Initial Diagnosis in Individuals with Congenital Insensitivity to Pain Disorders
Assess for fractures; avascular necrosis; septic arthritis / osteomyelitis; self-mutilation; joint subluxation; Charcot neuroarthropathy; leg length discrepancy; scoliosis.
Consider baseline radiography of lower spine, hips, knees, & ankles, if ambulatory.
Community or
Social work involvement for parental support.
ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance
Anhidrosis is more common in individuals with pathogenic variants in
Most often associated with pathogenic variants in
Most often associated with pathogenic variants in
Most often associated with pathogenic variants in
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
No consensus treatment or surveillance guidelines have been developed.
Treatment is supportive and is best provided by specialists in pediatrics, orthopedics, dentistry, ophthalmology, and dermatology (see
Treatment of Manifestations in Individuals with Congenital Insensitivity to Pain
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Developmental delay / intellectual disability educational issues may be seen in those with
In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary.
Irritability, hyperactivity, impulsivity, and acting-out behaviors typically improve with age.
Prevention of Primary Manifestations in Individuals with Congenital Insensitivity to Pain
Artificial tears are particularly helpful to those w/
All persons w/congenital corneal anesthesia have had
Good hand hygiene & care; use of antiseptic soaps; early use of topical antibiotics
Investigation of swollen joints, limping, & limb underuse for infection by radiograph & C-reactive protein
Prevention of Secondary Manifestations in Individuals with Congenital Insensitivity to Pain
In addition to regular evaluations by a pediatrician and dermatologist (to assess and advise on skin infections/injuries) the measures in
Recommended Surveillance for Individuals Congenital Insensitivity to Pain
Avoid the following:
Jumping, high-impact/contact sports, pastimes and jobs that involve the potential for blunt injury or severe bone and joint trauma
The paucity of males with CIP who are older than age 20 years correlates with behaviors fueled by inability to feel pain (e.g., greater risk taking, deliberately picking fights, participation in extreme sporting events).
Hot or cold environments; hot or cold foods, hot showers or baths; heating blankets, particularly in the perioperative period
Women with CIP are able to become pregnant and bear children normally.
Obstetric staff must be made aware of the diagnosis of CIP. Labor progresses normally, but will be painless, while other senses (stretch and touch) are intact. A delay in detecting pelvic fractures in an affected woman in the postnatal period has been reported [
Search
Individuals with CIP typically learn that others have pain and tend to respond to others' pain normally. They often learn to simulate having pain in appropriate situations, e.g., being tackled during football.
The possibility that naloxone may temporarily relieve CIP analgesia has been suggested [
• Assess for fractures; avascular necrosis; septic arthritis / osteomyelitis; self-mutilation; joint subluxation; Charcot neuroarthropathy; leg length discrepancy; scoliosis.
• Consider baseline radiography of lower spine, hips, knees, & ankles, if ambulatory.
• Community or
• Social work involvement for parental support.
• In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Artificial tears are particularly helpful to those w/
• All persons w/congenital corneal anesthesia have had
• Good hand hygiene & care; use of antiseptic soaps; early use of topical antibiotics
• Investigation of swollen joints, limping, & limb underuse for infection by radiograph & C-reactive protein
• Jumping, high-impact/contact sports, pastimes and jobs that involve the potential for blunt injury or severe bone and joint trauma
• The paucity of males with CIP who are older than age 20 years correlates with behaviors fueled by inability to feel pain (e.g., greater risk taking, deliberately picking fights, participation in extreme sporting events).
• Hot or cold environments; hot or cold foods, hot showers or baths; heating blankets, particularly in the perioperative period
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with congenital insensitivity to pain (CIPA), the evaluations summarized
Recommended Evaluations Following Initial Diagnosis in Individuals with Congenital Insensitivity to Pain Disorders
Assess for fractures; avascular necrosis; septic arthritis / osteomyelitis; self-mutilation; joint subluxation; Charcot neuroarthropathy; leg length discrepancy; scoliosis.
Consider baseline radiography of lower spine, hips, knees, & ankles, if ambulatory.
Community or
Social work involvement for parental support.
ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance
Anhidrosis is more common in individuals with pathogenic variants in
Most often associated with pathogenic variants in
Most often associated with pathogenic variants in
Most often associated with pathogenic variants in
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Assess for fractures; avascular necrosis; septic arthritis / osteomyelitis; self-mutilation; joint subluxation; Charcot neuroarthropathy; leg length discrepancy; scoliosis.
• Consider baseline radiography of lower spine, hips, knees, & ankles, if ambulatory.
• Community or
• Social work involvement for parental support.
## Treatment of Manifestations
No consensus treatment or surveillance guidelines have been developed.
Treatment is supportive and is best provided by specialists in pediatrics, orthopedics, dentistry, ophthalmology, and dermatology (see
Treatment of Manifestations in Individuals with Congenital Insensitivity to Pain
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Developmental delay / intellectual disability educational issues may be seen in those with
In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary.
Irritability, hyperactivity, impulsivity, and acting-out behaviors typically improve with age.
• In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Developmental delay / intellectual disability educational issues may be seen in those with
In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
## Social/Behavioral Concerns
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary.
Irritability, hyperactivity, impulsivity, and acting-out behaviors typically improve with age.
## Prevention of Primary Manifestations
Prevention of Primary Manifestations in Individuals with Congenital Insensitivity to Pain
Artificial tears are particularly helpful to those w/
All persons w/congenital corneal anesthesia have had
Good hand hygiene & care; use of antiseptic soaps; early use of topical antibiotics
Investigation of swollen joints, limping, & limb underuse for infection by radiograph & C-reactive protein
• Artificial tears are particularly helpful to those w/
• All persons w/congenital corneal anesthesia have had
• Good hand hygiene & care; use of antiseptic soaps; early use of topical antibiotics
• Investigation of swollen joints, limping, & limb underuse for infection by radiograph & C-reactive protein
## Prevention of Secondary Complications
Prevention of Secondary Manifestations in Individuals with Congenital Insensitivity to Pain
## Surveillance
In addition to regular evaluations by a pediatrician and dermatologist (to assess and advise on skin infections/injuries) the measures in
Recommended Surveillance for Individuals Congenital Insensitivity to Pain
## Agents/Circumstances to Avoid
Avoid the following:
Jumping, high-impact/contact sports, pastimes and jobs that involve the potential for blunt injury or severe bone and joint trauma
The paucity of males with CIP who are older than age 20 years correlates with behaviors fueled by inability to feel pain (e.g., greater risk taking, deliberately picking fights, participation in extreme sporting events).
Hot or cold environments; hot or cold foods, hot showers or baths; heating blankets, particularly in the perioperative period
• Jumping, high-impact/contact sports, pastimes and jobs that involve the potential for blunt injury or severe bone and joint trauma
• The paucity of males with CIP who are older than age 20 years correlates with behaviors fueled by inability to feel pain (e.g., greater risk taking, deliberately picking fights, participation in extreme sporting events).
• Hot or cold environments; hot or cold foods, hot showers or baths; heating blankets, particularly in the perioperative period
## Pregnancy Management
Women with CIP are able to become pregnant and bear children normally.
Obstetric staff must be made aware of the diagnosis of CIP. Labor progresses normally, but will be painless, while other senses (stretch and touch) are intact. A delay in detecting pelvic fractures in an affected woman in the postnatal period has been reported [
## Therapies Under Investigation
Search
## Other
Individuals with CIP typically learn that others have pain and tend to respond to others' pain normally. They often learn to simulate having pain in appropriate situations, e.g., being tackled during football.
The possibility that naloxone may temporarily relieve CIP analgesia has been suggested [
## Genetic Risk Assessment
Congenital insensitivity to pain (CIP) is inherited in an autosomal recessive manner, with the exceptions of
The parents of an affected child are obligate heterozygotes (i.e., carriers of one CIP-related pathogenic variant).
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk for developing the disorder.
See
Some individuals diagnosed with
Some individuals diagnosed with
Inheritance in the one family reported to date with
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
If a parent of the proband is affected, the risk to the sibs is 50%. Based on currently available, but limited, information,
If the parents have been tested for the pathogenic variant identified in the proband and:
A parent of the proband has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Based on currently available (limited) information,
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
If the parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. The sibs of a proband with clinically unaffected parents are still at increased risk for CIP because of the theoretic possibilities of reduced penetrance in a parent or parental germline mosaicism [
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the CIP-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one CIP-related pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk for developing the disorder.
• Some individuals diagnosed with
• Some individuals diagnosed with
• Inheritance in the one family reported to date with
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected, the risk to the sibs is 50%. Based on currently available, but limited, information,
• If the parents have been tested for the pathogenic variant identified in the proband and:
• A parent of the proband has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Based on currently available (limited) information,
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
• A parent of the proband has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Based on currently available (limited) information,
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
• If the parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. The sibs of a proband with clinically unaffected parents are still at increased risk for CIP because of the theoretic possibilities of reduced penetrance in a parent or parental germline mosaicism [
• A parent of the proband has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Based on currently available (limited) information,
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Congenital insensitivity to pain (CIP) is inherited in an autosomal recessive manner, with the exceptions of
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one CIP-related pathogenic variant).
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk for developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one CIP-related pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk for developing the disorder.
## Autosomal Dominant Inheritance (
See
Some individuals diagnosed with
Some individuals diagnosed with
Inheritance in the one family reported to date with
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
If a parent of the proband is affected, the risk to the sibs is 50%. Based on currently available, but limited, information,
If the parents have been tested for the pathogenic variant identified in the proband and:
A parent of the proband has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Based on currently available (limited) information,
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
If the parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. The sibs of a proband with clinically unaffected parents are still at increased risk for CIP because of the theoretic possibilities of reduced penetrance in a parent or parental germline mosaicism [
• Some individuals diagnosed with
• Some individuals diagnosed with
• Inheritance in the one family reported to date with
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected, the risk to the sibs is 50%. Based on currently available, but limited, information,
• If the parents have been tested for the pathogenic variant identified in the proband and:
• A parent of the proband has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Based on currently available (limited) information,
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
• A parent of the proband has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Based on currently available (limited) information,
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
• If the parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. The sibs of a proband with clinically unaffected parents are still at increased risk for CIP because of the theoretic possibilities of reduced penetrance in a parent or parental germline mosaicism [
• A parent of the proband has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Based on currently available (limited) information,
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the CIP-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Kitami 8-15-35-307
Tokyo 157-0067
Japan
•
•
•
•
• Kitami 8-15-35-307
• Tokyo 157-0067
• Japan
•
## Chapter Notes
AP+CGW run a clinical and advice service for diagnosis and management of CIP.
We thank families with congenital insensitivity to pain and colleagues for advice in writing this paper.
11 June 2020 (ma) Revision: added
8 February 2018 (ma) Review posted live
29 July 2017 (cgw) Original submission
• 11 June 2020 (ma) Revision: added
• 8 February 2018 (ma) Review posted live
• 29 July 2017 (cgw) Original submission
## Author Notes
AP+CGW run a clinical and advice service for diagnosis and management of CIP.
## Acknowledgments
We thank families with congenital insensitivity to pain and colleagues for advice in writing this paper.
## Revision History
11 June 2020 (ma) Revision: added
8 February 2018 (ma) Review posted live
29 July 2017 (cgw) Original submission
• 11 June 2020 (ma) Revision: added
• 8 February 2018 (ma) Review posted live
• 29 July 2017 (cgw) Original submission
## References
## Literature Cited
Examples of clinical findings in individuals with congenital insensitivity to pain (CIP)
A. Typical loss of fingertips secondary to trauma, poor wound healing, and chronic
B. Child age seven years with
C. Example of a Charcot joint, or neuropathic joint, in an individual with
D. Method for applying pressure to the proximal nail bed to test pain appreciation
|
[] |
8/2/2018
|
11/6/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
ciss
|
ciss
|
[
"Cardiotrophin-like cytokine factor 1",
"Cytokine receptor-like factor 1",
"CLCF1",
"CRLF1",
"Cold-Induced Sweating Syndrome Including Crisponi Syndrome"
] |
Cold-Induced Sweating Syndrome Including Crisponi Syndrome
|
Angelika F Hahn, Per Morten Knappskog
|
Summary Cold-induced sweating syndrome (CISS) and its infantile presentation, Crisponi syndrome(CS) is characterized by dysmorphic features (distinctive facies, lower facial weakness, flexion deformity at the elbows, camptodactyly with fisted hands, misshapen feet, and overriding toes); intermittent contracture of facial and oropharyngeal muscles when crying or being handled with puckering of lips and drooling of foamy saliva often associated with laryngospasm and respiratory distress; excessive startling and opisthotonus-like posturing with unexpected tactile or auditory stimuli; poor suck reflex and severely impaired swallowing; and a scaly erythematous rash. During the first decade of life, children with CISS/CS develop profuse sweating of the face, arms, and chest with ambient temperatures below 18º to 22º C, and with other stimuli including nervousness or ingestion of sweets. Affected individuals sweat very little in hot environments and may feel overheated. Progressive thoracolumbar kyphoscoliosis occurs, requiring intervention in the second decade. The diagnosis of CISS/CS is established in a proband with suggestive findings and biallelic pathogenic variants in either CISS/CS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
Cold-induced sweating syndrome (CISS) and its infantile presentation, Crisponi syndrome (CS)
Round face
Chubby cheeks
Low-set ears
Depressed nasal bridge and anteverted nares
Long philtrum, high-arched palate, and micrognathia
Cubitus valgus and flexion deformity at the elbows
Fisted hands, camptodactyly, overriding fingers, and transverse palmar creases
Misshapen feet and overriding toes
Intermittent contracture of facial and oropharyngeal muscles when crying or being handled, with puckering of the lips and drooling of foamy saliva
Normal facial expression when relaxed or sleeping (
Typically, excessive startling and opisthotonus-like posturing with unexpected tactile stimuli or loud noises (
Marked difficulty feeding that may necessitate nasogastric or gastrostomy tube feeding
Mild lower facial weakness that usually persists throughout life (
Present in infancy and persisting throughout early childhood
Affecting the face, fingers, and occasionally trunk
Profuse sweating on the face, arms, and anterior and posterior chest to the waist at environmental temperatures below 18º-22º C (64º-71º F) or on exposure to a cold draft or cold drink
Sweating is also observed with nervousness and ingestion of sweets (illustrated in
Minimal sweating in heat (limited to the lumbar region, groin, and thighs) that may result in uncomfortable overheating
In infancy, recurrent temperature spikes up to 42º C (108º F), not associated with infections, leading, in some children, to seizures and at times, to sudden death
The diagnosis of CISS/CS
Note: Identification of biallelic
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cold-Induced Sweating Syndrome/ Crisponi Syndrome (CISS/CS)
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Five distinct
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Seven large deletions/duplications involving parts or all of
• Round face
• Chubby cheeks
• Low-set ears
• Depressed nasal bridge and anteverted nares
• Long philtrum, high-arched palate, and micrognathia
• Cubitus valgus and flexion deformity at the elbows
• Fisted hands, camptodactyly, overriding fingers, and transverse palmar creases
• Misshapen feet and overriding toes
• Round face
• Chubby cheeks
• Low-set ears
• Depressed nasal bridge and anteverted nares
• Long philtrum, high-arched palate, and micrognathia
• Cubitus valgus and flexion deformity at the elbows
• Fisted hands, camptodactyly, overriding fingers, and transverse palmar creases
• Misshapen feet and overriding toes
• Intermittent contracture of facial and oropharyngeal muscles when crying or being handled, with puckering of the lips and drooling of foamy saliva
• Normal facial expression when relaxed or sleeping (
• Typically, excessive startling and opisthotonus-like posturing with unexpected tactile stimuli or loud noises (
• Intermittent contracture of facial and oropharyngeal muscles when crying or being handled, with puckering of the lips and drooling of foamy saliva
• Normal facial expression when relaxed or sleeping (
• Typically, excessive startling and opisthotonus-like posturing with unexpected tactile stimuli or loud noises (
•
• Marked difficulty feeding that may necessitate nasogastric or gastrostomy tube feeding
• Mild lower facial weakness that usually persists throughout life (
• Marked difficulty feeding that may necessitate nasogastric or gastrostomy tube feeding
• Mild lower facial weakness that usually persists throughout life (
• Present in infancy and persisting throughout early childhood
• Affecting the face, fingers, and occasionally trunk
• Present in infancy and persisting throughout early childhood
• Affecting the face, fingers, and occasionally trunk
•
• Profuse sweating on the face, arms, and anterior and posterior chest to the waist at environmental temperatures below 18º-22º C (64º-71º F) or on exposure to a cold draft or cold drink
• Sweating is also observed with nervousness and ingestion of sweets (illustrated in
• Profuse sweating on the face, arms, and anterior and posterior chest to the waist at environmental temperatures below 18º-22º C (64º-71º F) or on exposure to a cold draft or cold drink
• Sweating is also observed with nervousness and ingestion of sweets (illustrated in
•
• Minimal sweating in heat (limited to the lumbar region, groin, and thighs) that may result in uncomfortable overheating
• In infancy, recurrent temperature spikes up to 42º C (108º F), not associated with infections, leading, in some children, to seizures and at times, to sudden death
• Minimal sweating in heat (limited to the lumbar region, groin, and thighs) that may result in uncomfortable overheating
• In infancy, recurrent temperature spikes up to 42º C (108º F), not associated with infections, leading, in some children, to seizures and at times, to sudden death
• Round face
• Chubby cheeks
• Low-set ears
• Depressed nasal bridge and anteverted nares
• Long philtrum, high-arched palate, and micrognathia
• Cubitus valgus and flexion deformity at the elbows
• Fisted hands, camptodactyly, overriding fingers, and transverse palmar creases
• Misshapen feet and overriding toes
• Intermittent contracture of facial and oropharyngeal muscles when crying or being handled, with puckering of the lips and drooling of foamy saliva
• Normal facial expression when relaxed or sleeping (
• Typically, excessive startling and opisthotonus-like posturing with unexpected tactile stimuli or loud noises (
• Marked difficulty feeding that may necessitate nasogastric or gastrostomy tube feeding
• Mild lower facial weakness that usually persists throughout life (
• Present in infancy and persisting throughout early childhood
• Affecting the face, fingers, and occasionally trunk
• Profuse sweating on the face, arms, and anterior and posterior chest to the waist at environmental temperatures below 18º-22º C (64º-71º F) or on exposure to a cold draft or cold drink
• Sweating is also observed with nervousness and ingestion of sweets (illustrated in
• Minimal sweating in heat (limited to the lumbar region, groin, and thighs) that may result in uncomfortable overheating
• In infancy, recurrent temperature spikes up to 42º C (108º F), not associated with infections, leading, in some children, to seizures and at times, to sudden death
## Suggestive Findings
Cold-induced sweating syndrome (CISS) and its infantile presentation, Crisponi syndrome (CS)
Round face
Chubby cheeks
Low-set ears
Depressed nasal bridge and anteverted nares
Long philtrum, high-arched palate, and micrognathia
Cubitus valgus and flexion deformity at the elbows
Fisted hands, camptodactyly, overriding fingers, and transverse palmar creases
Misshapen feet and overriding toes
Intermittent contracture of facial and oropharyngeal muscles when crying or being handled, with puckering of the lips and drooling of foamy saliva
Normal facial expression when relaxed or sleeping (
Typically, excessive startling and opisthotonus-like posturing with unexpected tactile stimuli or loud noises (
Marked difficulty feeding that may necessitate nasogastric or gastrostomy tube feeding
Mild lower facial weakness that usually persists throughout life (
Present in infancy and persisting throughout early childhood
Affecting the face, fingers, and occasionally trunk
Profuse sweating on the face, arms, and anterior and posterior chest to the waist at environmental temperatures below 18º-22º C (64º-71º F) or on exposure to a cold draft or cold drink
Sweating is also observed with nervousness and ingestion of sweets (illustrated in
Minimal sweating in heat (limited to the lumbar region, groin, and thighs) that may result in uncomfortable overheating
In infancy, recurrent temperature spikes up to 42º C (108º F), not associated with infections, leading, in some children, to seizures and at times, to sudden death
• Round face
• Chubby cheeks
• Low-set ears
• Depressed nasal bridge and anteverted nares
• Long philtrum, high-arched palate, and micrognathia
• Cubitus valgus and flexion deformity at the elbows
• Fisted hands, camptodactyly, overriding fingers, and transverse palmar creases
• Misshapen feet and overriding toes
• Round face
• Chubby cheeks
• Low-set ears
• Depressed nasal bridge and anteverted nares
• Long philtrum, high-arched palate, and micrognathia
• Cubitus valgus and flexion deformity at the elbows
• Fisted hands, camptodactyly, overriding fingers, and transverse palmar creases
• Misshapen feet and overriding toes
• Intermittent contracture of facial and oropharyngeal muscles when crying or being handled, with puckering of the lips and drooling of foamy saliva
• Normal facial expression when relaxed or sleeping (
• Typically, excessive startling and opisthotonus-like posturing with unexpected tactile stimuli or loud noises (
• Intermittent contracture of facial and oropharyngeal muscles when crying or being handled, with puckering of the lips and drooling of foamy saliva
• Normal facial expression when relaxed or sleeping (
• Typically, excessive startling and opisthotonus-like posturing with unexpected tactile stimuli or loud noises (
•
• Marked difficulty feeding that may necessitate nasogastric or gastrostomy tube feeding
• Mild lower facial weakness that usually persists throughout life (
• Marked difficulty feeding that may necessitate nasogastric or gastrostomy tube feeding
• Mild lower facial weakness that usually persists throughout life (
• Present in infancy and persisting throughout early childhood
• Affecting the face, fingers, and occasionally trunk
• Present in infancy and persisting throughout early childhood
• Affecting the face, fingers, and occasionally trunk
•
• Profuse sweating on the face, arms, and anterior and posterior chest to the waist at environmental temperatures below 18º-22º C (64º-71º F) or on exposure to a cold draft or cold drink
• Sweating is also observed with nervousness and ingestion of sweets (illustrated in
• Profuse sweating on the face, arms, and anterior and posterior chest to the waist at environmental temperatures below 18º-22º C (64º-71º F) or on exposure to a cold draft or cold drink
• Sweating is also observed with nervousness and ingestion of sweets (illustrated in
•
• Minimal sweating in heat (limited to the lumbar region, groin, and thighs) that may result in uncomfortable overheating
• In infancy, recurrent temperature spikes up to 42º C (108º F), not associated with infections, leading, in some children, to seizures and at times, to sudden death
• Minimal sweating in heat (limited to the lumbar region, groin, and thighs) that may result in uncomfortable overheating
• In infancy, recurrent temperature spikes up to 42º C (108º F), not associated with infections, leading, in some children, to seizures and at times, to sudden death
• Round face
• Chubby cheeks
• Low-set ears
• Depressed nasal bridge and anteverted nares
• Long philtrum, high-arched palate, and micrognathia
• Cubitus valgus and flexion deformity at the elbows
• Fisted hands, camptodactyly, overriding fingers, and transverse palmar creases
• Misshapen feet and overriding toes
• Intermittent contracture of facial and oropharyngeal muscles when crying or being handled, with puckering of the lips and drooling of foamy saliva
• Normal facial expression when relaxed or sleeping (
• Typically, excessive startling and opisthotonus-like posturing with unexpected tactile stimuli or loud noises (
• Marked difficulty feeding that may necessitate nasogastric or gastrostomy tube feeding
• Mild lower facial weakness that usually persists throughout life (
• Present in infancy and persisting throughout early childhood
• Affecting the face, fingers, and occasionally trunk
• Profuse sweating on the face, arms, and anterior and posterior chest to the waist at environmental temperatures below 18º-22º C (64º-71º F) or on exposure to a cold draft or cold drink
• Sweating is also observed with nervousness and ingestion of sweets (illustrated in
• Minimal sweating in heat (limited to the lumbar region, groin, and thighs) that may result in uncomfortable overheating
• In infancy, recurrent temperature spikes up to 42º C (108º F), not associated with infections, leading, in some children, to seizures and at times, to sudden death
## Establishing the Diagnosis
The diagnosis of CISS/CS
Note: Identification of biallelic
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cold-Induced Sweating Syndrome/ Crisponi Syndrome (CISS/CS)
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Five distinct
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Seven large deletions/duplications involving parts or all of
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cold-Induced Sweating Syndrome/ Crisponi Syndrome (CISS/CS)
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Five distinct
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Seven large deletions/duplications involving parts or all of
## Clinical Characteristics
Cold-induced sweating syndrome (CISS) can present to the clinician in infancy as Crisponi syndrome, or from age three years onward as cold-induced sweating syndrome. Interviews with mothers of children or adults with CISS, review of a targeted questionnaire completed by caregivers of the infants, and review of early medical records revealed that probably
To date, 99 individuals have been identified with biallelic pathogenic variants in either
Cold-Induced Sweating Syndrome / Crisponi Syndrome (CISS/CS): Frequency of Select Features
It is important to note that the seizures noted in infants with this disorder occur in association with hyperthermia and not as a primary seizure disorder.
Laboratory tests, metabolic studies, and detailed studies of autonomic functions are normal, with the exception of sudomotor functions [
Once the difficulties of early childhood have been overcome, individuals with CISS/CS are for the most part able to lead a fairly normal and productive life, obtain a secondary education, and have children. Life expectancy is probably normal; to date only one individual has been followed to the eighth decade [
Clinical manifestations are identical in individuals with
No genotype-phenotype correlations for either
The term "cold-induced sweating syndrome" was coined [
Following the demonstration of locus heterogeneity, the abbreviations CISS1 and CISS2 were introduced [
With time, survivors of infantile-onset Crisponi syndrome [
CISS/CS has been observed in individuals originating from every continent except Africa.
To date only four individuals with
## Clinical Description
Cold-induced sweating syndrome (CISS) can present to the clinician in infancy as Crisponi syndrome, or from age three years onward as cold-induced sweating syndrome. Interviews with mothers of children or adults with CISS, review of a targeted questionnaire completed by caregivers of the infants, and review of early medical records revealed that probably
To date, 99 individuals have been identified with biallelic pathogenic variants in either
Cold-Induced Sweating Syndrome / Crisponi Syndrome (CISS/CS): Frequency of Select Features
It is important to note that the seizures noted in infants with this disorder occur in association with hyperthermia and not as a primary seizure disorder.
Laboratory tests, metabolic studies, and detailed studies of autonomic functions are normal, with the exception of sudomotor functions [
Once the difficulties of early childhood have been overcome, individuals with CISS/CS are for the most part able to lead a fairly normal and productive life, obtain a secondary education, and have children. Life expectancy is probably normal; to date only one individual has been followed to the eighth decade [
## Presentation in Infancy (Crisponi Syndrome)
It is important to note that the seizures noted in infants with this disorder occur in association with hyperthermia and not as a primary seizure disorder.
## Presentation in Childhood and Adulthood
## Other Findings
Laboratory tests, metabolic studies, and detailed studies of autonomic functions are normal, with the exception of sudomotor functions [
## Prognosis
Once the difficulties of early childhood have been overcome, individuals with CISS/CS are for the most part able to lead a fairly normal and productive life, obtain a secondary education, and have children. Life expectancy is probably normal; to date only one individual has been followed to the eighth decade [
## Genotype-Phenotype Correlations
Clinical manifestations are identical in individuals with
No genotype-phenotype correlations for either
## Nomenclature
The term "cold-induced sweating syndrome" was coined [
Following the demonstration of locus heterogeneity, the abbreviations CISS1 and CISS2 were introduced [
With time, survivors of infantile-onset Crisponi syndrome [
## Prevalence
CISS/CS has been observed in individuals originating from every continent except Africa.
To date only four individuals with
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The primary disorder of interest in the differential diagnosis of cold-induced sweating syndrome / Crisponi syndrome (CISS/CS) is Stüve-Wiedemann syndrome (STWS). STWS and CISS/CS share the same pathogenic mechanism [
STWS and other disorders in the differential diagnosis of CISS/CS are summarized in
Genes and Disorders of Interest in the Differential Diagnosis of Cold-Induced Sweating Syndrome / Crisponi Syndrome (CISS/CS)
AD = autosomal dominant; AR = autosomal recessive; CISS = cold-induced sweating syndrome; CS = Crisponi syndrome; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; NG = nasogastric
Schaaf-Yang syndrome is inherited in an autosomal dominant, maternally imprinted manner (i.e., a heterozygous pathogenic variant on the paternally derived
## Management
Clinical practice guidelines for cold-induced sweating syndrome / Crisponi syndrome (CISS/CS) have been published in
To establish the extent of disease and needs in an individual diagnosed with CISS/CS, the evaluations summarized in
Note: Any evaluation of an infant needs to proceed with extreme care in handling to avoid startling the infant, which can result in laryngospasm. Supplemental oxygen and a cooling blanket need to be readily available at the bedside.
Recommended Evaluations Following Initial Diagnosis in Individuals with Cold-Induced Sweating Syndrome / Crisponi Syndrome (CISS/CS)
Swallowing test
Esophageal manometry
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist
Including cold-induced sweating, profuse sweating triggered by other stimuli, & heat intolerance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Management by multidisciplinary specialists including neonatologist, pediatrician, neurologist, geneticist, gastroenterologist, dermatologist, orthopedist, hand surgeon, dietician, physical therapist, occupational therapist, speech therapist, psychologist, dentist is recommended.
Infants with CISS/CS are extremely fragile and require special care, including the following:
Continuous monitoring of cardiorespiratory parameters with supplementary oxygen readily available
Room temperature or incubator temperature constant at 20° C
Quiet and somewhat darkened room
Gentle handling for diaper changes and turning
Minimized painful stimuli such as venipunctures
Preparedness for hyperthermic crisis (cooling blankets on site)
Preparedness for seizures (associated with hyperthermia) and respiratory distress
Other specific treatments are listed in
Treatment of Manifestations in Individuals with Cold-Induced Sweating Syndrome / Crisponi Syndrome (CISS/CS)
NG = nasogastric; OT = occupational therapy; PT = physical therapy
Options for the treatment of cold-induced sweating include clonidine alone, clonidine plus amitriptyline, or moxonidine alone.
Before initiating any of these medications, the potential interaction with already-prescribed medications should be assessed. If there are no contraindications, the drugs should be maintained at the lowest dose required for acceptable symptom control.
Recommended regimen is as follows:
Start with clonidine alone.
This dose is usually well tolerated and will effectively reduce or abolish sweating.
The beneficial effects of clonidine may lessen within a few weeks due to habituation.
If necessary, increase the daily dose gradually in steps of 0.05 mg twice daily to effectiveness and tolerance to a maximum dose of 0.1 mg four times daily.
Side effects include dry mouth, sedation, and postural hypotension (can be mitigated by increased salt and fluid intake).
If clonidine needs to be discontinued, it should be phased out over six days; abrupt cessation of clonidine can lead to rebound hypertension.
If control of sweating is insufficient at the tolerated dose of clonidine, amitriptyline may be added.
The dose of amitriptyline may need to be increased to a maximum of 25 mg four times daily (taken with clonidine).
If combined clonidine plus amitriptyline is not tolerated or not effective, moxonidine alone can be tried [
See
Recommended Surveillance for Individuals with Cold-Induced Sweating Syndrome / Crisponi Syndrome (CISS/CS)
Nutritionist to evaluate growth parameters to assess success of feeding strategies
Gastroenterologist eval may be required for assistance w/feeding or aspiration concerns.
Affected individuals should avoid heat exposure and prolonged physical activity in a hot climate.
See
Females with CISS/CS may conceive normally. No complications during pregnancy have been reported to date.
Treatments for cold-induced sweating (clonidine, amitriptyline, moxonidine) should be discontinued during pregnancy, as the potential for teratogenic effects on the fetus is not well studied and remains possible. Clonidine should not be discontinued abruptly, but rather phased out over four to six days.
See
Search
• Swallowing test
• Esophageal manometry
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
• Continuous monitoring of cardiorespiratory parameters with supplementary oxygen readily available
• Room temperature or incubator temperature constant at 20° C
• Quiet and somewhat darkened room
• Gentle handling for diaper changes and turning
• Minimized painful stimuli such as venipunctures
• Preparedness for hyperthermic crisis (cooling blankets on site)
• Preparedness for seizures (associated with hyperthermia) and respiratory distress
• Start with clonidine alone.
• This dose is usually well tolerated and will effectively reduce or abolish sweating.
• The beneficial effects of clonidine may lessen within a few weeks due to habituation.
• If necessary, increase the daily dose gradually in steps of 0.05 mg twice daily to effectiveness and tolerance to a maximum dose of 0.1 mg four times daily.
• Side effects include dry mouth, sedation, and postural hypotension (can be mitigated by increased salt and fluid intake).
• If clonidine needs to be discontinued, it should be phased out over six days; abrupt cessation of clonidine can lead to rebound hypertension.
• This dose is usually well tolerated and will effectively reduce or abolish sweating.
• The beneficial effects of clonidine may lessen within a few weeks due to habituation.
• If necessary, increase the daily dose gradually in steps of 0.05 mg twice daily to effectiveness and tolerance to a maximum dose of 0.1 mg four times daily.
• Side effects include dry mouth, sedation, and postural hypotension (can be mitigated by increased salt and fluid intake).
• If clonidine needs to be discontinued, it should be phased out over six days; abrupt cessation of clonidine can lead to rebound hypertension.
• If control of sweating is insufficient at the tolerated dose of clonidine, amitriptyline may be added.
• The dose of amitriptyline may need to be increased to a maximum of 25 mg four times daily (taken with clonidine).
• If combined clonidine plus amitriptyline is not tolerated or not effective, moxonidine alone can be tried [
• This dose is usually well tolerated and will effectively reduce or abolish sweating.
• The beneficial effects of clonidine may lessen within a few weeks due to habituation.
• If necessary, increase the daily dose gradually in steps of 0.05 mg twice daily to effectiveness and tolerance to a maximum dose of 0.1 mg four times daily.
• Side effects include dry mouth, sedation, and postural hypotension (can be mitigated by increased salt and fluid intake).
• If clonidine needs to be discontinued, it should be phased out over six days; abrupt cessation of clonidine can lead to rebound hypertension.
• Nutritionist to evaluate growth parameters to assess success of feeding strategies
• Gastroenterologist eval may be required for assistance w/feeding or aspiration concerns.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CISS/CS, the evaluations summarized in
Note: Any evaluation of an infant needs to proceed with extreme care in handling to avoid startling the infant, which can result in laryngospasm. Supplemental oxygen and a cooling blanket need to be readily available at the bedside.
Recommended Evaluations Following Initial Diagnosis in Individuals with Cold-Induced Sweating Syndrome / Crisponi Syndrome (CISS/CS)
Swallowing test
Esophageal manometry
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist
Including cold-induced sweating, profuse sweating triggered by other stimuli, & heat intolerance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Swallowing test
• Esophageal manometry
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
## Treatment of Manifestations
Management by multidisciplinary specialists including neonatologist, pediatrician, neurologist, geneticist, gastroenterologist, dermatologist, orthopedist, hand surgeon, dietician, physical therapist, occupational therapist, speech therapist, psychologist, dentist is recommended.
Infants with CISS/CS are extremely fragile and require special care, including the following:
Continuous monitoring of cardiorespiratory parameters with supplementary oxygen readily available
Room temperature or incubator temperature constant at 20° C
Quiet and somewhat darkened room
Gentle handling for diaper changes and turning
Minimized painful stimuli such as venipunctures
Preparedness for hyperthermic crisis (cooling blankets on site)
Preparedness for seizures (associated with hyperthermia) and respiratory distress
Other specific treatments are listed in
Treatment of Manifestations in Individuals with Cold-Induced Sweating Syndrome / Crisponi Syndrome (CISS/CS)
NG = nasogastric; OT = occupational therapy; PT = physical therapy
Options for the treatment of cold-induced sweating include clonidine alone, clonidine plus amitriptyline, or moxonidine alone.
Before initiating any of these medications, the potential interaction with already-prescribed medications should be assessed. If there are no contraindications, the drugs should be maintained at the lowest dose required for acceptable symptom control.
Recommended regimen is as follows:
Start with clonidine alone.
This dose is usually well tolerated and will effectively reduce or abolish sweating.
The beneficial effects of clonidine may lessen within a few weeks due to habituation.
If necessary, increase the daily dose gradually in steps of 0.05 mg twice daily to effectiveness and tolerance to a maximum dose of 0.1 mg four times daily.
Side effects include dry mouth, sedation, and postural hypotension (can be mitigated by increased salt and fluid intake).
If clonidine needs to be discontinued, it should be phased out over six days; abrupt cessation of clonidine can lead to rebound hypertension.
If control of sweating is insufficient at the tolerated dose of clonidine, amitriptyline may be added.
The dose of amitriptyline may need to be increased to a maximum of 25 mg four times daily (taken with clonidine).
If combined clonidine plus amitriptyline is not tolerated or not effective, moxonidine alone can be tried [
• Continuous monitoring of cardiorespiratory parameters with supplementary oxygen readily available
• Room temperature or incubator temperature constant at 20° C
• Quiet and somewhat darkened room
• Gentle handling for diaper changes and turning
• Minimized painful stimuli such as venipunctures
• Preparedness for hyperthermic crisis (cooling blankets on site)
• Preparedness for seizures (associated with hyperthermia) and respiratory distress
• Start with clonidine alone.
• This dose is usually well tolerated and will effectively reduce or abolish sweating.
• The beneficial effects of clonidine may lessen within a few weeks due to habituation.
• If necessary, increase the daily dose gradually in steps of 0.05 mg twice daily to effectiveness and tolerance to a maximum dose of 0.1 mg four times daily.
• Side effects include dry mouth, sedation, and postural hypotension (can be mitigated by increased salt and fluid intake).
• If clonidine needs to be discontinued, it should be phased out over six days; abrupt cessation of clonidine can lead to rebound hypertension.
• This dose is usually well tolerated and will effectively reduce or abolish sweating.
• The beneficial effects of clonidine may lessen within a few weeks due to habituation.
• If necessary, increase the daily dose gradually in steps of 0.05 mg twice daily to effectiveness and tolerance to a maximum dose of 0.1 mg four times daily.
• Side effects include dry mouth, sedation, and postural hypotension (can be mitigated by increased salt and fluid intake).
• If clonidine needs to be discontinued, it should be phased out over six days; abrupt cessation of clonidine can lead to rebound hypertension.
• If control of sweating is insufficient at the tolerated dose of clonidine, amitriptyline may be added.
• The dose of amitriptyline may need to be increased to a maximum of 25 mg four times daily (taken with clonidine).
• If combined clonidine plus amitriptyline is not tolerated or not effective, moxonidine alone can be tried [
• This dose is usually well tolerated and will effectively reduce or abolish sweating.
• The beneficial effects of clonidine may lessen within a few weeks due to habituation.
• If necessary, increase the daily dose gradually in steps of 0.05 mg twice daily to effectiveness and tolerance to a maximum dose of 0.1 mg four times daily.
• Side effects include dry mouth, sedation, and postural hypotension (can be mitigated by increased salt and fluid intake).
• If clonidine needs to be discontinued, it should be phased out over six days; abrupt cessation of clonidine can lead to rebound hypertension.
## Pharmacologic Management of Cold-Induced Sweating
Options for the treatment of cold-induced sweating include clonidine alone, clonidine plus amitriptyline, or moxonidine alone.
Before initiating any of these medications, the potential interaction with already-prescribed medications should be assessed. If there are no contraindications, the drugs should be maintained at the lowest dose required for acceptable symptom control.
Recommended regimen is as follows:
Start with clonidine alone.
This dose is usually well tolerated and will effectively reduce or abolish sweating.
The beneficial effects of clonidine may lessen within a few weeks due to habituation.
If necessary, increase the daily dose gradually in steps of 0.05 mg twice daily to effectiveness and tolerance to a maximum dose of 0.1 mg four times daily.
Side effects include dry mouth, sedation, and postural hypotension (can be mitigated by increased salt and fluid intake).
If clonidine needs to be discontinued, it should be phased out over six days; abrupt cessation of clonidine can lead to rebound hypertension.
If control of sweating is insufficient at the tolerated dose of clonidine, amitriptyline may be added.
The dose of amitriptyline may need to be increased to a maximum of 25 mg four times daily (taken with clonidine).
If combined clonidine plus amitriptyline is not tolerated or not effective, moxonidine alone can be tried [
• Start with clonidine alone.
• This dose is usually well tolerated and will effectively reduce or abolish sweating.
• The beneficial effects of clonidine may lessen within a few weeks due to habituation.
• If necessary, increase the daily dose gradually in steps of 0.05 mg twice daily to effectiveness and tolerance to a maximum dose of 0.1 mg four times daily.
• Side effects include dry mouth, sedation, and postural hypotension (can be mitigated by increased salt and fluid intake).
• If clonidine needs to be discontinued, it should be phased out over six days; abrupt cessation of clonidine can lead to rebound hypertension.
• This dose is usually well tolerated and will effectively reduce or abolish sweating.
• The beneficial effects of clonidine may lessen within a few weeks due to habituation.
• If necessary, increase the daily dose gradually in steps of 0.05 mg twice daily to effectiveness and tolerance to a maximum dose of 0.1 mg four times daily.
• Side effects include dry mouth, sedation, and postural hypotension (can be mitigated by increased salt and fluid intake).
• If clonidine needs to be discontinued, it should be phased out over six days; abrupt cessation of clonidine can lead to rebound hypertension.
• If control of sweating is insufficient at the tolerated dose of clonidine, amitriptyline may be added.
• The dose of amitriptyline may need to be increased to a maximum of 25 mg four times daily (taken with clonidine).
• If combined clonidine plus amitriptyline is not tolerated or not effective, moxonidine alone can be tried [
• This dose is usually well tolerated and will effectively reduce or abolish sweating.
• The beneficial effects of clonidine may lessen within a few weeks due to habituation.
• If necessary, increase the daily dose gradually in steps of 0.05 mg twice daily to effectiveness and tolerance to a maximum dose of 0.1 mg four times daily.
• Side effects include dry mouth, sedation, and postural hypotension (can be mitigated by increased salt and fluid intake).
• If clonidine needs to be discontinued, it should be phased out over six days; abrupt cessation of clonidine can lead to rebound hypertension.
## Prevention of Primary Manifestations
See
## Surveillance
Recommended Surveillance for Individuals with Cold-Induced Sweating Syndrome / Crisponi Syndrome (CISS/CS)
Nutritionist to evaluate growth parameters to assess success of feeding strategies
Gastroenterologist eval may be required for assistance w/feeding or aspiration concerns.
• Nutritionist to evaluate growth parameters to assess success of feeding strategies
• Gastroenterologist eval may be required for assistance w/feeding or aspiration concerns.
## Agents/Circumstances to Avoid
Affected individuals should avoid heat exposure and prolonged physical activity in a hot climate.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Females with CISS/CS may conceive normally. No complications during pregnancy have been reported to date.
Treatments for cold-induced sweating (clonidine, amitriptyline, moxonidine) should be discontinued during pregnancy, as the potential for teratogenic effects on the fetus is not well studied and remains possible. Clonidine should not be discontinued abruptly, but rather phased out over four to six days.
See
## Therapies Under Investigation
Search
## Genetic Counseling
Cold-induced sweating syndrome / Crisponi syndrome (CISS/CS) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Cold-induced sweating syndrome / Crisponi syndrome (CISS/CS) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
Cold-Induced Sweating Syndrome including Crisponi Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Cold-Induced Sweating Syndrome including Crisponi Syndrome (
The ciliary neurotrophic factor receptor (CNTFR) pathway supports the differentiation and survival of a wide range of neuronal cell types (motor, sensory, and autonomic) during development and in adult life. CLCF1 and CRLF1 (encoded by
Mature sweat glands are known to be innervated by cholinergic sympathetic neurons. However, at birth immature sweat glands retain their embryonic noradrenergic sympathetic innervation. As sweat glands mature postnatally, they secrete a retrogradely acting cytokine which directs the innervating sympathetic neurons to change their transmitter phenotype from noradrenergic to cholinergic [
Skin biopsies from an individual with CISS associated with pathogenic variants in
Biopsies from the glabrous skin and from anhidrotic hairy skin (fingertip and leg, respectively) revealed length-dependent severe dermal sensory and autonomic denervation involving sweat glands and all skin adnexa, and the complete absence of cholinergic nerves, with few residual sweat glands and noradrenergic fibers present. These findings indicate a severe, possibly developmental derangement of cutaneous somatic and autonomic innervation, providing an explanation for the unusual reduction of sweating in the lower limbs and possibly also for the impaired pain perception reported in a proportion of individuals with CISS/CS [
Infants with CISS/CS manifest lower facial weakness and inability to suckle and swallow. Mouse pups with targeted deletions of
Due to its high GC content of exon 1,
The frequent p.Leu26del variant (allele frequency of 0.2 in gnomAD Database) may also cause problems in interpreting the exon 1 sequence; sequencing of both strands is recommended.
Cold-Induced Sweating Syndrome / Crisponi Syndrome (CISS/CS):
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Together, the variants c.226T>G and c.676dupA are the most common in Sardinia, with a joint carrier frequency of 1.4% [
• Due to its high GC content of exon 1,
• The frequent p.Leu26del variant (allele frequency of 0.2 in gnomAD Database) may also cause problems in interpreting the exon 1 sequence; sequencing of both strands is recommended.
## Molecular Pathogenesis
The ciliary neurotrophic factor receptor (CNTFR) pathway supports the differentiation and survival of a wide range of neuronal cell types (motor, sensory, and autonomic) during development and in adult life. CLCF1 and CRLF1 (encoded by
Mature sweat glands are known to be innervated by cholinergic sympathetic neurons. However, at birth immature sweat glands retain their embryonic noradrenergic sympathetic innervation. As sweat glands mature postnatally, they secrete a retrogradely acting cytokine which directs the innervating sympathetic neurons to change their transmitter phenotype from noradrenergic to cholinergic [
Skin biopsies from an individual with CISS associated with pathogenic variants in
Biopsies from the glabrous skin and from anhidrotic hairy skin (fingertip and leg, respectively) revealed length-dependent severe dermal sensory and autonomic denervation involving sweat glands and all skin adnexa, and the complete absence of cholinergic nerves, with few residual sweat glands and noradrenergic fibers present. These findings indicate a severe, possibly developmental derangement of cutaneous somatic and autonomic innervation, providing an explanation for the unusual reduction of sweating in the lower limbs and possibly also for the impaired pain perception reported in a proportion of individuals with CISS/CS [
Infants with CISS/CS manifest lower facial weakness and inability to suckle and swallow. Mouse pups with targeted deletions of
Due to its high GC content of exon 1,
The frequent p.Leu26del variant (allele frequency of 0.2 in gnomAD Database) may also cause problems in interpreting the exon 1 sequence; sequencing of both strands is recommended.
Cold-Induced Sweating Syndrome / Crisponi Syndrome (CISS/CS):
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Together, the variants c.226T>G and c.676dupA are the most common in Sardinia, with a joint carrier frequency of 1.4% [
• Due to its high GC content of exon 1,
• The frequent p.Leu26del variant (allele frequency of 0.2 in gnomAD Database) may also cause problems in interpreting the exon 1 sequence; sequencing of both strands is recommended.
## Chapter Notes
Dr Angelika F Hahn can be contacted directly at [email protected].
Dr Per Morten Knappskog can be contacted directly at [email protected].
The authors wish to recognize the invaluable contributions to this work from the late Prof Dr Helge Boman, MD, PhD, Prof Stefan Johansson, PhD, and Prof Maria Nolano, MD.
Helge Boman, MD, PhD; Haukeland University Hospital, Bergen (2011-2021)Angelika F Hahn, MD, FRCP (2011-present)Per Morten Knappskog, PhD (2021-present)
12 August 2021 (ha) Comprehensive update posted live
17 March 2016 (sw) Comprehensive update posted live
18 July 2013 (me) Comprehensive update posted live
3 March 2011 (me) Review posted live
1 June 2010 (hb) Original submission
• 12 August 2021 (ha) Comprehensive update posted live
• 17 March 2016 (sw) Comprehensive update posted live
• 18 July 2013 (me) Comprehensive update posted live
• 3 March 2011 (me) Review posted live
• 1 June 2010 (hb) Original submission
## Author Notes
Dr Angelika F Hahn can be contacted directly at [email protected].
Dr Per Morten Knappskog can be contacted directly at [email protected].
## Acknowledgments
The authors wish to recognize the invaluable contributions to this work from the late Prof Dr Helge Boman, MD, PhD, Prof Stefan Johansson, PhD, and Prof Maria Nolano, MD.
## Author History
Helge Boman, MD, PhD; Haukeland University Hospital, Bergen (2011-2021)Angelika F Hahn, MD, FRCP (2011-present)Per Morten Knappskog, PhD (2021-present)
## Revision History
12 August 2021 (ha) Comprehensive update posted live
17 March 2016 (sw) Comprehensive update posted live
18 July 2013 (me) Comprehensive update posted live
3 March 2011 (me) Review posted live
1 June 2010 (hb) Original submission
• 12 August 2021 (ha) Comprehensive update posted live
• 17 March 2016 (sw) Comprehensive update posted live
• 18 July 2013 (me) Comprehensive update posted live
• 3 March 2011 (me) Review posted live
• 1 June 2010 (hb) Original submission
## References
## Literature Cited
A. Newborn with Crisponi syndrome, caused by biallelic
B. Same infant at age three months in a relaxed state without the facial grimacing.
A. Girl age 18 months with Crisponi syndrome, caused by biallelic
B. Younger sister to A at a similar age; note the signs of lower facial weakness in the perioral region. She also has a facial rash.
Infant with Crisponi syndrome, caused by
|
[
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"NG Forger, D Prevette, O deLapeyrière, B de Bovis, S Wang, P Bartlett, RW Oppenheim. Cardiotrophin-Like Cytokine/Cytokine-Like Factor 1 is an essential trophic factor for lumbar and facial motorneurons in vivo.. J Neurosci 2003;23:8854-58",
"IM Gaspar, T Saldanha, P Cabral, MM Vilhena, M Tuna, C Costa, N Dagoneau, V Cormier Daire, RCM Hennekam. Long-term follow-up in Stuve-Wiedemann syndrome: A clinical report.. Am J Med Genet A 2008;146A:1748-53",
"BA Habecker, A Symes, N Stahl, NJ Francis, A Economides, J Fink, GD Yancopoulos, SC Landis. A sweat gland-derived differentiation activity acts through known cytokine signaling pathways.. J Biol Chem 1997;272:30421-28",
"AF Hahn, DL Jones, PM Knappskog, H Boman, JG McLoed. Cold-induced sweating syndrome: a report of two cases and demonstration of genetic heterogeneity.. J Neurol Sci 2006;250:62-70",
"AF Hahn, PE Waaler, PH Kvistad, JS Bamforth, JH Miles, JG McLeod, PM Knappskog, H Boman. Cold-induced sweating syndrome: CISS1 and CISS2. Manifestations from infancy to adulthood. Four new cases.. J Neurol Sci 2010;293:68-75",
"PC Heinrich, I Behrmann, S Haan, HM Hermanns, G Müller-Newen, F Schaper. Principles of interleukin (IL)-6-type cytokine signaling and its regulation.. Biochem J 2003;374:1-20",
"J Herholz, L Crisponi, BN Mallick, F Rutsch. Successful treatment of cold-induced sweating in Crisponi syndrome and its possible mechanism of action.. Dev Med Child Neurol 2010;52:494-7",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"PM Knappskog, J Majewski, A Livneh, PTE Nilsen, JS Bringsli, J Ott, H Boman. Cold-induced sweating syndrome is caused by mutations in the CRLF1 gene.. Am J Hum Genet 2003;72:375-83",
"B Lozic, S Johansson, S Lovric Kojundzic, J Markic, PM Knappskog, AF Hahn, H Boman. Novel NALCN variant: altered respiratory and circadian rhythm, anesthetic sensitivity.. Ann Clin Trans Neurol 2016;3:876-83",
"J McCarthy, PJ Lupo, E Kovar, M Rech, B Bostwick, D Scott, K Kraft, T Roscolli, J Charrow, SA Schier Vergano, E Lose, R Smiegel, Y Lacassie, CP Schaaf. Schaaf-Yang syndrome overview: Report of 78 individuals.. Am J Med Genet 2018;176A:2564-74",
"MAB Melone, MJ Pellegrino, M Nolano, BA Habecker, S Johansson, NM Nathanson, PM Knappskog, AF Hahn, H Boman. Unusual Stüve-Wiedemann syndrome with complete maternal chromosome 5 isodisomy.. Ann Clin Transl Neurol 2014;1:926-32",
"D Mikelonis, CL Jorcyk, K Tawara, JT Oxford. Stüve-Wiedemann syndrome: LIFR and associated cytokines in clinical course and etiology.. Orphanet J Rare Dis. 2014;9:34",
"R Piras, F Chiappe, IL Torraca, I Buers, G Usula, A Angius, MA Akin, L Basel-Vanagaite, F Benedicenti, E Chiodin, O El Assy, M Feingold-Zadok, J Guibert, B Kamien, CS Kasapkara, E Kiliç, K Boduroğlu, S Kurtoglu, AY Manzur, EE Onal, E Paderi, CH Roche, L Tümer, S Unal, GE Utine, G Zanda, A Zankl, G Zampino, G Crisponi, L Crisponi, F Rutsch. Expanding the mutational spectrum of CRLF1 in Crisponi/CISS1 syndrome.. Hum Mutat 2014;35:424-33",
"F Rousseau, JF Gauchat, JG McLeod, S Chevalier, C Guillet, F Guilhot, I Cognet, J Froger, AF Hahn, PM Knappskog, H Gascan, H Boman. Inactivation of cardiotrophin-like cytokine, a second ligand for ciliary neurotrophic factor receptor, leads to cold-induced sweating syndrome in a patient.. Proc Natl Acad Sci USA 2006;103:10068-73",
"IAM Schierz, G Serra, V Antona, I Persico, G Corsello, E Piro. Infant developmental profile of Crisponi syndrome due to compound heterozygosity for CRLF1 deletion.. Clin Dysmorph 2020;29:141-43",
"R Schotzinger, X Yiu, S Landis. Target determination of neurotransmitter phenotype in sympathetic neurons. J Neurobiol 1994;25:620-39",
"E Sohar, Y Shoenfeld, R Udassin, A Magazanik, M Revach. Cold-induced profuse sweating on back and chest: a new genetic entity?. Lancet 1978;2:1073-4",
"M Stanke, CV Duong, M Pape, M Geissen, G Burbach, T Deller, H Gascan, C Otto, R Parlato, G Schütz, H Rohrer. Target-dependent specification of the neurotransmitter phenotype: cholinergic differentiation of sympathetic neurons is mediated in vivo by gp130 signaling.. Development. 2006;133:141-50",
"PD Stenson, M Mort, EV Ball, K Evans, M Hayden, S Heywood, M Hussain, AD Phillips, DN Cooper. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies.. Hum Genet. 2017;136:665-77"
] |
3/3/2011
|
12/8/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
citrin
|
citrin
|
[
"Citrullinemia Type II (CTLN2)",
"Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD)",
"Failure to Thrive and Dyslipidemia Caused by Citrin Deficiency (FTTDCD)",
"Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial",
"SLC25A13",
"Citrin Deficiency"
] |
Citrin Deficiency
|
Yuan-Zong Song, Kimihiko Oishi, Takeyori Saheki
|
Summary Citrin deficiency can manifest in newborns or infants as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), in older children as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and in adults as recurrent hyperammonemia with neuropsychiatric symptoms in citrullinemia type II (CTLN2). Often citrin deficiency is characterized by strong preference for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods. The diagnosis of citrin deficiency is established in an individual with characteristic biochemical analytes (increased blood or plasma concentration of ammonia, plasma or serum concentration of citrulline and arginine, plasma or serum threonine-to-serine ratio) and biallelic pathogenic variants in Citrin deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD)
Failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD)
Citrullinemia type II (CTLN2)
• Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD)
• Failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD)
• Citrullinemia type II (CTLN2)
## Diagnosis
Citrin deficiency has three clinical phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and citrullinemia type II (CTLN2) (see
Note: Dried blood spots also show elevated galactose, methionine, and/or phenylalanine in 40% of children with NICCD [
Citrulline values above the out-of-range cutoffs reported by the screening laboratory are considered positive and require follow-up biochemical testing, which usually demonstrates the following:
Plasma amino acids show elevated threonine, methionine, and tyrosine.
Urinary organic acids show normal 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate concentrations.
Note: Normal citrulline values on NBS does not exclude the diagnosis of citrin deficiency.
If the follow-up biochemical testing supports the likelihood of citrin deficiency, additional testing is required to
The following medical interventions need to begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether this is a true positive NBS result and to establish the diagnosis of citrin deficiency definitively:
Lactose-free and MCT-enriched formula
Fat-soluble vitamins (vitamins A, D, E, and K)
Variable liver disease (elevated liver transaminases, cholestasis with elevated conjugated bilirubin and subsequent jaundice, hyperlipidemia, hypoproteinemia, hyperammonemia, prolonged prothrombin time, markedly elevated serum alpha-fetoprotein) and hepatomegaly. Liver histopathology can show diffuse macrovesicular and microvesicular steatosis, parenchymal cellular infiltration, siderosis, and fibrosis.
Pre- and postnatal growth delays with full cheeks
Hypoglycemia
Anemia
Seizures
Plasma amino acids show elevated citrulline, threonine, arginine, methionine, and tyrosine concentrations; urine organic acids show normal 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate concentrations.
Positive reducing substances on urine testing
Poor weight gain and growth delays
Aversion to carbohydrates and fondness for protein- and lipid-rich foods
Abnormalities of serum lipid concentrations, including elevated triglycerides, total cholesterol, and low-density lipoprotein (LDL) cholesterol. High-density lipoprotein (HDL) can be elevated [
Childhood- to adult-onset recurring episodes of hyperammonemia
Neuropsychiatric manifestations
Recurrent pancreatitis
Hyperlipidemia
Fatty liver or hepatoma
Elevated plasma citrulline, arginine, and threonine-to-serine ratio
The diagnosis of citrin deficiency
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
When NBS results and other laboratory analytes suggest the diagnosis of citrin deficiency, molecular genetic testing approaches can include
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Japanese or Chinese ancestry [
For an introduction to multigene panels click
A symptomatic individual may have untreated NICCD (resulting from NBS not performed or false negative NBS result) or later-onset citrin deficiency not identified on NBS (FTTDCD or CTLN2).
Molecular genetic testing approaches can include a combination of
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Japanese or Chinese ancestry [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Citrin Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
• Plasma amino acids show elevated threonine, methionine, and tyrosine.
• Urinary organic acids show normal 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate concentrations.
• Lactose-free and MCT-enriched formula
• Fat-soluble vitamins (vitamins A, D, E, and K)
• Variable liver disease (elevated liver transaminases, cholestasis with elevated conjugated bilirubin and subsequent jaundice, hyperlipidemia, hypoproteinemia, hyperammonemia, prolonged prothrombin time, markedly elevated serum alpha-fetoprotein) and hepatomegaly. Liver histopathology can show diffuse macrovesicular and microvesicular steatosis, parenchymal cellular infiltration, siderosis, and fibrosis.
• Pre- and postnatal growth delays with full cheeks
• Hypoglycemia
• Anemia
• Seizures
• Plasma amino acids show elevated citrulline, threonine, arginine, methionine, and tyrosine concentrations; urine organic acids show normal 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate concentrations.
• Positive reducing substances on urine testing
• Poor weight gain and growth delays
• Aversion to carbohydrates and fondness for protein- and lipid-rich foods
• Abnormalities of serum lipid concentrations, including elevated triglycerides, total cholesterol, and low-density lipoprotein (LDL) cholesterol. High-density lipoprotein (HDL) can be elevated [
• Childhood- to adult-onset recurring episodes of hyperammonemia
• Neuropsychiatric manifestations
• Recurrent pancreatitis
• Hyperlipidemia
• Fatty liver or hepatoma
• Elevated plasma citrulline, arginine, and threonine-to-serine ratio
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Japanese or Chinese ancestry [
• For an introduction to multigene panels click
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Japanese or Chinese ancestry [
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Note: Dried blood spots also show elevated galactose, methionine, and/or phenylalanine in 40% of children with NICCD [
Citrulline values above the out-of-range cutoffs reported by the screening laboratory are considered positive and require follow-up biochemical testing, which usually demonstrates the following:
Plasma amino acids show elevated threonine, methionine, and tyrosine.
Urinary organic acids show normal 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate concentrations.
Note: Normal citrulline values on NBS does not exclude the diagnosis of citrin deficiency.
If the follow-up biochemical testing supports the likelihood of citrin deficiency, additional testing is required to
The following medical interventions need to begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether this is a true positive NBS result and to establish the diagnosis of citrin deficiency definitively:
Lactose-free and MCT-enriched formula
Fat-soluble vitamins (vitamins A, D, E, and K)
Variable liver disease (elevated liver transaminases, cholestasis with elevated conjugated bilirubin and subsequent jaundice, hyperlipidemia, hypoproteinemia, hyperammonemia, prolonged prothrombin time, markedly elevated serum alpha-fetoprotein) and hepatomegaly. Liver histopathology can show diffuse macrovesicular and microvesicular steatosis, parenchymal cellular infiltration, siderosis, and fibrosis.
Pre- and postnatal growth delays with full cheeks
Hypoglycemia
Anemia
Seizures
Plasma amino acids show elevated citrulline, threonine, arginine, methionine, and tyrosine concentrations; urine organic acids show normal 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate concentrations.
Positive reducing substances on urine testing
Poor weight gain and growth delays
Aversion to carbohydrates and fondness for protein- and lipid-rich foods
Abnormalities of serum lipid concentrations, including elevated triglycerides, total cholesterol, and low-density lipoprotein (LDL) cholesterol. High-density lipoprotein (HDL) can be elevated [
Childhood- to adult-onset recurring episodes of hyperammonemia
Neuropsychiatric manifestations
Recurrent pancreatitis
Hyperlipidemia
Fatty liver or hepatoma
Elevated plasma citrulline, arginine, and threonine-to-serine ratio
• Plasma amino acids show elevated threonine, methionine, and tyrosine.
• Urinary organic acids show normal 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate concentrations.
• Lactose-free and MCT-enriched formula
• Fat-soluble vitamins (vitamins A, D, E, and K)
• Variable liver disease (elevated liver transaminases, cholestasis with elevated conjugated bilirubin and subsequent jaundice, hyperlipidemia, hypoproteinemia, hyperammonemia, prolonged prothrombin time, markedly elevated serum alpha-fetoprotein) and hepatomegaly. Liver histopathology can show diffuse macrovesicular and microvesicular steatosis, parenchymal cellular infiltration, siderosis, and fibrosis.
• Pre- and postnatal growth delays with full cheeks
• Hypoglycemia
• Anemia
• Seizures
• Plasma amino acids show elevated citrulline, threonine, arginine, methionine, and tyrosine concentrations; urine organic acids show normal 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate concentrations.
• Positive reducing substances on urine testing
• Poor weight gain and growth delays
• Aversion to carbohydrates and fondness for protein- and lipid-rich foods
• Abnormalities of serum lipid concentrations, including elevated triglycerides, total cholesterol, and low-density lipoprotein (LDL) cholesterol. High-density lipoprotein (HDL) can be elevated [
• Childhood- to adult-onset recurring episodes of hyperammonemia
• Neuropsychiatric manifestations
• Recurrent pancreatitis
• Hyperlipidemia
• Fatty liver or hepatoma
• Elevated plasma citrulline, arginine, and threonine-to-serine ratio
## Scenario 1: NICCD (includes abnormal NBS result and symptomatic newborn)
Note: Dried blood spots also show elevated galactose, methionine, and/or phenylalanine in 40% of children with NICCD [
Citrulline values above the out-of-range cutoffs reported by the screening laboratory are considered positive and require follow-up biochemical testing, which usually demonstrates the following:
Plasma amino acids show elevated threonine, methionine, and tyrosine.
Urinary organic acids show normal 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate concentrations.
Note: Normal citrulline values on NBS does not exclude the diagnosis of citrin deficiency.
If the follow-up biochemical testing supports the likelihood of citrin deficiency, additional testing is required to
The following medical interventions need to begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether this is a true positive NBS result and to establish the diagnosis of citrin deficiency definitively:
Lactose-free and MCT-enriched formula
Fat-soluble vitamins (vitamins A, D, E, and K)
Variable liver disease (elevated liver transaminases, cholestasis with elevated conjugated bilirubin and subsequent jaundice, hyperlipidemia, hypoproteinemia, hyperammonemia, prolonged prothrombin time, markedly elevated serum alpha-fetoprotein) and hepatomegaly. Liver histopathology can show diffuse macrovesicular and microvesicular steatosis, parenchymal cellular infiltration, siderosis, and fibrosis.
Pre- and postnatal growth delays with full cheeks
Hypoglycemia
Anemia
Seizures
Plasma amino acids show elevated citrulline, threonine, arginine, methionine, and tyrosine concentrations; urine organic acids show normal 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate concentrations.
Positive reducing substances on urine testing
• Plasma amino acids show elevated threonine, methionine, and tyrosine.
• Urinary organic acids show normal 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate concentrations.
• Lactose-free and MCT-enriched formula
• Fat-soluble vitamins (vitamins A, D, E, and K)
• Variable liver disease (elevated liver transaminases, cholestasis with elevated conjugated bilirubin and subsequent jaundice, hyperlipidemia, hypoproteinemia, hyperammonemia, prolonged prothrombin time, markedly elevated serum alpha-fetoprotein) and hepatomegaly. Liver histopathology can show diffuse macrovesicular and microvesicular steatosis, parenchymal cellular infiltration, siderosis, and fibrosis.
• Pre- and postnatal growth delays with full cheeks
• Hypoglycemia
• Anemia
• Seizures
• Plasma amino acids show elevated citrulline, threonine, arginine, methionine, and tyrosine concentrations; urine organic acids show normal 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate concentrations.
• Positive reducing substances on urine testing
## Scenario 2: FTTDCD and CTLN2 (symptomatic individual)
Poor weight gain and growth delays
Aversion to carbohydrates and fondness for protein- and lipid-rich foods
Abnormalities of serum lipid concentrations, including elevated triglycerides, total cholesterol, and low-density lipoprotein (LDL) cholesterol. High-density lipoprotein (HDL) can be elevated [
Childhood- to adult-onset recurring episodes of hyperammonemia
Neuropsychiatric manifestations
Recurrent pancreatitis
Hyperlipidemia
Fatty liver or hepatoma
Elevated plasma citrulline, arginine, and threonine-to-serine ratio
• Poor weight gain and growth delays
• Aversion to carbohydrates and fondness for protein- and lipid-rich foods
• Abnormalities of serum lipid concentrations, including elevated triglycerides, total cholesterol, and low-density lipoprotein (LDL) cholesterol. High-density lipoprotein (HDL) can be elevated [
• Childhood- to adult-onset recurring episodes of hyperammonemia
• Neuropsychiatric manifestations
• Recurrent pancreatitis
• Hyperlipidemia
• Fatty liver or hepatoma
• Elevated plasma citrulline, arginine, and threonine-to-serine ratio
## Establishing the Diagnosis
The diagnosis of citrin deficiency
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
When NBS results and other laboratory analytes suggest the diagnosis of citrin deficiency, molecular genetic testing approaches can include
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Japanese or Chinese ancestry [
For an introduction to multigene panels click
A symptomatic individual may have untreated NICCD (resulting from NBS not performed or false negative NBS result) or later-onset citrin deficiency not identified on NBS (FTTDCD or CTLN2).
Molecular genetic testing approaches can include a combination of
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Japanese or Chinese ancestry [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Citrin Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Japanese or Chinese ancestry [
• For an introduction to multigene panels click
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Japanese or Chinese ancestry [
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Scenario 1: Abnormal NBS Result for NICCD (includes symptomatic infant)
When NBS results and other laboratory analytes suggest the diagnosis of citrin deficiency, molecular genetic testing approaches can include
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Japanese or Chinese ancestry [
For an introduction to multigene panels click
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Japanese or Chinese ancestry [
• For an introduction to multigene panels click
## Scenario 2: Symptomatic Individual
A symptomatic individual may have untreated NICCD (resulting from NBS not performed or false negative NBS result) or later-onset citrin deficiency not identified on NBS (FTTDCD or CTLN2).
Molecular genetic testing approaches can include a combination of
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Japanese or Chinese ancestry [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Citrin Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Japanese or Chinese ancestry [
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Citrin deficiency has three age-dependent, variable clinical phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and citrullinemia type II (CTLN2). Citrin deficiency can manifest in newborns or infants as NICCD characterized by a diverse set of metabolic abnormalities, including citrullinemia, galactosemia, hypoglycemia, and sometimes hyperammonemia that is likely secondary to liver dysfunction. In most individuals, the clinical manifestations of NICCD improve or resolve by age 12 months. However, some individuals remain symptomatic with progression to FTTDCD, which is characterized by poor weight gain, poor linear growth, dyslipidemia, recurrent hypoglycemia, and fatigue. These individuals may have a silent remission period until after adolescence; 10%-20% evolve into the very severe or even fatal metabolic condition CTLN2, characterized by hyperammonemia, severe liver steatosis, cognitive impairment with sudden episodes of unconsciousness due to brain edema, and pancreatitis. The proportion of people with NICCD that evolve into CTLN2 is unknown. Often, FTTDCD and CTLN2 are characterized by the individual's preference for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods.
Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency: Frequency of Select Features
Starting around age one to two years, children show a strong preference for protein- and lipid-rich foods and an aversion to sugar- and carbohydrate-rich foods. This might compensate for the metabolic derangement and result in improved growth [
Forty-five percent of individuals experience hypoglycemic episodes, presenting with a loss of consciousness, convulsion, sweating, fatigue, or "not doing well" in a catabolic state. Some of these symptoms are repetitive or intractable. Milk or food intake can help to correct the hypoglycemia symptoms, and when necessary, intravenous glucose infusion to maintain normal blood glucose levels can be considered [
In the second or later decades, some individuals with citrin deficiency develop severe CTLN2 with neurobehavioral/psychiatric manifestations [
Most individuals are thin. More than 90% have a body mass index lower than 20, and approximately 40% have a body mass index lower than 17 (range: 15.6-19.1; n=110) [
Neurobehavioral/psychiatric manifestations include aggression, irritability, restlessness, hyperactivity, delusions, and nocturnal delirium that closely resemble those of hepatic encephalopathy or urea cycle disorders. Onset is typically sudden and usually between ages 20 and 50 years (range: 11-79 years; mean: 34.4±12.8 years; n=103) [
Neurologic manifestations include flapping tremors, memory loss, disorientation, drowsiness, convulsive seizures, and coma. Brain imaging is normal, and EEG shows diffuse slow waves. Brain edema is observed in those with severe hyperammonemia.
Select Features of Citrin Deficiency (FTTDCD and CTLN2)
Based on
+ = may be present
No clinically relevant genotype-phenotype correlations are known for this disorder.
Notably, the penetrance is not 100% for citrin deficiency as an autosomal recessive condition. In addition, there appears to be a difference in penetrance of the CTLN2 phenotype related to the sex of the individual.
Of 418 individuals with biallelic
The male-to-female ratio in individuals with NICCD is roughly equal (73:80), while the male-to-female ratio in individuals with CTLN2 is 2.4 to 1 (120:50) [
In Japan, the prevalence of CTLN2 is one in 100,000 and the prevalence of NICCD is one in 19,000. The carrier frequency of
• Of 418 individuals with biallelic
• The male-to-female ratio in individuals with NICCD is roughly equal (73:80), while the male-to-female ratio in individuals with CTLN2 is 2.4 to 1 (120:50) [
## Clinical Description
Citrin deficiency has three age-dependent, variable clinical phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and citrullinemia type II (CTLN2). Citrin deficiency can manifest in newborns or infants as NICCD characterized by a diverse set of metabolic abnormalities, including citrullinemia, galactosemia, hypoglycemia, and sometimes hyperammonemia that is likely secondary to liver dysfunction. In most individuals, the clinical manifestations of NICCD improve or resolve by age 12 months. However, some individuals remain symptomatic with progression to FTTDCD, which is characterized by poor weight gain, poor linear growth, dyslipidemia, recurrent hypoglycemia, and fatigue. These individuals may have a silent remission period until after adolescence; 10%-20% evolve into the very severe or even fatal metabolic condition CTLN2, characterized by hyperammonemia, severe liver steatosis, cognitive impairment with sudden episodes of unconsciousness due to brain edema, and pancreatitis. The proportion of people with NICCD that evolve into CTLN2 is unknown. Often, FTTDCD and CTLN2 are characterized by the individual's preference for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods.
Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency: Frequency of Select Features
Starting around age one to two years, children show a strong preference for protein- and lipid-rich foods and an aversion to sugar- and carbohydrate-rich foods. This might compensate for the metabolic derangement and result in improved growth [
Forty-five percent of individuals experience hypoglycemic episodes, presenting with a loss of consciousness, convulsion, sweating, fatigue, or "not doing well" in a catabolic state. Some of these symptoms are repetitive or intractable. Milk or food intake can help to correct the hypoglycemia symptoms, and when necessary, intravenous glucose infusion to maintain normal blood glucose levels can be considered [
In the second or later decades, some individuals with citrin deficiency develop severe CTLN2 with neurobehavioral/psychiatric manifestations [
Most individuals are thin. More than 90% have a body mass index lower than 20, and approximately 40% have a body mass index lower than 17 (range: 15.6-19.1; n=110) [
Neurobehavioral/psychiatric manifestations include aggression, irritability, restlessness, hyperactivity, delusions, and nocturnal delirium that closely resemble those of hepatic encephalopathy or urea cycle disorders. Onset is typically sudden and usually between ages 20 and 50 years (range: 11-79 years; mean: 34.4±12.8 years; n=103) [
Neurologic manifestations include flapping tremors, memory loss, disorientation, drowsiness, convulsive seizures, and coma. Brain imaging is normal, and EEG shows diffuse slow waves. Brain edema is observed in those with severe hyperammonemia.
Select Features of Citrin Deficiency (FTTDCD and CTLN2)
Based on
+ = may be present
## Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD)
Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency: Frequency of Select Features
Starting around age one to two years, children show a strong preference for protein- and lipid-rich foods and an aversion to sugar- and carbohydrate-rich foods. This might compensate for the metabolic derangement and result in improved growth [
Forty-five percent of individuals experience hypoglycemic episodes, presenting with a loss of consciousness, convulsion, sweating, fatigue, or "not doing well" in a catabolic state. Some of these symptoms are repetitive or intractable. Milk or food intake can help to correct the hypoglycemia symptoms, and when necessary, intravenous glucose infusion to maintain normal blood glucose levels can be considered [
## Failure to Thrive and Dyslipidemia Caused by Citrin Deficiency (FTTDCD)
## Citrullinemia Type II (CTLN2)
In the second or later decades, some individuals with citrin deficiency develop severe CTLN2 with neurobehavioral/psychiatric manifestations [
Most individuals are thin. More than 90% have a body mass index lower than 20, and approximately 40% have a body mass index lower than 17 (range: 15.6-19.1; n=110) [
Neurobehavioral/psychiatric manifestations include aggression, irritability, restlessness, hyperactivity, delusions, and nocturnal delirium that closely resemble those of hepatic encephalopathy or urea cycle disorders. Onset is typically sudden and usually between ages 20 and 50 years (range: 11-79 years; mean: 34.4±12.8 years; n=103) [
Neurologic manifestations include flapping tremors, memory loss, disorientation, drowsiness, convulsive seizures, and coma. Brain imaging is normal, and EEG shows diffuse slow waves. Brain edema is observed in those with severe hyperammonemia.
Select Features of Citrin Deficiency (FTTDCD and CTLN2)
Based on
+ = may be present
## Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations are known for this disorder.
## Penetrance
Notably, the penetrance is not 100% for citrin deficiency as an autosomal recessive condition. In addition, there appears to be a difference in penetrance of the CTLN2 phenotype related to the sex of the individual.
Of 418 individuals with biallelic
The male-to-female ratio in individuals with NICCD is roughly equal (73:80), while the male-to-female ratio in individuals with CTLN2 is 2.4 to 1 (120:50) [
• Of 418 individuals with biallelic
• The male-to-female ratio in individuals with NICCD is roughly equal (73:80), while the male-to-female ratio in individuals with CTLN2 is 2.4 to 1 (120:50) [
## Prevalence
In Japan, the prevalence of CTLN2 is one in 100,000 and the prevalence of NICCD is one in 19,000. The carrier frequency of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genetic Disorders of Interest in the Differential Diagnosis of Citrin Deficiency: NICCD
↑ citrulline (classic: >2,000 μmol/L, mild: up to 800 μmol/L)
Shortly after birth, infants w/acute neonatal form develop hyperammonemia & its complications, from which they die w/o prompt intervention.
Those who are treated promptly may survive for an indeterminate period of time, but usually w/significant neurologic deficit.
↑ citrulline (up to 600 μmol/L) on NBS
Severe neonatal-onset ASL deficiency is assoc w/hyperammonemia w/in 1st few days after birth that can manifest as increasing lethargy, somnolence, refusal to feed, vomiting, tachypnea, & respiratory alkalosis.
↑ citrulline (up to 200 μmol/L) on NBS
Type A (infantile form): most affected children die in infancy or early childhood
Type B (severe neonatal form): biochemical abnormalities, hypoglycemia, hyperammonemia, hypernatremia, anorexia, hepatomegaly, convulsions, stupor, hypotonia, pyramidal tract signs, abnormal movements (incl high-amplitude tremor & dyskinesia), & abnormal ocular movements
Mildly ↑ plasma citrulline (up to 150 μmol/L) in NBS & later in life
↑ urinary excretion of cationic amino acids, esp lysine
Recurrent vomiting, diarrhea, episodes of stupor, & coma after a protein-rich meal, poor feeding, aversion to protein-rich food, poor weight gain, hepatosplenomegaly, & muscular hypotonia
Severe neonatal-onset form: hyperammonemia w/in 1st few days after birth
Late-onset form: episodic hyperammonemia, cognitive impairment, behavioral abnormalities, learning disabilities
Most severe cause of urea cycle disorders
Persons w/complete CPS1 deficiency rapidly develop hyperammonemia in newborn period.
↑ citrulline on NBS
↑ ammonia & glutamine
Early-onset DLD deficiency typically manifests in infancy as hypotonia w/lactic acidosis.
Affected infants frequently do not survive their initial metabolic decompensation or die w/in 1st few years of life during a recurrent metabolic decompensation.
Primary cholestatic liver disease caused by defects that impair bile acid transport & result in progressive cholestasis
The high-serum γ-GTP levels of NICCD may distinguish it from other intrahepatic cholestasis disorders w/low-normal γ-GTP levels, incl PFIC.
Wide spectrum of clinical variability
Major clinical manifestations are bile duct paucity on liver biopsy, cholestasis, congenital cardiac defects, butterfly vertebrae, ophthalmologic abnormalities, & characteristic facial features.
Feeding problems, poor growth, hepatocellular damage, bleeding, &
In 1 neonate, classic galactosemia presented as citrin deficiency.
AR = autosomal recessive; NBS = newborn screening; NICCD = neonatal intrahepatic cholestasis caused by citrin deficiency; MOI = mode of inheritance; XL = X-linked; γ-GTP = gamma-glutamyl transpeptidase
See Pediatric Genetic Cholestatic Liver Disease Overview,
Other etiologies to consider in children with poor weight gain and dyslipidemia include growth hormone deficiency, Turner syndrome, and
More than 30% of individuals with CTLN2 are misdiagnosed initially as having epileptic seizures and/or a psychological disorder (e.g., depression, schizophrenia) [Y-Z Song, unpublished data]. Other diagnoses that can be considered in individuals with CTLN2 include hepatoma, pancreatitis, and hyperlipidemia.
• ↑ citrulline (classic: >2,000 μmol/L, mild: up to 800 μmol/L)
• Shortly after birth, infants w/acute neonatal form develop hyperammonemia & its complications, from which they die w/o prompt intervention.
• Those who are treated promptly may survive for an indeterminate period of time, but usually w/significant neurologic deficit.
• ↑ citrulline (up to 600 μmol/L) on NBS
• Severe neonatal-onset ASL deficiency is assoc w/hyperammonemia w/in 1st few days after birth that can manifest as increasing lethargy, somnolence, refusal to feed, vomiting, tachypnea, & respiratory alkalosis.
• ↑ citrulline (up to 200 μmol/L) on NBS
• Type A (infantile form): most affected children die in infancy or early childhood
• Type B (severe neonatal form): biochemical abnormalities, hypoglycemia, hyperammonemia, hypernatremia, anorexia, hepatomegaly, convulsions, stupor, hypotonia, pyramidal tract signs, abnormal movements (incl high-amplitude tremor & dyskinesia), & abnormal ocular movements
• Mildly ↑ plasma citrulline (up to 150 μmol/L) in NBS & later in life
• ↑ urinary excretion of cationic amino acids, esp lysine
• Recurrent vomiting, diarrhea, episodes of stupor, & coma after a protein-rich meal, poor feeding, aversion to protein-rich food, poor weight gain, hepatosplenomegaly, & muscular hypotonia
• Severe neonatal-onset form: hyperammonemia w/in 1st few days after birth
• Late-onset form: episodic hyperammonemia, cognitive impairment, behavioral abnormalities, learning disabilities
• Most severe cause of urea cycle disorders
• Persons w/complete CPS1 deficiency rapidly develop hyperammonemia in newborn period.
• ↑ citrulline on NBS
• ↑ ammonia & glutamine
• Early-onset DLD deficiency typically manifests in infancy as hypotonia w/lactic acidosis.
• Affected infants frequently do not survive their initial metabolic decompensation or die w/in 1st few years of life during a recurrent metabolic decompensation.
• Primary cholestatic liver disease caused by defects that impair bile acid transport & result in progressive cholestasis
• The high-serum γ-GTP levels of NICCD may distinguish it from other intrahepatic cholestasis disorders w/low-normal γ-GTP levels, incl PFIC.
• Wide spectrum of clinical variability
• Major clinical manifestations are bile duct paucity on liver biopsy, cholestasis, congenital cardiac defects, butterfly vertebrae, ophthalmologic abnormalities, & characteristic facial features.
• Feeding problems, poor growth, hepatocellular damage, bleeding, &
• In 1 neonate, classic galactosemia presented as citrin deficiency.
## Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD)
Genetic Disorders of Interest in the Differential Diagnosis of Citrin Deficiency: NICCD
↑ citrulline (classic: >2,000 μmol/L, mild: up to 800 μmol/L)
Shortly after birth, infants w/acute neonatal form develop hyperammonemia & its complications, from which they die w/o prompt intervention.
Those who are treated promptly may survive for an indeterminate period of time, but usually w/significant neurologic deficit.
↑ citrulline (up to 600 μmol/L) on NBS
Severe neonatal-onset ASL deficiency is assoc w/hyperammonemia w/in 1st few days after birth that can manifest as increasing lethargy, somnolence, refusal to feed, vomiting, tachypnea, & respiratory alkalosis.
↑ citrulline (up to 200 μmol/L) on NBS
Type A (infantile form): most affected children die in infancy or early childhood
Type B (severe neonatal form): biochemical abnormalities, hypoglycemia, hyperammonemia, hypernatremia, anorexia, hepatomegaly, convulsions, stupor, hypotonia, pyramidal tract signs, abnormal movements (incl high-amplitude tremor & dyskinesia), & abnormal ocular movements
Mildly ↑ plasma citrulline (up to 150 μmol/L) in NBS & later in life
↑ urinary excretion of cationic amino acids, esp lysine
Recurrent vomiting, diarrhea, episodes of stupor, & coma after a protein-rich meal, poor feeding, aversion to protein-rich food, poor weight gain, hepatosplenomegaly, & muscular hypotonia
Severe neonatal-onset form: hyperammonemia w/in 1st few days after birth
Late-onset form: episodic hyperammonemia, cognitive impairment, behavioral abnormalities, learning disabilities
Most severe cause of urea cycle disorders
Persons w/complete CPS1 deficiency rapidly develop hyperammonemia in newborn period.
↑ citrulline on NBS
↑ ammonia & glutamine
Early-onset DLD deficiency typically manifests in infancy as hypotonia w/lactic acidosis.
Affected infants frequently do not survive their initial metabolic decompensation or die w/in 1st few years of life during a recurrent metabolic decompensation.
Primary cholestatic liver disease caused by defects that impair bile acid transport & result in progressive cholestasis
The high-serum γ-GTP levels of NICCD may distinguish it from other intrahepatic cholestasis disorders w/low-normal γ-GTP levels, incl PFIC.
Wide spectrum of clinical variability
Major clinical manifestations are bile duct paucity on liver biopsy, cholestasis, congenital cardiac defects, butterfly vertebrae, ophthalmologic abnormalities, & characteristic facial features.
Feeding problems, poor growth, hepatocellular damage, bleeding, &
In 1 neonate, classic galactosemia presented as citrin deficiency.
AR = autosomal recessive; NBS = newborn screening; NICCD = neonatal intrahepatic cholestasis caused by citrin deficiency; MOI = mode of inheritance; XL = X-linked; γ-GTP = gamma-glutamyl transpeptidase
See Pediatric Genetic Cholestatic Liver Disease Overview,
• ↑ citrulline (classic: >2,000 μmol/L, mild: up to 800 μmol/L)
• Shortly after birth, infants w/acute neonatal form develop hyperammonemia & its complications, from which they die w/o prompt intervention.
• Those who are treated promptly may survive for an indeterminate period of time, but usually w/significant neurologic deficit.
• ↑ citrulline (up to 600 μmol/L) on NBS
• Severe neonatal-onset ASL deficiency is assoc w/hyperammonemia w/in 1st few days after birth that can manifest as increasing lethargy, somnolence, refusal to feed, vomiting, tachypnea, & respiratory alkalosis.
• ↑ citrulline (up to 200 μmol/L) on NBS
• Type A (infantile form): most affected children die in infancy or early childhood
• Type B (severe neonatal form): biochemical abnormalities, hypoglycemia, hyperammonemia, hypernatremia, anorexia, hepatomegaly, convulsions, stupor, hypotonia, pyramidal tract signs, abnormal movements (incl high-amplitude tremor & dyskinesia), & abnormal ocular movements
• Mildly ↑ plasma citrulline (up to 150 μmol/L) in NBS & later in life
• ↑ urinary excretion of cationic amino acids, esp lysine
• Recurrent vomiting, diarrhea, episodes of stupor, & coma after a protein-rich meal, poor feeding, aversion to protein-rich food, poor weight gain, hepatosplenomegaly, & muscular hypotonia
• Severe neonatal-onset form: hyperammonemia w/in 1st few days after birth
• Late-onset form: episodic hyperammonemia, cognitive impairment, behavioral abnormalities, learning disabilities
• Most severe cause of urea cycle disorders
• Persons w/complete CPS1 deficiency rapidly develop hyperammonemia in newborn period.
• ↑ citrulline on NBS
• ↑ ammonia & glutamine
• Early-onset DLD deficiency typically manifests in infancy as hypotonia w/lactic acidosis.
• Affected infants frequently do not survive their initial metabolic decompensation or die w/in 1st few years of life during a recurrent metabolic decompensation.
• Primary cholestatic liver disease caused by defects that impair bile acid transport & result in progressive cholestasis
• The high-serum γ-GTP levels of NICCD may distinguish it from other intrahepatic cholestasis disorders w/low-normal γ-GTP levels, incl PFIC.
• Wide spectrum of clinical variability
• Major clinical manifestations are bile duct paucity on liver biopsy, cholestasis, congenital cardiac defects, butterfly vertebrae, ophthalmologic abnormalities, & characteristic facial features.
• Feeding problems, poor growth, hepatocellular damage, bleeding, &
• In 1 neonate, classic galactosemia presented as citrin deficiency.
## Failure to Gain Weight and Dyslipidemia Caused by Citrin Deficiency (FTTDCD)
Other etiologies to consider in children with poor weight gain and dyslipidemia include growth hormone deficiency, Turner syndrome, and
## Citrullinemia Type II (CTLN2)
More than 30% of individuals with CTLN2 are misdiagnosed initially as having epileptic seizures and/or a psychological disorder (e.g., depression, schizophrenia) [Y-Z Song, unpublished data]. Other diagnoses that can be considered in individuals with CTLN2 include hepatoma, pancreatitis, and hyperlipidemia.
## Management
Although progress has been made [
To establish the extent of disease and needs in an individual diagnosed with citrin deficiency, the evaluations summarized in
Citrin Deficiency: Recommended Evaluations Following Initial Diagnosis by Phenotype
Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended).
Plasma amino acid analysis to measure citrulline & other amino acids
Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis).
Assess size & stiffness of liver & spleen; consider appropriate imaging studies (CT/MRI/US).
Biochemical analytes (ALT, AST, albumin, γ-GTP, ALP, bilirubin, bile acids, cholesterol, triglyceride, AFP, & ammonia)
Coagulation
Referral to GI as needed
Assess size & stiffness of liver; consider appropriate imaging studies (CT/MRI/US).
Biochemical analytes(ALT, AST, albumin, γ-GTP, ALP, bilirubin, bile acids, cholesterol, triglyceride, AFP, & ammonia)
Coagulation
ADHD = attention-deficit/hyperactivity disorder; AFP = alpha-fetoprotein; ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; CTLN2 = citrullinemia type II; FTTDCD = failure to thrive and dyslipidemia caused by citrin deficiency; IQ = intelligence quotient; MOI = mode of inheritance; NA = not applicable; NICCD = neonatal intrahepatic cholestasis caused by citrin deficiency; US = ultrasound; γ-GTP = gamma-glutamyl transpeptidase
After a new diagnosis of NICCD in a child, the closest hospital and local pediatrician should also be informed.
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
All individuals with citrin deficiency and feeding difficulties require supervision of a specialist metabolic dietitian with experience in managing diet in citrin deficiency. One of the most important components of management (as it relates to prevention of secondary complications) is the education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see
Treatment includes fat-soluble vitamin supplementation and use of lactose-free therapeutic formulas (for those with secondary galactosemia) and medium-chain triglyceride (MCT)-enriched therapeutic formulas [
Citrin Deficiency: Treatment of Manifestations by Phenotype
Diet: lactose-free & MCT-enriched therapeutic formula
Fat-soluble vitamin supplementation
Zinc supplementation as needed
Diet rich in protein & lipids & low in carbohydrates to prevent hyperammonemia & improve growth
Sodium pyruvate, MCT oil may ↑ growth.
Diet: ↓ carbohydrate intake & ↑ protein/lipid intake to ameliorate hypertriglyceridemia
Sodium pyruvate can ↑ weight.
Sodium pyruvate (4-9 g/day) can ↓ frequency of hyperammonemia
Arginine (5-10 g/day) to ↓ blood ammonia
MCT oil (Macton oil containing 85% MCT) (45 mL/day) to help prevent hyperammonemia
Use of sodium pyruvate, arginine, & MCT oil may delay need for liver transplantation.
CTLN2 = citrullinemia type II; FTTDCD = failure to thrive and dyslipidemia caused by citrin deficiency; NA = not applicable; NICCD = neonatal intrahepatic cholestasis caused by citrin deficiency
Some children with NICCD improve without treatment, which could be the effect of reduction of breast milk and/or common formulas while simultaneously introducing solid supplements such as eggs and meat, which are rich in protein and lipids and therefore beneficial for citrin-deficient individuals [
The treatment with therapeutic formulas is not lifelong. Most infants with NICCD will recover clinically and biochemically by age one year, before which point protein- and lipid-enriched supplements could be introduced. Whether continued treatment beyond a year can reduce the likelihood of FTTDCD and CTLN2 is currently unknown.
Introduction of arginine, sodium pyruvate, and MCT oil may help decrease the need for liver transplantation [
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Citrin Deficiency: Recommended Surveillance
Serum amylase, lipase, & PSTI
Imaging studies (CT/MRI/US)
Neuropsychological testing using age-appropriate standardized assessment batteries
Standardized quality-of-life assessment tools for affected persons & parents/caregivers
AFP = alpha-fetoprotein; ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; PSTI = pancreatic secretory trypsin inhibitor; US = ultrasound; γ-GTP = gamma-glutamyl transpeptidase
Increases in plasma citrulline concentration and serum PSTI suggest onset of citrullinemia type II (CTLN2) [
Infusion of high-concentration glucose may also exacerbate hyperammonemia [
See
Search
• Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended).
• Plasma amino acid analysis to measure citrulline & other amino acids
• Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis).
• Assess size & stiffness of liver & spleen; consider appropriate imaging studies (CT/MRI/US).
• Biochemical analytes (ALT, AST, albumin, γ-GTP, ALP, bilirubin, bile acids, cholesterol, triglyceride, AFP, & ammonia)
• Coagulation
• Referral to GI as needed
• Assess size & stiffness of liver; consider appropriate imaging studies (CT/MRI/US).
• Biochemical analytes(ALT, AST, albumin, γ-GTP, ALP, bilirubin, bile acids, cholesterol, triglyceride, AFP, & ammonia)
• Coagulation
• Diet: lactose-free & MCT-enriched therapeutic formula
• Fat-soluble vitamin supplementation
• Zinc supplementation as needed
• Diet rich in protein & lipids & low in carbohydrates to prevent hyperammonemia & improve growth
• Sodium pyruvate, MCT oil may ↑ growth.
• Diet: ↓ carbohydrate intake & ↑ protein/lipid intake to ameliorate hypertriglyceridemia
• Sodium pyruvate can ↑ weight.
• Sodium pyruvate (4-9 g/day) can ↓ frequency of hyperammonemia
• Arginine (5-10 g/day) to ↓ blood ammonia
• MCT oil (Macton oil containing 85% MCT) (45 mL/day) to help prevent hyperammonemia
• Use of sodium pyruvate, arginine, & MCT oil may delay need for liver transplantation.
• Serum amylase, lipase, & PSTI
• Imaging studies (CT/MRI/US)
• Neuropsychological testing using age-appropriate standardized assessment batteries
• Standardized quality-of-life assessment tools for affected persons & parents/caregivers
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with citrin deficiency, the evaluations summarized in
Citrin Deficiency: Recommended Evaluations Following Initial Diagnosis by Phenotype
Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended).
Plasma amino acid analysis to measure citrulline & other amino acids
Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis).
Assess size & stiffness of liver & spleen; consider appropriate imaging studies (CT/MRI/US).
Biochemical analytes (ALT, AST, albumin, γ-GTP, ALP, bilirubin, bile acids, cholesterol, triglyceride, AFP, & ammonia)
Coagulation
Referral to GI as needed
Assess size & stiffness of liver; consider appropriate imaging studies (CT/MRI/US).
Biochemical analytes(ALT, AST, albumin, γ-GTP, ALP, bilirubin, bile acids, cholesterol, triglyceride, AFP, & ammonia)
Coagulation
ADHD = attention-deficit/hyperactivity disorder; AFP = alpha-fetoprotein; ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; CTLN2 = citrullinemia type II; FTTDCD = failure to thrive and dyslipidemia caused by citrin deficiency; IQ = intelligence quotient; MOI = mode of inheritance; NA = not applicable; NICCD = neonatal intrahepatic cholestasis caused by citrin deficiency; US = ultrasound; γ-GTP = gamma-glutamyl transpeptidase
After a new diagnosis of NICCD in a child, the closest hospital and local pediatrician should also be informed.
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended).
• Plasma amino acid analysis to measure citrulline & other amino acids
• Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis).
• Assess size & stiffness of liver & spleen; consider appropriate imaging studies (CT/MRI/US).
• Biochemical analytes (ALT, AST, albumin, γ-GTP, ALP, bilirubin, bile acids, cholesterol, triglyceride, AFP, & ammonia)
• Coagulation
• Referral to GI as needed
• Assess size & stiffness of liver; consider appropriate imaging studies (CT/MRI/US).
• Biochemical analytes(ALT, AST, albumin, γ-GTP, ALP, bilirubin, bile acids, cholesterol, triglyceride, AFP, & ammonia)
• Coagulation
## Treatment of Manifestations
All individuals with citrin deficiency and feeding difficulties require supervision of a specialist metabolic dietitian with experience in managing diet in citrin deficiency. One of the most important components of management (as it relates to prevention of secondary complications) is the education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see
Treatment includes fat-soluble vitamin supplementation and use of lactose-free therapeutic formulas (for those with secondary galactosemia) and medium-chain triglyceride (MCT)-enriched therapeutic formulas [
Citrin Deficiency: Treatment of Manifestations by Phenotype
Diet: lactose-free & MCT-enriched therapeutic formula
Fat-soluble vitamin supplementation
Zinc supplementation as needed
Diet rich in protein & lipids & low in carbohydrates to prevent hyperammonemia & improve growth
Sodium pyruvate, MCT oil may ↑ growth.
Diet: ↓ carbohydrate intake & ↑ protein/lipid intake to ameliorate hypertriglyceridemia
Sodium pyruvate can ↑ weight.
Sodium pyruvate (4-9 g/day) can ↓ frequency of hyperammonemia
Arginine (5-10 g/day) to ↓ blood ammonia
MCT oil (Macton oil containing 85% MCT) (45 mL/day) to help prevent hyperammonemia
Use of sodium pyruvate, arginine, & MCT oil may delay need for liver transplantation.
CTLN2 = citrullinemia type II; FTTDCD = failure to thrive and dyslipidemia caused by citrin deficiency; NA = not applicable; NICCD = neonatal intrahepatic cholestasis caused by citrin deficiency
Some children with NICCD improve without treatment, which could be the effect of reduction of breast milk and/or common formulas while simultaneously introducing solid supplements such as eggs and meat, which are rich in protein and lipids and therefore beneficial for citrin-deficient individuals [
The treatment with therapeutic formulas is not lifelong. Most infants with NICCD will recover clinically and biochemically by age one year, before which point protein- and lipid-enriched supplements could be introduced. Whether continued treatment beyond a year can reduce the likelihood of FTTDCD and CTLN2 is currently unknown.
Introduction of arginine, sodium pyruvate, and MCT oil may help decrease the need for liver transplantation [
• Diet: lactose-free & MCT-enriched therapeutic formula
• Fat-soluble vitamin supplementation
• Zinc supplementation as needed
• Diet rich in protein & lipids & low in carbohydrates to prevent hyperammonemia & improve growth
• Sodium pyruvate, MCT oil may ↑ growth.
• Diet: ↓ carbohydrate intake & ↑ protein/lipid intake to ameliorate hypertriglyceridemia
• Sodium pyruvate can ↑ weight.
• Sodium pyruvate (4-9 g/day) can ↓ frequency of hyperammonemia
• Arginine (5-10 g/day) to ↓ blood ammonia
• MCT oil (Macton oil containing 85% MCT) (45 mL/day) to help prevent hyperammonemia
• Use of sodium pyruvate, arginine, & MCT oil may delay need for liver transplantation.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Citrin Deficiency: Recommended Surveillance
Serum amylase, lipase, & PSTI
Imaging studies (CT/MRI/US)
Neuropsychological testing using age-appropriate standardized assessment batteries
Standardized quality-of-life assessment tools for affected persons & parents/caregivers
AFP = alpha-fetoprotein; ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; PSTI = pancreatic secretory trypsin inhibitor; US = ultrasound; γ-GTP = gamma-glutamyl transpeptidase
Increases in plasma citrulline concentration and serum PSTI suggest onset of citrullinemia type II (CTLN2) [
• Serum amylase, lipase, & PSTI
• Imaging studies (CT/MRI/US)
• Neuropsychological testing using age-appropriate standardized assessment batteries
• Standardized quality-of-life assessment tools for affected persons & parents/caregivers
## Agents/Circumstances to Avoid
Infusion of high-concentration glucose may also exacerbate hyperammonemia [
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Citrin deficiency – encompassing neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and citrullinemia type II (CTLN2) – is inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygotes for an
Occasionally a parent may have two
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
If one parent is known to be heterozygous for an
In general, sibs who inherit biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with citrin deficiency. Citrin deficiency has been observed in many world populations; however, it is most common in Asia, where the carrier frequency is one in 65 [
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider the use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygotes for an
• Occasionally a parent may have two
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• If one parent is known to be heterozygous for an
• In general, sibs who inherit biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with citrin deficiency. Citrin deficiency has been observed in many world populations; however, it is most common in Asia, where the carrier frequency is one in 65 [
## Mode of Inheritance
Citrin deficiency – encompassing neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and citrullinemia type II (CTLN2) – is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are presumed to be heterozygotes for an
Occasionally a parent may have two
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
If one parent is known to be heterozygous for an
In general, sibs who inherit biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are presumed to be heterozygotes for an
• Occasionally a parent may have two
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• If one parent is known to be heterozygous for an
• In general, sibs who inherit biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with citrin deficiency. Citrin deficiency has been observed in many world populations; however, it is most common in Asia, where the carrier frequency is one in 65 [
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with citrin deficiency. Citrin deficiency has been observed in many world populations; however, it is most common in Asia, where the carrier frequency is one in 65 [
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider the use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Singapore
Japan
United Kingdom
United Kingdom
•
• Singapore
•
•
•
•
• Japan
•
•
• United Kingdom
•
•
• United Kingdom
•
## Molecular Genetics
Citrin Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Citrin Deficiency (
Citrin (also called electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial), encoded by
In citrin deficiency, NADH cannot be oxidized because the mitochondria cannot supply aspartate to the cytosol, and NADH produced in the cytoplasm is not taken up by the mitochondria, thereby increasing the cytoplasmic NADH:NAD ratio.
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
The allele frequency varies between these populations [
## Molecular Pathogenesis
Citrin (also called electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial), encoded by
In citrin deficiency, NADH cannot be oxidized because the mitochondria cannot supply aspartate to the cytosol, and NADH produced in the cytoplasm is not taken up by the mitochondria, thereby increasing the cytoplasmic NADH:NAD ratio.
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
The allele frequency varies between these populations [
## Chapter Notes
Keiko Kobayashi, PhD, a great scientist, teacher, and friend in the field of citrin deficiency, died of colon cancer on December 21, 2010.
Keiko Kobayashi is recognized internationally as a pioneer in citrin deficiency research. As an investigator in the research group of Professor Takeyori Saheki (Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University, Japan), in 1999 she cloned the causative gene
Keiko Kobayashi, the "mother of citrin deficiency," will be remembered and sorely missed by her friends, students, colleagues, and the citrin-deficient individuals whom she diagnosed.
This research was supported in part by Grants-in-Aid for Scientific Research (Nos. 16390100, 19390096, and 19591230) and for Asia-Africa Scientific Platform Program (AASPP) from the Japan Society for the Promotion of Science (JSPS), by a Grant for Child Health and Development (17-2) from the Ministry of Health, Labour and Welfare in Japan, by a Grant for Research for Promoting Technological Seeds from the Japan Science and Technology Agency and by the Projects 81070279, 81270957, 81570793, and 82400673 supported by the National Natural Science Foundation (NSFC) of China. The authors thank Dr Wei-Xia Lin for her technical assistance during the revision process of this review.
Kimihiko Oishi, MD (2025-present)Keiko Kobayashi, PhD; Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan (2004-2010)Takeyori Saheki, MD, PhD (2004-present)Yuan-Zong Song, MD, PhD (2012-present)
20 March 2025 (gf) Comprehensive update posted live
10 August 2017 (ha) Comprehensive update posted live
31 July 2014 (me) Comprehensive update posted live
5 January 2012 (me) Comprehensive update posted live
1 July 2008 (me) Comprehensive update posted live
16 September 2005 (me) Review posted live
5 November 2004 (kk) Original submission
• 20 March 2025 (gf) Comprehensive update posted live
• 10 August 2017 (ha) Comprehensive update posted live
• 31 July 2014 (me) Comprehensive update posted live
• 5 January 2012 (me) Comprehensive update posted live
• 1 July 2008 (me) Comprehensive update posted live
• 16 September 2005 (me) Review posted live
• 5 November 2004 (kk) Original submission
## Author Notes
Keiko Kobayashi, PhD, a great scientist, teacher, and friend in the field of citrin deficiency, died of colon cancer on December 21, 2010.
Keiko Kobayashi is recognized internationally as a pioneer in citrin deficiency research. As an investigator in the research group of Professor Takeyori Saheki (Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University, Japan), in 1999 she cloned the causative gene
Keiko Kobayashi, the "mother of citrin deficiency," will be remembered and sorely missed by her friends, students, colleagues, and the citrin-deficient individuals whom she diagnosed.
## Acknowledgments
This research was supported in part by Grants-in-Aid for Scientific Research (Nos. 16390100, 19390096, and 19591230) and for Asia-Africa Scientific Platform Program (AASPP) from the Japan Society for the Promotion of Science (JSPS), by a Grant for Child Health and Development (17-2) from the Ministry of Health, Labour and Welfare in Japan, by a Grant for Research for Promoting Technological Seeds from the Japan Science and Technology Agency and by the Projects 81070279, 81270957, 81570793, and 82400673 supported by the National Natural Science Foundation (NSFC) of China. The authors thank Dr Wei-Xia Lin for her technical assistance during the revision process of this review.
## Author History
Kimihiko Oishi, MD (2025-present)Keiko Kobayashi, PhD; Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan (2004-2010)Takeyori Saheki, MD, PhD (2004-present)Yuan-Zong Song, MD, PhD (2012-present)
## Revision History
20 March 2025 (gf) Comprehensive update posted live
10 August 2017 (ha) Comprehensive update posted live
31 July 2014 (me) Comprehensive update posted live
5 January 2012 (me) Comprehensive update posted live
1 July 2008 (me) Comprehensive update posted live
16 September 2005 (me) Review posted live
5 November 2004 (kk) Original submission
• 20 March 2025 (gf) Comprehensive update posted live
• 10 August 2017 (ha) Comprehensive update posted live
• 31 July 2014 (me) Comprehensive update posted live
• 5 January 2012 (me) Comprehensive update posted live
• 1 July 2008 (me) Comprehensive update posted live
• 16 September 2005 (me) Review posted live
• 5 November 2004 (kk) Original submission
## References
## Literature Cited
Clinical and laboratory manifestations of citrin deficiency
AA = amino acids; AFP = alpha-fetoprotein; Arg = arginine; Cit = citrulline; CTLN2 = type II citrullinemia; FTTDCD = failure to thrive and dyslipidemia caused by citrin deficiency; Met = methionine; NICCD = neonatal intrahepatic cholestasis caused by citrin deficiency; Thr = threonine; Tyr = tyrosine
|
[] |
16/9/2005
|
20/3/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
clcn4-ndd
|
clcn4-ndd
|
[
"Raynaud-Claes Syndrome",
"H(+)/Cl(-) exchange transporter 4",
"CLCN4",
"CLCN4-Related Neurodevelopmental Disorder"
] |
Elizabeth Emma Palmer, Matthew Huu Nguyen, Caitlin Forwood, Vera Kalscheuer
|
Summary The diagnosis of
|
## Diagnosis
No consensus clinical diagnostic criteria for
Developmental delay or intellectual disability
Autism spectrum disorder
Epilepsy
Mental health conditions including anxiety and bipolar disorder
Gastrointestinal dysfunction
Unremarkable facial features. Although a subtle lengthening of the face and squaring of the chin that becomes more prominent with age has been noted in several individuals (see
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
One additional individual with a contiguous gene deletion (not included in these calculations) has been reported (see
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted array CGH (a gene-targeted microarray designed to detect single-exon deletions or duplications).
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• Developmental delay or intellectual disability
• Autism spectrum disorder
• Epilepsy
• Mental health conditions including anxiety and bipolar disorder
• Gastrointestinal dysfunction
• Unremarkable facial features. Although a subtle lengthening of the face and squaring of the chin that becomes more prominent with age has been noted in several individuals (see
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Developmental delay or intellectual disability
Autism spectrum disorder
Epilepsy
Mental health conditions including anxiety and bipolar disorder
Gastrointestinal dysfunction
Unremarkable facial features. Although a subtle lengthening of the face and squaring of the chin that becomes more prominent with age has been noted in several individuals (see
• Developmental delay or intellectual disability
• Autism spectrum disorder
• Epilepsy
• Mental health conditions including anxiety and bipolar disorder
• Gastrointestinal dysfunction
• Unremarkable facial features. Although a subtle lengthening of the face and squaring of the chin that becomes more prominent with age has been noted in several individuals (see
## Establishing the Diagnosis
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
One additional individual with a contiguous gene deletion (not included in these calculations) has been reported (see
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted array CGH (a gene-targeted microarray designed to detect single-exon deletions or duplications).
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
The findings of affected individuals reported to date are summarized in
Features in Affected Males and Heterozygous Females with
Based on
GI = gastrointestinal; ID = intellectual disability; NA = not available
Males with
Although not a common feature, developmental regression has been reported in two families by
Difficulties in sleep initiation and maintenance have been reported [
A proportion of older males have mental health conditions including diagnoses of depression (1/27), obsessive compulsive features (1/27), bipolar disorder (2/27), or anxiety (4/27), with improvements noted with appropriate treatment (see
The severity of seizures and response to treatment vary; 12 of 22 males (55%) who had epilepsy had seizures resistant to multiple anti-seizure medications and features consistent with a developmental and epileptic encephalopathy (DEE).
Although epilepsy was reported in 61% of individuals and was reported as drug resistant in 55%, this incidence of epilepsy may reflect ascertainment bias, as several studies were based on cohorts with severe epilepsy [
Other less common findings included the following [
Strabismus
Cortical visual impairment
Sensorineural hearing loss
Inguinal hernia
The phenotypes of 30 females heterozygous for a
Thus, although a
To date, X-chromosome inactivation studies have not been helpful in distinguishing between female heterozygotes who are asymptomatic and those who are symptomatic [
No genotype-phenotype correlations have been identified to date.
Significant phenotypic variability has been observed both between individuals from different families with a recurrent variant and among individuals from a single family who have the same variant [
The phenotypes of males with haploinsufficiency (due to exon deletions or frameshift or nonsense variants) were noted to be relatively milder than the phenotypes of individuals with missense variants [
• Strabismus
• Cortical visual impairment
• Sensorineural hearing loss
• Inguinal hernia
## Clinical Description
The findings of affected individuals reported to date are summarized in
Features in Affected Males and Heterozygous Females with
Based on
GI = gastrointestinal; ID = intellectual disability; NA = not available
Males with
Although not a common feature, developmental regression has been reported in two families by
Difficulties in sleep initiation and maintenance have been reported [
A proportion of older males have mental health conditions including diagnoses of depression (1/27), obsessive compulsive features (1/27), bipolar disorder (2/27), or anxiety (4/27), with improvements noted with appropriate treatment (see
The severity of seizures and response to treatment vary; 12 of 22 males (55%) who had epilepsy had seizures resistant to multiple anti-seizure medications and features consistent with a developmental and epileptic encephalopathy (DEE).
Although epilepsy was reported in 61% of individuals and was reported as drug resistant in 55%, this incidence of epilepsy may reflect ascertainment bias, as several studies were based on cohorts with severe epilepsy [
Other less common findings included the following [
Strabismus
Cortical visual impairment
Sensorineural hearing loss
Inguinal hernia
The phenotypes of 30 females heterozygous for a
Thus, although a
To date, X-chromosome inactivation studies have not been helpful in distinguishing between female heterozygotes who are asymptomatic and those who are symptomatic [
• Strabismus
• Cortical visual impairment
• Sensorineural hearing loss
• Inguinal hernia
## Affected Males
Males with
Although not a common feature, developmental regression has been reported in two families by
Difficulties in sleep initiation and maintenance have been reported [
A proportion of older males have mental health conditions including diagnoses of depression (1/27), obsessive compulsive features (1/27), bipolar disorder (2/27), or anxiety (4/27), with improvements noted with appropriate treatment (see
The severity of seizures and response to treatment vary; 12 of 22 males (55%) who had epilepsy had seizures resistant to multiple anti-seizure medications and features consistent with a developmental and epileptic encephalopathy (DEE).
Although epilepsy was reported in 61% of individuals and was reported as drug resistant in 55%, this incidence of epilepsy may reflect ascertainment bias, as several studies were based on cohorts with severe epilepsy [
Other less common findings included the following [
Strabismus
Cortical visual impairment
Sensorineural hearing loss
Inguinal hernia
• Strabismus
• Cortical visual impairment
• Sensorineural hearing loss
• Inguinal hernia
## Heterozygous Females
The phenotypes of 30 females heterozygous for a
Thus, although a
To date, X-chromosome inactivation studies have not been helpful in distinguishing between female heterozygotes who are asymptomatic and those who are symptomatic [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified to date.
Significant phenotypic variability has been observed both between individuals from different families with a recurrent variant and among individuals from a single family who have the same variant [
The phenotypes of males with haploinsufficiency (due to exon deletions or frameshift or nonsense variants) were noted to be relatively milder than the phenotypes of individuals with missense variants [
## Nomenclature
## Prevalence
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Because the phenotypic features associated with
•
•
•
•
•
•
•
## Management
No consensus clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / educational support
Eval for epilepsy, hypotonia, spasticity, abnormal mvmts / ataxia
Consider EEG if seizures are a concern.
Consider brain MRI as part of investigation for neurologic manifestations (e.g., therapy-resistant epilepsy).
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl eval of gastroesophageal reflux.
Consider need for nasogastric feeding or percutaneous gastrostomy depending on nutritional status.
Assess for constipation.
Community or
Social work involvement for parental support.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI= mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment is supportive and often includes multidisciplinary specialists in neurology, pediatrics, mental health, physiatry, occupational and physical therapy, gastroenterology, feeding therapy, ophthalmology, audiology, and medical genetics.
Treatment of Manifestations in Individuals with
While 5/25 persons w/epilepsy had some response to lamotrigine, more dedicated natural history studies are needed to clarify which ASMs are more (or less) effective.
Education of parents/caregivers
Review by pediatrician or adult disability specialist
Regular conversations between affected person, family, & health care professionals
Refer to developmental pediatrician or psychiatrist if concerns re ASD.
Refer to psychiatrist w/expertise in mgmt of persons w/learning disabilities if concerns re mental health complications.
Consultation w/sleep physician if warranted
Consider appropriate pharmacotherapy in consultation w/pediatrician or psychiatrist as indicated.
Consider treatment for symptoms of gastroesophageal reflux &/or constipation.
Feeding therapy; nasogastric or gastrostomy tube placement may be required for persistent feeding issues.
Mgmt by pediatrician, developmental pediatrician, or physiatrist as appropriate
Consultation w/neurologist if required
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ASD = autism spectrum disorder; ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; GI = gastrointestinal; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
Author, unpublished observations
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Recommended Surveillance for Individuals with
Physical medicine, OT/PT assessment of mobility, self-help skills
Monitor for joint hyperextensibility,
ADD = attention deficit disorder; OT = occupational therapy; PT = physical therapy
See
Search
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / educational support
• Eval for epilepsy, hypotonia, spasticity, abnormal mvmts / ataxia
• Consider EEG if seizures are a concern.
• Consider brain MRI as part of investigation for neurologic manifestations (e.g., therapy-resistant epilepsy).
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl eval of gastroesophageal reflux.
• Consider need for nasogastric feeding or percutaneous gastrostomy depending on nutritional status.
• Assess for constipation.
• Community or
• Social work involvement for parental support.
• While 5/25 persons w/epilepsy had some response to lamotrigine, more dedicated natural history studies are needed to clarify which ASMs are more (or less) effective.
• Education of parents/caregivers
• Review by pediatrician or adult disability specialist
• Regular conversations between affected person, family, & health care professionals
• Refer to developmental pediatrician or psychiatrist if concerns re ASD.
• Refer to psychiatrist w/expertise in mgmt of persons w/learning disabilities if concerns re mental health complications.
• Consultation w/sleep physician if warranted
• Consider appropriate pharmacotherapy in consultation w/pediatrician or psychiatrist as indicated.
• Consider treatment for symptoms of gastroesophageal reflux &/or constipation.
• Feeding therapy; nasogastric or gastrostomy tube placement may be required for persistent feeding issues.
• Mgmt by pediatrician, developmental pediatrician, or physiatrist as appropriate
• Consultation w/neurologist if required
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Monitor for joint hyperextensibility,
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / educational support
Eval for epilepsy, hypotonia, spasticity, abnormal mvmts / ataxia
Consider EEG if seizures are a concern.
Consider brain MRI as part of investigation for neurologic manifestations (e.g., therapy-resistant epilepsy).
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl eval of gastroesophageal reflux.
Consider need for nasogastric feeding or percutaneous gastrostomy depending on nutritional status.
Assess for constipation.
Community or
Social work involvement for parental support.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI= mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / educational support
• Eval for epilepsy, hypotonia, spasticity, abnormal mvmts / ataxia
• Consider EEG if seizures are a concern.
• Consider brain MRI as part of investigation for neurologic manifestations (e.g., therapy-resistant epilepsy).
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl eval of gastroesophageal reflux.
• Consider need for nasogastric feeding or percutaneous gastrostomy depending on nutritional status.
• Assess for constipation.
• Community or
• Social work involvement for parental support.
## Treatment of Manifestations
Treatment is supportive and often includes multidisciplinary specialists in neurology, pediatrics, mental health, physiatry, occupational and physical therapy, gastroenterology, feeding therapy, ophthalmology, audiology, and medical genetics.
Treatment of Manifestations in Individuals with
While 5/25 persons w/epilepsy had some response to lamotrigine, more dedicated natural history studies are needed to clarify which ASMs are more (or less) effective.
Education of parents/caregivers
Review by pediatrician or adult disability specialist
Regular conversations between affected person, family, & health care professionals
Refer to developmental pediatrician or psychiatrist if concerns re ASD.
Refer to psychiatrist w/expertise in mgmt of persons w/learning disabilities if concerns re mental health complications.
Consultation w/sleep physician if warranted
Consider appropriate pharmacotherapy in consultation w/pediatrician or psychiatrist as indicated.
Consider treatment for symptoms of gastroesophageal reflux &/or constipation.
Feeding therapy; nasogastric or gastrostomy tube placement may be required for persistent feeding issues.
Mgmt by pediatrician, developmental pediatrician, or physiatrist as appropriate
Consultation w/neurologist if required
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ASD = autism spectrum disorder; ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; GI = gastrointestinal; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
Author, unpublished observations
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• While 5/25 persons w/epilepsy had some response to lamotrigine, more dedicated natural history studies are needed to clarify which ASMs are more (or less) effective.
• Education of parents/caregivers
• Review by pediatrician or adult disability specialist
• Regular conversations between affected person, family, & health care professionals
• Refer to developmental pediatrician or psychiatrist if concerns re ASD.
• Refer to psychiatrist w/expertise in mgmt of persons w/learning disabilities if concerns re mental health complications.
• Consultation w/sleep physician if warranted
• Consider appropriate pharmacotherapy in consultation w/pediatrician or psychiatrist as indicated.
• Consider treatment for symptoms of gastroesophageal reflux &/or constipation.
• Feeding therapy; nasogastric or gastrostomy tube placement may be required for persistent feeding issues.
• Mgmt by pediatrician, developmental pediatrician, or physiatrist as appropriate
• Consultation w/neurologist if required
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Recommended Surveillance for Individuals with
Physical medicine, OT/PT assessment of mobility, self-help skills
Monitor for joint hyperextensibility,
ADD = attention deficit disorder; OT = occupational therapy; PT = physical therapy
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Monitor for joint hyperextensibility,
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
The father of an affected male will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
About 16% of affected males have the disorder as the result of a
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
If the mother of the proband has a
Males who inherit the pathogenic variant will be affected.
Females who inherit the pathogenic variant will be heterozygotes and may be unaffected or have clinical findings ranging from mild learning difficulties and mental health concerns to severe manifestations (see Clinical Description,
If the proband represents a simplex case and if the
A female proband may have inherited the
Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
If the mother of the proband has a
Males who inherit the pathogenic variant will be affected.
Females who inherit the pathogenic variant will be heterozygotes and may be unaffected or have clinical findings ranging from mild learning difficulties and mental health concerns to severe manifestations (see Clinical Description,
The manifestations of
X-chromosome inactivation status has not been found to be helpful in assessing degree of severity of features in female heterozygotes [
If the father of the proband has a
If the proband represents a simplex case and if the
Note: Molecular genetic testing may be able to identify the family member in whom a
Identification of female heterozygotes requires prior identification of the familial
Note: Females who inherit the pathogenic variant will be heterozygotes and may be unaffected or have clinical findings ranging from mild learning difficulties and mental health concerns to severe manifestations (see Clinical Description,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes or who are at increased risk of being heterozygotes.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
• About 16% of affected males have the disorder as the result of a
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• If the mother of the proband has a
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be unaffected or have clinical findings ranging from mild learning difficulties and mental health concerns to severe manifestations (see Clinical Description,
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be unaffected or have clinical findings ranging from mild learning difficulties and mental health concerns to severe manifestations (see Clinical Description,
• If the proband represents a simplex case and if the
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be unaffected or have clinical findings ranging from mild learning difficulties and mental health concerns to severe manifestations (see Clinical Description,
• A female proband may have inherited the
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
• If the mother of the proband has a
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be unaffected or have clinical findings ranging from mild learning difficulties and mental health concerns to severe manifestations (see Clinical Description,
• The manifestations of
• X-chromosome inactivation status has not been found to be helpful in assessing degree of severity of features in female heterozygotes [
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be unaffected or have clinical findings ranging from mild learning difficulties and mental health concerns to severe manifestations (see Clinical Description,
• The manifestations of
• X-chromosome inactivation status has not been found to be helpful in assessing degree of severity of features in female heterozygotes [
• If the father of the proband has a
• If the proband represents a simplex case and if the
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be unaffected or have clinical findings ranging from mild learning difficulties and mental health concerns to severe manifestations (see Clinical Description,
• The manifestations of
• X-chromosome inactivation status has not been found to be helpful in assessing degree of severity of features in female heterozygotes [
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes or who are at increased risk of being heterozygotes.
## Mode of Inheritance
## Risk to Family Members
The father of an affected male will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
About 16% of affected males have the disorder as the result of a
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
If the mother of the proband has a
Males who inherit the pathogenic variant will be affected.
Females who inherit the pathogenic variant will be heterozygotes and may be unaffected or have clinical findings ranging from mild learning difficulties and mental health concerns to severe manifestations (see Clinical Description,
If the proband represents a simplex case and if the
A female proband may have inherited the
Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
If the mother of the proband has a
Males who inherit the pathogenic variant will be affected.
Females who inherit the pathogenic variant will be heterozygotes and may be unaffected or have clinical findings ranging from mild learning difficulties and mental health concerns to severe manifestations (see Clinical Description,
The manifestations of
X-chromosome inactivation status has not been found to be helpful in assessing degree of severity of features in female heterozygotes [
If the father of the proband has a
If the proband represents a simplex case and if the
Note: Molecular genetic testing may be able to identify the family member in whom a
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
• About 16% of affected males have the disorder as the result of a
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• If the mother of the proband has a
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be unaffected or have clinical findings ranging from mild learning difficulties and mental health concerns to severe manifestations (see Clinical Description,
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be unaffected or have clinical findings ranging from mild learning difficulties and mental health concerns to severe manifestations (see Clinical Description,
• If the proband represents a simplex case and if the
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be unaffected or have clinical findings ranging from mild learning difficulties and mental health concerns to severe manifestations (see Clinical Description,
• A female proband may have inherited the
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
• If the mother of the proband has a
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be unaffected or have clinical findings ranging from mild learning difficulties and mental health concerns to severe manifestations (see Clinical Description,
• The manifestations of
• X-chromosome inactivation status has not been found to be helpful in assessing degree of severity of features in female heterozygotes [
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be unaffected or have clinical findings ranging from mild learning difficulties and mental health concerns to severe manifestations (see Clinical Description,
• The manifestations of
• X-chromosome inactivation status has not been found to be helpful in assessing degree of severity of features in female heterozygotes [
• If the father of the proband has a
• If the proband represents a simplex case and if the
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be unaffected or have clinical findings ranging from mild learning difficulties and mental health concerns to severe manifestations (see Clinical Description,
• The manifestations of
• X-chromosome inactivation status has not been found to be helpful in assessing degree of severity of features in female heterozygotes [
## Heterozygote Detection
Identification of female heterozygotes requires prior identification of the familial
Note: Females who inherit the pathogenic variant will be heterozygotes and may be unaffected or have clinical findings ranging from mild learning difficulties and mental health concerns to severe manifestations (see Clinical Description,
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes or who are at increased risk of being heterozygotes.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes or who are at increased risk of being heterozygotes.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
## Molecular Genetics
CLCN4-Related Neurodevelopmental Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CLCN4-Related Neurodevelopmental Disorder (
CLCN4/ClC-4 is broadly expressed in many tissues, with highest expression in brain and skeletal muscle. ClC-4 is a strongly outwardly rectifying, electrogenic 2Cl-/H+ exchanger, predominantly expressed in membranes of the endolysosomal system. Its biological function remains largely unknown but may be related to ion homeostasis [
ClC-4 forms heterodimers with its close homolog ClC-3, encoded by
It is currently unknown how genetic alterations in
## Molecular Pathogenesis
CLCN4/ClC-4 is broadly expressed in many tissues, with highest expression in brain and skeletal muscle. ClC-4 is a strongly outwardly rectifying, electrogenic 2Cl-/H+ exchanger, predominantly expressed in membranes of the endolysosomal system. Its biological function remains largely unknown but may be related to ion homeostasis [
ClC-4 forms heterodimers with its close homolog ClC-3, encoded by
It is currently unknown how genetic alterations in
## Chapter Notes
Dr Vera Kalscheuer (PhD) is a scientist at the Max Planck Institute for Molecular Genetics in Berlin, Germany. She obtained her degree and PhD in biochemistry from the Free University in Berlin, Germany and conducted postdoctoral research at the Radboud University Nijmegen Medical Centre, the Netherlands. Her work focuses on the identification of novel genes linked to neurodevelopmental disabilities, and on the molecular and functional characterization of selected genes and proteins in order to better understand the underlying molecular and pathogenic mechanisms. With her research, she has discovered and contributed to the identification of numerous genes associated with various forms of neurodevelopmental disabilities, including
Dr Emma Palmer (PhD, MBBS, FRACP, BA (Hons I) Oxon) is a clinician scientist at Sydney Children's Hospital Network & University of New South Wales in Sydney, Australia. She has extensive experience at the interface of clinical and research genetics leading multidisciplinary teams and establishing international collaborations to discover new genetic conditions. She has led five international projects delineating the following novel genetic conditions:
She works closely with rare genetic disease advocacy and consumer reference groups and aims to translate genomic discoveries to improved education and management for patients and families. She was the first author on a publication describing the effect of
We thank the Cure CLCN4 patient support group and Simons Foundation for their efforts supporting families with
16 December 2021 (bp) Review posted live
27 August 2021 (ep) Original submission
• 16 December 2021 (bp) Review posted live
• 27 August 2021 (ep) Original submission
## Author Notes
Dr Vera Kalscheuer (PhD) is a scientist at the Max Planck Institute for Molecular Genetics in Berlin, Germany. She obtained her degree and PhD in biochemistry from the Free University in Berlin, Germany and conducted postdoctoral research at the Radboud University Nijmegen Medical Centre, the Netherlands. Her work focuses on the identification of novel genes linked to neurodevelopmental disabilities, and on the molecular and functional characterization of selected genes and proteins in order to better understand the underlying molecular and pathogenic mechanisms. With her research, she has discovered and contributed to the identification of numerous genes associated with various forms of neurodevelopmental disabilities, including
Dr Emma Palmer (PhD, MBBS, FRACP, BA (Hons I) Oxon) is a clinician scientist at Sydney Children's Hospital Network & University of New South Wales in Sydney, Australia. She has extensive experience at the interface of clinical and research genetics leading multidisciplinary teams and establishing international collaborations to discover new genetic conditions. She has led five international projects delineating the following novel genetic conditions:
She works closely with rare genetic disease advocacy and consumer reference groups and aims to translate genomic discoveries to improved education and management for patients and families. She was the first author on a publication describing the effect of
## Acknowledgments
We thank the Cure CLCN4 patient support group and Simons Foundation for their efforts supporting families with
## Revision History
16 December 2021 (bp) Review posted live
27 August 2021 (ep) Original submission
• 16 December 2021 (bp) Review posted live
• 27 August 2021 (ep) Original submission
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"EE Palmer, T Stuhlmann, S Weinert, E Haan, H Van Esch, M Holvoet, J Boyle, M Leffler, M Raynaud, C Moraine, H van Bokhoven, T Kleefstra, K Kahrizi, H Najmabadi, HH Ropers, MR Delgado, D Sirsi, S Golla, A Sommer, MP Pietryga, WK Chung, J Wynn, L Rohena, E Bernardo, D Hamlin, BM Faux, DK Grange, L Manwaring, J Tolmie, S Joss, DDD Study, JM Cobben, FAM Duijkers, JM Goehringer, TD Challman, F Hennig, U Fischer, A Grimme, V Suckow, L Musante, J Nicholl, M Shaw, SP Lodh, Z Niu, JA Rosenfeld, P Stankiewicz, TJ Jentsch, J Gecz, M Field, VM Kalscheuer. De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females.. Mol Psychiatry. 2018;23:222-30",
"M Raynaud, C Gendrot, B Dessay, A Moncla, AD Ayrault, MP Moizard, A Toutain, S Briault, L Villard, N Ronce, C Moraine. X-linked mental retardation with neonatal hypotonia in a French family (MRX15): gene assignment to Xp11.22-Xp21.1.. Am J Med Genet. 1996;64:97-106",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"KR Veeramah, L Johnstone, TM Karafet, D Wolf, R Sprissler, J Salogiannis, A Barth-Maron, ME Greenberg, T Stuhlmann, S Weinert, TJ Jentsch, M Pazzi, LL Restifo, D Talwar, RP Erickson, MF Hammer. Exome sequencing reveals new causal mutations in children with epileptic encephalopathies.. Epilepsia. 2013;54:1270-81",
"S Weinert, N Gimber, D Deuschel, T Stuhlmann, D Puchkov, Z Farsi, CF Ludwig, G Novarino, KI López-Cayuqueo, R Planells-Cases, TJ Jentsch. Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration.. EMBO J. 2020;39",
"X Xu, F Lu, L Zhang, H Li, S Du, J. Tang. Novel CLCN4 variant associated with syndromic X-linked intellectual disability in a Chinese girl: a case report.. BMC Pediatr. 2021;21:384",
"P Zhou, N He, JW Zhang, ZJ Lin, J Wang, LM Yan, H Meng, B Tang, BM Li, XR Liu, YW Shi, QX Zhai, YH Yi, WP Liao. Novel mutations and phenotypes of epilepsy-associated genes in epileptic encephalopathies.. Genes Brain Behav. 2018;17"
] |
16/12/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
clcn7
|
clcn7
|
[
"Autosomal Dominant Osteopetrosis Type II (ADOII)",
"Autosomal Recessive Osteopetrosis (ARO)",
"Intermediate Autosomal Osteopetrosis (IAO)",
"H(+)/Cl(-) exchange transporter 7",
"CLCN7",
"CLCN7-Related Osteopetrosis"
] |
Cristina Sobacchi, Anna Villa, Ansgar Schulz, Uwe Kornak
|
Summary The spectrum of The diagnosis of a Once the
|
For other genetic causes of these phenotypes see
## Diagnosis
The spectrum of
Autosomal recessive osteopetrosis (ARO; infantile malignant
Intermediate autosomal osteopetrosis (IAO)
Autosomal dominant osteopetrosis type II (ADOII; Albers-Schönberg disease)
A
Diagnostic Features of the Subtypes of
ADOII = autosomal dominant osteopetrosis type II; ARO = infantile malignant
Generalized osteosclerosis, club-shaped long bones, sclerosis of the skull base, bone-within-bone appearance; these signs are observed in all types of ARO.
Findings similar to ARO, already present in early childhood, but less severe
Findings: • Osteosclerosis of the spine ("sandwich vertebrae") • Bone-within-bone appearance, mainly in iliac wings • Erlenmeyer-shaped femoral metaphysis • Mild osteosclerosis of the skull base • Transverse bands of osteosclerosis in long bones
Typical signs of CNS involvement: • Delayed psychomotor development • Loss of abilities • Seizures (can be also due to hypocalcemia) • On MRI: global brain atrophy, cortical abnormalities, and in rare individuals, heterotopias
The diagnosis of a
Note: Identification of biallelic
Because the phenotype of a
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
A noncoding deep intronic variant in
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A homozygous 101-kb contiguous gene deletion including exons 7-25 of
• Autosomal recessive osteopetrosis (ARO; infantile malignant
• Intermediate autosomal osteopetrosis (IAO)
• Autosomal dominant osteopetrosis type II (ADOII; Albers-Schönberg disease)
## Suggestive Findings
A
Diagnostic Features of the Subtypes of
ADOII = autosomal dominant osteopetrosis type II; ARO = infantile malignant
Generalized osteosclerosis, club-shaped long bones, sclerosis of the skull base, bone-within-bone appearance; these signs are observed in all types of ARO.
Findings similar to ARO, already present in early childhood, but less severe
Findings: • Osteosclerosis of the spine ("sandwich vertebrae") • Bone-within-bone appearance, mainly in iliac wings • Erlenmeyer-shaped femoral metaphysis • Mild osteosclerosis of the skull base • Transverse bands of osteosclerosis in long bones
Typical signs of CNS involvement: • Delayed psychomotor development • Loss of abilities • Seizures (can be also due to hypocalcemia) • On MRI: global brain atrophy, cortical abnormalities, and in rare individuals, heterotopias
## Establishing the Diagnosis
The diagnosis of a
Note: Identification of biallelic
Because the phenotype of a
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
A noncoding deep intronic variant in
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A homozygous 101-kb contiguous gene deletion including exons 7-25 of
## Clinical Characteristics
To date, approximately 300 individuals have been identified with a pathogenic variant in
ARO is a systemic, life-threatening disorder. Onset of symptoms is at birth. Without treatment, life span is approximately ten years (although rare exceptions of far longer survival have occurred). Note: Many of the most complete clinical descriptions of ARO were published prior to the discovery of the causative gene.
Possible clinical manifestations of ARO include the following.
Visual impairment beginning shortly after birth is common. In most individuals it is caused by optic nerve compression within the osteosclerotic skull base.
Skull changes may also cause hydrocephalus.
A prominent and large anterior fontanelle is common and sometimes associated with hydrocephalus, possibly caused by obstruction of cerebral blood flow and cerebrospinal fluid circulation as a result of hyperostosis.
Facial palsy caused by facial nerve entrapment is an uncommon manifestation.
Seizures can result from hypocalcemia.
IAO is characterized by childhood onset with a milder course than ARO. Life expectancy is normal in most individuals. Children may present with fractures after minor trauma or characteristic changes on x-rays obtained for other clinical indications. Hematologic signs are milder than those in ARO and are usually restricted to anemia. Although CNS involvement is usually absent, visual impairment secondary to optic nerve encroachment can occur [
Although ADOII is sometimes called "benign osteopetrosis," as many as 60%-80% of individuals with radiologic signs of ADOII experience clinical problems (
Onset of radiologic and clinical manifestations of ADOII is usually in late childhood or adolescence, although earlier occurrence has been reported. Osteosclerosis of the spine predominates, with a "sandwich vertebra" appearance, a diagnostic criterion for ADOII. Most affected individuals have a "bone-within-bone" appearance primarily in the iliac wings, but also in other bones. Transverse bands of sclerosis, perpendicular to the main axis, are often observed in long bones. Increase in the skull base density can be seen [
Clinical findings vary even within the same family [
The main complications affect the skeleton:
Cranial nerve compression caused by osteosclerosis of the skull base is rare. Hearing loss and visual loss occurs in up to 19% of affected individuals.
No genotype-phenotype correlations have been identified.
Penetrance ranges from 60% to 90% in families with ADOII [
The prevalence of ADOII has been estimated at up to 1:20,000 [
ARO is less common, with an estimated prevalence of 1:250,000.
•
• Visual impairment beginning shortly after birth is common. In most individuals it is caused by optic nerve compression within the osteosclerotic skull base.
• Skull changes may also cause hydrocephalus.
• A prominent and large anterior fontanelle is common and sometimes associated with hydrocephalus, possibly caused by obstruction of cerebral blood flow and cerebrospinal fluid circulation as a result of hyperostosis.
• Facial palsy caused by facial nerve entrapment is an uncommon manifestation.
• Seizures can result from hypocalcemia.
• Visual impairment beginning shortly after birth is common. In most individuals it is caused by optic nerve compression within the osteosclerotic skull base.
• Skull changes may also cause hydrocephalus.
• A prominent and large anterior fontanelle is common and sometimes associated with hydrocephalus, possibly caused by obstruction of cerebral blood flow and cerebrospinal fluid circulation as a result of hyperostosis.
• Facial palsy caused by facial nerve entrapment is an uncommon manifestation.
• Seizures can result from hypocalcemia.
• Visual impairment beginning shortly after birth is common. In most individuals it is caused by optic nerve compression within the osteosclerotic skull base.
• Skull changes may also cause hydrocephalus.
• A prominent and large anterior fontanelle is common and sometimes associated with hydrocephalus, possibly caused by obstruction of cerebral blood flow and cerebrospinal fluid circulation as a result of hyperostosis.
• Facial palsy caused by facial nerve entrapment is an uncommon manifestation.
• Seizures can result from hypocalcemia.
## Clinical Description
To date, approximately 300 individuals have been identified with a pathogenic variant in
ARO is a systemic, life-threatening disorder. Onset of symptoms is at birth. Without treatment, life span is approximately ten years (although rare exceptions of far longer survival have occurred). Note: Many of the most complete clinical descriptions of ARO were published prior to the discovery of the causative gene.
Possible clinical manifestations of ARO include the following.
Visual impairment beginning shortly after birth is common. In most individuals it is caused by optic nerve compression within the osteosclerotic skull base.
Skull changes may also cause hydrocephalus.
A prominent and large anterior fontanelle is common and sometimes associated with hydrocephalus, possibly caused by obstruction of cerebral blood flow and cerebrospinal fluid circulation as a result of hyperostosis.
Facial palsy caused by facial nerve entrapment is an uncommon manifestation.
Seizures can result from hypocalcemia.
IAO is characterized by childhood onset with a milder course than ARO. Life expectancy is normal in most individuals. Children may present with fractures after minor trauma or characteristic changes on x-rays obtained for other clinical indications. Hematologic signs are milder than those in ARO and are usually restricted to anemia. Although CNS involvement is usually absent, visual impairment secondary to optic nerve encroachment can occur [
Although ADOII is sometimes called "benign osteopetrosis," as many as 60%-80% of individuals with radiologic signs of ADOII experience clinical problems (
Onset of radiologic and clinical manifestations of ADOII is usually in late childhood or adolescence, although earlier occurrence has been reported. Osteosclerosis of the spine predominates, with a "sandwich vertebra" appearance, a diagnostic criterion for ADOII. Most affected individuals have a "bone-within-bone" appearance primarily in the iliac wings, but also in other bones. Transverse bands of sclerosis, perpendicular to the main axis, are often observed in long bones. Increase in the skull base density can be seen [
Clinical findings vary even within the same family [
The main complications affect the skeleton:
Cranial nerve compression caused by osteosclerosis of the skull base is rare. Hearing loss and visual loss occurs in up to 19% of affected individuals.
•
• Visual impairment beginning shortly after birth is common. In most individuals it is caused by optic nerve compression within the osteosclerotic skull base.
• Skull changes may also cause hydrocephalus.
• A prominent and large anterior fontanelle is common and sometimes associated with hydrocephalus, possibly caused by obstruction of cerebral blood flow and cerebrospinal fluid circulation as a result of hyperostosis.
• Facial palsy caused by facial nerve entrapment is an uncommon manifestation.
• Seizures can result from hypocalcemia.
• Visual impairment beginning shortly after birth is common. In most individuals it is caused by optic nerve compression within the osteosclerotic skull base.
• Skull changes may also cause hydrocephalus.
• A prominent and large anterior fontanelle is common and sometimes associated with hydrocephalus, possibly caused by obstruction of cerebral blood flow and cerebrospinal fluid circulation as a result of hyperostosis.
• Facial palsy caused by facial nerve entrapment is an uncommon manifestation.
• Seizures can result from hypocalcemia.
• Visual impairment beginning shortly after birth is common. In most individuals it is caused by optic nerve compression within the osteosclerotic skull base.
• Skull changes may also cause hydrocephalus.
• A prominent and large anterior fontanelle is common and sometimes associated with hydrocephalus, possibly caused by obstruction of cerebral blood flow and cerebrospinal fluid circulation as a result of hyperostosis.
• Facial palsy caused by facial nerve entrapment is an uncommon manifestation.
• Seizures can result from hypocalcemia.
## Infantile Malignant
ARO is a systemic, life-threatening disorder. Onset of symptoms is at birth. Without treatment, life span is approximately ten years (although rare exceptions of far longer survival have occurred). Note: Many of the most complete clinical descriptions of ARO were published prior to the discovery of the causative gene.
Possible clinical manifestations of ARO include the following.
Visual impairment beginning shortly after birth is common. In most individuals it is caused by optic nerve compression within the osteosclerotic skull base.
Skull changes may also cause hydrocephalus.
A prominent and large anterior fontanelle is common and sometimes associated with hydrocephalus, possibly caused by obstruction of cerebral blood flow and cerebrospinal fluid circulation as a result of hyperostosis.
Facial palsy caused by facial nerve entrapment is an uncommon manifestation.
Seizures can result from hypocalcemia.
•
• Visual impairment beginning shortly after birth is common. In most individuals it is caused by optic nerve compression within the osteosclerotic skull base.
• Skull changes may also cause hydrocephalus.
• A prominent and large anterior fontanelle is common and sometimes associated with hydrocephalus, possibly caused by obstruction of cerebral blood flow and cerebrospinal fluid circulation as a result of hyperostosis.
• Facial palsy caused by facial nerve entrapment is an uncommon manifestation.
• Seizures can result from hypocalcemia.
• Visual impairment beginning shortly after birth is common. In most individuals it is caused by optic nerve compression within the osteosclerotic skull base.
• Skull changes may also cause hydrocephalus.
• A prominent and large anterior fontanelle is common and sometimes associated with hydrocephalus, possibly caused by obstruction of cerebral blood flow and cerebrospinal fluid circulation as a result of hyperostosis.
• Facial palsy caused by facial nerve entrapment is an uncommon manifestation.
• Seizures can result from hypocalcemia.
• Visual impairment beginning shortly after birth is common. In most individuals it is caused by optic nerve compression within the osteosclerotic skull base.
• Skull changes may also cause hydrocephalus.
• A prominent and large anterior fontanelle is common and sometimes associated with hydrocephalus, possibly caused by obstruction of cerebral blood flow and cerebrospinal fluid circulation as a result of hyperostosis.
• Facial palsy caused by facial nerve entrapment is an uncommon manifestation.
• Seizures can result from hypocalcemia.
## Intermediate Autosomal Osteopetrosis (IAO)
IAO is characterized by childhood onset with a milder course than ARO. Life expectancy is normal in most individuals. Children may present with fractures after minor trauma or characteristic changes on x-rays obtained for other clinical indications. Hematologic signs are milder than those in ARO and are usually restricted to anemia. Although CNS involvement is usually absent, visual impairment secondary to optic nerve encroachment can occur [
## Autosomal Dominant Osteopetrosis Type II (ADOII)
Although ADOII is sometimes called "benign osteopetrosis," as many as 60%-80% of individuals with radiologic signs of ADOII experience clinical problems (
Onset of radiologic and clinical manifestations of ADOII is usually in late childhood or adolescence, although earlier occurrence has been reported. Osteosclerosis of the spine predominates, with a "sandwich vertebra" appearance, a diagnostic criterion for ADOII. Most affected individuals have a "bone-within-bone" appearance primarily in the iliac wings, but also in other bones. Transverse bands of sclerosis, perpendicular to the main axis, are often observed in long bones. Increase in the skull base density can be seen [
Clinical findings vary even within the same family [
The main complications affect the skeleton:
Cranial nerve compression caused by osteosclerosis of the skull base is rare. Hearing loss and visual loss occurs in up to 19% of affected individuals.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Penetrance
Penetrance ranges from 60% to 90% in families with ADOII [
## Prevalence
The prevalence of ADOII has been estimated at up to 1:20,000 [
ARO is less common, with an estimated prevalence of 1:250,000.
## Genetically Related (Allelic) Disorders
Heterozygous germline pathogenic variants in
## Differential Diagnosis
Pathogenic variants in
Other Types of Autosomal Recessive Osteopetrosis
ADOII = autosomal dominant osteopetrosis type II; ARO = autosomal recessive osteopetrosis; CNS = central nervous system; ID = intellectual disability; HSCT = hematopoietic stem cell transplantation
Heterozygous pathogenic variants in
Other Disorders to Consider in the Differential Diagnosis of
Clinical hallmark is skull hyperostosis → deep-set eyes & paranasal bossing. Facial nerve palsy is common & more frequent than optic nerve compression.
The femur shows a modeling defect, but no osteosclerosis. Susceptibility to fractures is not ↑.
Short-limbed short stature, typical facial appearance (convex nasal ridge & small jaw w/obtuse mandibular angle), osteosclerosis w/↑ bone fragility, acroosteolysis of distal phalanges, delayed closure of cranial sutures, & dysplasia of clavicle
In some affected persons clinical presentation can resemble IAO.
Typical features of craniometaphyseal dysplasia (macrocephaly, hearing loss, skull hyperostosis w/paranasal bossing, metaphyseal widening) but less pronounced calvarial thickening
Due to diaphyseal osteosclerosis; can occasionally resemble mild forms of osteopetrosis
While the disorder name differs,
Assoc w/platyspondyly (a distinguishing feature). Disorder appears to be osteoclast-poor. No neurologic complications.
AD = autosomal dominant; ADO = autosomal dominant osteopetrosis; AR = autosomal recessive; ARO = autosomal recessive osteopetrosis; IAO = intermediate autosomal osteopetrosis; MOI = mode of inheritance
• Clinical hallmark is skull hyperostosis → deep-set eyes & paranasal bossing. Facial nerve palsy is common & more frequent than optic nerve compression.
• The femur shows a modeling defect, but no osteosclerosis. Susceptibility to fractures is not ↑.
• Short-limbed short stature, typical facial appearance (convex nasal ridge & small jaw w/obtuse mandibular angle), osteosclerosis w/↑ bone fragility, acroosteolysis of distal phalanges, delayed closure of cranial sutures, & dysplasia of clavicle
• In some affected persons clinical presentation can resemble IAO.
• Typical features of craniometaphyseal dysplasia (macrocephaly, hearing loss, skull hyperostosis w/paranasal bossing, metaphyseal widening) but less pronounced calvarial thickening
• Due to diaphyseal osteosclerosis; can occasionally resemble mild forms of osteopetrosis
• While the disorder name differs,
• Assoc w/platyspondyly (a distinguishing feature). Disorder appears to be osteoclast-poor. No neurologic complications.
## ARO
Other Types of Autosomal Recessive Osteopetrosis
ADOII = autosomal dominant osteopetrosis type II; ARO = autosomal recessive osteopetrosis; CNS = central nervous system; ID = intellectual disability; HSCT = hematopoietic stem cell transplantation
## Autosomal Dominant Osteopetrosis (ADO)
Heterozygous pathogenic variants in
## Other
Other Disorders to Consider in the Differential Diagnosis of
Clinical hallmark is skull hyperostosis → deep-set eyes & paranasal bossing. Facial nerve palsy is common & more frequent than optic nerve compression.
The femur shows a modeling defect, but no osteosclerosis. Susceptibility to fractures is not ↑.
Short-limbed short stature, typical facial appearance (convex nasal ridge & small jaw w/obtuse mandibular angle), osteosclerosis w/↑ bone fragility, acroosteolysis of distal phalanges, delayed closure of cranial sutures, & dysplasia of clavicle
In some affected persons clinical presentation can resemble IAO.
Typical features of craniometaphyseal dysplasia (macrocephaly, hearing loss, skull hyperostosis w/paranasal bossing, metaphyseal widening) but less pronounced calvarial thickening
Due to diaphyseal osteosclerosis; can occasionally resemble mild forms of osteopetrosis
While the disorder name differs,
Assoc w/platyspondyly (a distinguishing feature). Disorder appears to be osteoclast-poor. No neurologic complications.
AD = autosomal dominant; ADO = autosomal dominant osteopetrosis; AR = autosomal recessive; ARO = autosomal recessive osteopetrosis; IAO = intermediate autosomal osteopetrosis; MOI = mode of inheritance
• Clinical hallmark is skull hyperostosis → deep-set eyes & paranasal bossing. Facial nerve palsy is common & more frequent than optic nerve compression.
• The femur shows a modeling defect, but no osteosclerosis. Susceptibility to fractures is not ↑.
• Short-limbed short stature, typical facial appearance (convex nasal ridge & small jaw w/obtuse mandibular angle), osteosclerosis w/↑ bone fragility, acroosteolysis of distal phalanges, delayed closure of cranial sutures, & dysplasia of clavicle
• In some affected persons clinical presentation can resemble IAO.
• Typical features of craniometaphyseal dysplasia (macrocephaly, hearing loss, skull hyperostosis w/paranasal bossing, metaphyseal widening) but less pronounced calvarial thickening
• Due to diaphyseal osteosclerosis; can occasionally resemble mild forms of osteopetrosis
• While the disorder name differs,
• Assoc w/platyspondyly (a distinguishing feature). Disorder appears to be osteoclast-poor. No neurologic complications.
## Management
General guidelines for diagnosis, therapy, and follow up are available for all forms of osteopetrosis; see
Due to the difference in severity, the evaluation, treatment, and surveillance recommendations for infantile malignant
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with Infantile Malignant
Community or
Social work involvement for parental support;
Home nursing referral.
ARO = autosomal recessive osteopetrosis; MOI = mode of inheritance; VEP = visual evoked potential
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
ADOII = autosomal dominant osteopetrosis type II; MOI = mode of inheritance; VEP = visual evoked potential
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Due to the difference in severity, treatment strategies for ARO and ADOII differ. IAO lies between these two forms and has a variable prognosis. Therefore, treatment options must be evaluated on an individual basis.
Treatment of Manifestations in Individuals with Infantile Malignant
ARO = autosomal recessive osteopetrosis; HSCT = hematopoietic stem cell transplantation
The management of calcium homeostasis may be difficult and recommendations are conflicting: whereas physiologic doses of calcium and vitamin D have been used to treat children with osteopetrosis who have rickets, restriction of calcium and vitamin D has been used to prevent progression of disease and hypercalcemic crisis following HSCT. Treatment needs to take into account the particular situation of the affected individual.
Treatment of Manifestations in Individuals with
ADOII = autosomal dominant osteopetrosis type II
Restricted intake of calcium and vitamin D just before, during, and following HSCT to prevent hypercalcemia is recommended.
Secondary neurosensory impairments caused by nerve compression may be prevented by early transplantation, but not reversed when they are already present.
Cranial nerve dysfunction (visual impairment caused by optic nerve atrophy) is irreversible in most individuals. In the authors' series including about 30 individuals, about two thirds of affected individuals were visually impaired after successful transplantation [A Schulz, unpublished results].
Primary neurologic problems and retinal degeneration developing in the neuronopathic form of ARO, however, are independent of the bone disease and therefore cannot be improved or prevented by HSCT. Persons with ARO resulting from
It is highly important but difficult to exclude individuals with the neuronopathic form from this invasive treatment [
Progressive neurologic sequelae, developmental delay, and repeated seizures occur in a subset of individuals after successful HSCT [
The incidence of severe complications post-HSCT is high, particularly when alternative stem cell sources are used. Complications include rejection, delayed hematopoietic reconstitution, venous occlusive disease, pulmonary hypertension, and hypercalcemic crisis [
The outcome of HSCT in ARO has been analyzed in a retrospective survey of the European Society of Immunodeficiencies (ESID) and the European Group of Bone Marrow Transplantation (EBMT) [
In a published report of 193 individuals transplanted in various centers by a cyclophosphamide-based regimen, the five-year probabilities of survival were 62% after HLA-matched sib transplantation and 42% after alternative donor transplantation [
A further improved outcome was reported from three large transplant centers using a fludarabine-based conditioning regimen [
In HLA-haploidentical HSCT, the implementation of post-transplant cyclophosphamide according to a modified Baltimore protocol achieved promising results. Therefore, this protocol was included in the recently updated treatment guidelines of the EBMT/ESID inborn errors working party [
Note: Because
Recommended Surveillance for Individuals with Infantile Malignant
CBC = complete blood count; HSCT = hematopoietic stem cell transplantation
Recommended Surveillance for Individuals with
Activities with high fracture risk should be avoided.
Orthopedic surgery should only be performed when absolutely necessary and the surgeon should be aware of potential complications and difficulties in handling osteopetrotic bone.
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing of the
See
Search
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Restricted intake of calcium and vitamin D just before, during, and following HSCT to prevent hypercalcemia is recommended.
• Secondary neurosensory impairments caused by nerve compression may be prevented by early transplantation, but not reversed when they are already present.
• Cranial nerve dysfunction (visual impairment caused by optic nerve atrophy) is irreversible in most individuals. In the authors' series including about 30 individuals, about two thirds of affected individuals were visually impaired after successful transplantation [A Schulz, unpublished results].
• Primary neurologic problems and retinal degeneration developing in the neuronopathic form of ARO, however, are independent of the bone disease and therefore cannot be improved or prevented by HSCT. Persons with ARO resulting from
• It is highly important but difficult to exclude individuals with the neuronopathic form from this invasive treatment [
• Progressive neurologic sequelae, developmental delay, and repeated seizures occur in a subset of individuals after successful HSCT [
•
• The incidence of severe complications post-HSCT is high, particularly when alternative stem cell sources are used. Complications include rejection, delayed hematopoietic reconstitution, venous occlusive disease, pulmonary hypertension, and hypercalcemic crisis [
• The outcome of HSCT in ARO has been analyzed in a retrospective survey of the European Society of Immunodeficiencies (ESID) and the European Group of Bone Marrow Transplantation (EBMT) [
• In a published report of 193 individuals transplanted in various centers by a cyclophosphamide-based regimen, the five-year probabilities of survival were 62% after HLA-matched sib transplantation and 42% after alternative donor transplantation [
• A further improved outcome was reported from three large transplant centers using a fludarabine-based conditioning regimen [
• In HLA-haploidentical HSCT, the implementation of post-transplant cyclophosphamide according to a modified Baltimore protocol achieved promising results. Therefore, this protocol was included in the recently updated treatment guidelines of the EBMT/ESID inborn errors working party [
• The incidence of severe complications post-HSCT is high, particularly when alternative stem cell sources are used. Complications include rejection, delayed hematopoietic reconstitution, venous occlusive disease, pulmonary hypertension, and hypercalcemic crisis [
• The outcome of HSCT in ARO has been analyzed in a retrospective survey of the European Society of Immunodeficiencies (ESID) and the European Group of Bone Marrow Transplantation (EBMT) [
• In a published report of 193 individuals transplanted in various centers by a cyclophosphamide-based regimen, the five-year probabilities of survival were 62% after HLA-matched sib transplantation and 42% after alternative donor transplantation [
• A further improved outcome was reported from three large transplant centers using a fludarabine-based conditioning regimen [
• In HLA-haploidentical HSCT, the implementation of post-transplant cyclophosphamide according to a modified Baltimore protocol achieved promising results. Therefore, this protocol was included in the recently updated treatment guidelines of the EBMT/ESID inborn errors working party [
• The incidence of severe complications post-HSCT is high, particularly when alternative stem cell sources are used. Complications include rejection, delayed hematopoietic reconstitution, venous occlusive disease, pulmonary hypertension, and hypercalcemic crisis [
• The outcome of HSCT in ARO has been analyzed in a retrospective survey of the European Society of Immunodeficiencies (ESID) and the European Group of Bone Marrow Transplantation (EBMT) [
• In a published report of 193 individuals transplanted in various centers by a cyclophosphamide-based regimen, the five-year probabilities of survival were 62% after HLA-matched sib transplantation and 42% after alternative donor transplantation [
• A further improved outcome was reported from three large transplant centers using a fludarabine-based conditioning regimen [
• In HLA-haploidentical HSCT, the implementation of post-transplant cyclophosphamide according to a modified Baltimore protocol achieved promising results. Therefore, this protocol was included in the recently updated treatment guidelines of the EBMT/ESID inborn errors working party [
• Activities with high fracture risk should be avoided.
• Orthopedic surgery should only be performed when absolutely necessary and the surgeon should be aware of potential complications and difficulties in handling osteopetrotic bone.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with Infantile Malignant
Community or
Social work involvement for parental support;
Home nursing referral.
ARO = autosomal recessive osteopetrosis; MOI = mode of inheritance; VEP = visual evoked potential
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
ADOII = autosomal dominant osteopetrosis type II; MOI = mode of inheritance; VEP = visual evoked potential
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Due to the difference in severity, treatment strategies for ARO and ADOII differ. IAO lies between these two forms and has a variable prognosis. Therefore, treatment options must be evaluated on an individual basis.
Treatment of Manifestations in Individuals with Infantile Malignant
ARO = autosomal recessive osteopetrosis; HSCT = hematopoietic stem cell transplantation
The management of calcium homeostasis may be difficult and recommendations are conflicting: whereas physiologic doses of calcium and vitamin D have been used to treat children with osteopetrosis who have rickets, restriction of calcium and vitamin D has been used to prevent progression of disease and hypercalcemic crisis following HSCT. Treatment needs to take into account the particular situation of the affected individual.
Treatment of Manifestations in Individuals with
ADOII = autosomal dominant osteopetrosis type II
## Prevention of Primary Manifestations
Restricted intake of calcium and vitamin D just before, during, and following HSCT to prevent hypercalcemia is recommended.
Secondary neurosensory impairments caused by nerve compression may be prevented by early transplantation, but not reversed when they are already present.
Cranial nerve dysfunction (visual impairment caused by optic nerve atrophy) is irreversible in most individuals. In the authors' series including about 30 individuals, about two thirds of affected individuals were visually impaired after successful transplantation [A Schulz, unpublished results].
Primary neurologic problems and retinal degeneration developing in the neuronopathic form of ARO, however, are independent of the bone disease and therefore cannot be improved or prevented by HSCT. Persons with ARO resulting from
It is highly important but difficult to exclude individuals with the neuronopathic form from this invasive treatment [
Progressive neurologic sequelae, developmental delay, and repeated seizures occur in a subset of individuals after successful HSCT [
The incidence of severe complications post-HSCT is high, particularly when alternative stem cell sources are used. Complications include rejection, delayed hematopoietic reconstitution, venous occlusive disease, pulmonary hypertension, and hypercalcemic crisis [
The outcome of HSCT in ARO has been analyzed in a retrospective survey of the European Society of Immunodeficiencies (ESID) and the European Group of Bone Marrow Transplantation (EBMT) [
In a published report of 193 individuals transplanted in various centers by a cyclophosphamide-based regimen, the five-year probabilities of survival were 62% after HLA-matched sib transplantation and 42% after alternative donor transplantation [
A further improved outcome was reported from three large transplant centers using a fludarabine-based conditioning regimen [
In HLA-haploidentical HSCT, the implementation of post-transplant cyclophosphamide according to a modified Baltimore protocol achieved promising results. Therefore, this protocol was included in the recently updated treatment guidelines of the EBMT/ESID inborn errors working party [
Note: Because
• Restricted intake of calcium and vitamin D just before, during, and following HSCT to prevent hypercalcemia is recommended.
• Secondary neurosensory impairments caused by nerve compression may be prevented by early transplantation, but not reversed when they are already present.
• Cranial nerve dysfunction (visual impairment caused by optic nerve atrophy) is irreversible in most individuals. In the authors' series including about 30 individuals, about two thirds of affected individuals were visually impaired after successful transplantation [A Schulz, unpublished results].
• Primary neurologic problems and retinal degeneration developing in the neuronopathic form of ARO, however, are independent of the bone disease and therefore cannot be improved or prevented by HSCT. Persons with ARO resulting from
• It is highly important but difficult to exclude individuals with the neuronopathic form from this invasive treatment [
• Progressive neurologic sequelae, developmental delay, and repeated seizures occur in a subset of individuals after successful HSCT [
•
• The incidence of severe complications post-HSCT is high, particularly when alternative stem cell sources are used. Complications include rejection, delayed hematopoietic reconstitution, venous occlusive disease, pulmonary hypertension, and hypercalcemic crisis [
• The outcome of HSCT in ARO has been analyzed in a retrospective survey of the European Society of Immunodeficiencies (ESID) and the European Group of Bone Marrow Transplantation (EBMT) [
• In a published report of 193 individuals transplanted in various centers by a cyclophosphamide-based regimen, the five-year probabilities of survival were 62% after HLA-matched sib transplantation and 42% after alternative donor transplantation [
• A further improved outcome was reported from three large transplant centers using a fludarabine-based conditioning regimen [
• In HLA-haploidentical HSCT, the implementation of post-transplant cyclophosphamide according to a modified Baltimore protocol achieved promising results. Therefore, this protocol was included in the recently updated treatment guidelines of the EBMT/ESID inborn errors working party [
• The incidence of severe complications post-HSCT is high, particularly when alternative stem cell sources are used. Complications include rejection, delayed hematopoietic reconstitution, venous occlusive disease, pulmonary hypertension, and hypercalcemic crisis [
• The outcome of HSCT in ARO has been analyzed in a retrospective survey of the European Society of Immunodeficiencies (ESID) and the European Group of Bone Marrow Transplantation (EBMT) [
• In a published report of 193 individuals transplanted in various centers by a cyclophosphamide-based regimen, the five-year probabilities of survival were 62% after HLA-matched sib transplantation and 42% after alternative donor transplantation [
• A further improved outcome was reported from three large transplant centers using a fludarabine-based conditioning regimen [
• In HLA-haploidentical HSCT, the implementation of post-transplant cyclophosphamide according to a modified Baltimore protocol achieved promising results. Therefore, this protocol was included in the recently updated treatment guidelines of the EBMT/ESID inborn errors working party [
• The incidence of severe complications post-HSCT is high, particularly when alternative stem cell sources are used. Complications include rejection, delayed hematopoietic reconstitution, venous occlusive disease, pulmonary hypertension, and hypercalcemic crisis [
• The outcome of HSCT in ARO has been analyzed in a retrospective survey of the European Society of Immunodeficiencies (ESID) and the European Group of Bone Marrow Transplantation (EBMT) [
• In a published report of 193 individuals transplanted in various centers by a cyclophosphamide-based regimen, the five-year probabilities of survival were 62% after HLA-matched sib transplantation and 42% after alternative donor transplantation [
• A further improved outcome was reported from three large transplant centers using a fludarabine-based conditioning regimen [
• In HLA-haploidentical HSCT, the implementation of post-transplant cyclophosphamide according to a modified Baltimore protocol achieved promising results. Therefore, this protocol was included in the recently updated treatment guidelines of the EBMT/ESID inborn errors working party [
## Infantile Malignant
Restricted intake of calcium and vitamin D just before, during, and following HSCT to prevent hypercalcemia is recommended.
Secondary neurosensory impairments caused by nerve compression may be prevented by early transplantation, but not reversed when they are already present.
Cranial nerve dysfunction (visual impairment caused by optic nerve atrophy) is irreversible in most individuals. In the authors' series including about 30 individuals, about two thirds of affected individuals were visually impaired after successful transplantation [A Schulz, unpublished results].
Primary neurologic problems and retinal degeneration developing in the neuronopathic form of ARO, however, are independent of the bone disease and therefore cannot be improved or prevented by HSCT. Persons with ARO resulting from
It is highly important but difficult to exclude individuals with the neuronopathic form from this invasive treatment [
Progressive neurologic sequelae, developmental delay, and repeated seizures occur in a subset of individuals after successful HSCT [
The incidence of severe complications post-HSCT is high, particularly when alternative stem cell sources are used. Complications include rejection, delayed hematopoietic reconstitution, venous occlusive disease, pulmonary hypertension, and hypercalcemic crisis [
The outcome of HSCT in ARO has been analyzed in a retrospective survey of the European Society of Immunodeficiencies (ESID) and the European Group of Bone Marrow Transplantation (EBMT) [
In a published report of 193 individuals transplanted in various centers by a cyclophosphamide-based regimen, the five-year probabilities of survival were 62% after HLA-matched sib transplantation and 42% after alternative donor transplantation [
A further improved outcome was reported from three large transplant centers using a fludarabine-based conditioning regimen [
In HLA-haploidentical HSCT, the implementation of post-transplant cyclophosphamide according to a modified Baltimore protocol achieved promising results. Therefore, this protocol was included in the recently updated treatment guidelines of the EBMT/ESID inborn errors working party [
Note: Because
• Restricted intake of calcium and vitamin D just before, during, and following HSCT to prevent hypercalcemia is recommended.
• Secondary neurosensory impairments caused by nerve compression may be prevented by early transplantation, but not reversed when they are already present.
• Cranial nerve dysfunction (visual impairment caused by optic nerve atrophy) is irreversible in most individuals. In the authors' series including about 30 individuals, about two thirds of affected individuals were visually impaired after successful transplantation [A Schulz, unpublished results].
• Primary neurologic problems and retinal degeneration developing in the neuronopathic form of ARO, however, are independent of the bone disease and therefore cannot be improved or prevented by HSCT. Persons with ARO resulting from
• It is highly important but difficult to exclude individuals with the neuronopathic form from this invasive treatment [
• Progressive neurologic sequelae, developmental delay, and repeated seizures occur in a subset of individuals after successful HSCT [
•
• The incidence of severe complications post-HSCT is high, particularly when alternative stem cell sources are used. Complications include rejection, delayed hematopoietic reconstitution, venous occlusive disease, pulmonary hypertension, and hypercalcemic crisis [
• The outcome of HSCT in ARO has been analyzed in a retrospective survey of the European Society of Immunodeficiencies (ESID) and the European Group of Bone Marrow Transplantation (EBMT) [
• In a published report of 193 individuals transplanted in various centers by a cyclophosphamide-based regimen, the five-year probabilities of survival were 62% after HLA-matched sib transplantation and 42% after alternative donor transplantation [
• A further improved outcome was reported from three large transplant centers using a fludarabine-based conditioning regimen [
• In HLA-haploidentical HSCT, the implementation of post-transplant cyclophosphamide according to a modified Baltimore protocol achieved promising results. Therefore, this protocol was included in the recently updated treatment guidelines of the EBMT/ESID inborn errors working party [
• The incidence of severe complications post-HSCT is high, particularly when alternative stem cell sources are used. Complications include rejection, delayed hematopoietic reconstitution, venous occlusive disease, pulmonary hypertension, and hypercalcemic crisis [
• The outcome of HSCT in ARO has been analyzed in a retrospective survey of the European Society of Immunodeficiencies (ESID) and the European Group of Bone Marrow Transplantation (EBMT) [
• In a published report of 193 individuals transplanted in various centers by a cyclophosphamide-based regimen, the five-year probabilities of survival were 62% after HLA-matched sib transplantation and 42% after alternative donor transplantation [
• A further improved outcome was reported from three large transplant centers using a fludarabine-based conditioning regimen [
• In HLA-haploidentical HSCT, the implementation of post-transplant cyclophosphamide according to a modified Baltimore protocol achieved promising results. Therefore, this protocol was included in the recently updated treatment guidelines of the EBMT/ESID inborn errors working party [
• The incidence of severe complications post-HSCT is high, particularly when alternative stem cell sources are used. Complications include rejection, delayed hematopoietic reconstitution, venous occlusive disease, pulmonary hypertension, and hypercalcemic crisis [
• The outcome of HSCT in ARO has been analyzed in a retrospective survey of the European Society of Immunodeficiencies (ESID) and the European Group of Bone Marrow Transplantation (EBMT) [
• In a published report of 193 individuals transplanted in various centers by a cyclophosphamide-based regimen, the five-year probabilities of survival were 62% after HLA-matched sib transplantation and 42% after alternative donor transplantation [
• A further improved outcome was reported from three large transplant centers using a fludarabine-based conditioning regimen [
• In HLA-haploidentical HSCT, the implementation of post-transplant cyclophosphamide according to a modified Baltimore protocol achieved promising results. Therefore, this protocol was included in the recently updated treatment guidelines of the EBMT/ESID inborn errors working party [
## Surveillance
Recommended Surveillance for Individuals with Infantile Malignant
CBC = complete blood count; HSCT = hematopoietic stem cell transplantation
Recommended Surveillance for Individuals with
## Agents/Circumstances to Avoid
Activities with high fracture risk should be avoided.
Orthopedic surgery should only be performed when absolutely necessary and the surgeon should be aware of potential complications and difficulties in handling osteopetrotic bone.
• Activities with high fracture risk should be avoided.
• Orthopedic surgery should only be performed when absolutely necessary and the surgeon should be aware of potential complications and difficulties in handling osteopetrotic bone.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing of the
See
## Therapies Under Investigation
Search
## Genetic Counseling
Infantile malignant
About 40% of
The parents of an affected child are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Individuals who are heterozygous for a
If both parents are known to be heterozygous for a
The limited data available suggest that in the presence of ARO, a similar presentation of the disorder is expected in individuals with biallelic
Individuals who are heterozygous for a
The offspring of an individual with autosomal recessive
In general, individuals with ARO reproduce only if successfully treated by hematopoietic stem cell transplantation.
Carrier testing for at-risk relatives requires prior identification of the
Most individuals diagnosed with autosomal dominant
A proband with autosomal dominant
If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of parents include x-ray investigation of the skeleton and molecular genetic testing for the pathogenic variant identified in the proband. Evaluation of the parents is used to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of reduced penetrance, failure by health care professionals to recognize the syndrome, and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
If a parent of the proband is affected and/or is known to have the
If the proband has a known
If the parents have not been tested for the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Infantile malignant
• About 40% of
• The parents of an affected child are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Individuals who are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• The limited data available suggest that in the presence of ARO, a similar presentation of the disorder is expected in individuals with biallelic
• Individuals who are heterozygous for a
• The offspring of an individual with autosomal recessive
• In general, individuals with ARO reproduce only if successfully treated by hematopoietic stem cell transplantation.
• Most individuals diagnosed with autosomal dominant
• A proband with autosomal dominant
• If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of parents include x-ray investigation of the skeleton and molecular genetic testing for the pathogenic variant identified in the proband. Evaluation of the parents is used to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of reduced penetrance, failure by health care professionals to recognize the syndrome, and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the
• If the proband has a known
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or at risk of being carriers.
## Mode of Inheritance
Infantile malignant
About 40% of
• Infantile malignant
• About 40% of
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected child are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Individuals who are heterozygous for a
If both parents are known to be heterozygous for a
The limited data available suggest that in the presence of ARO, a similar presentation of the disorder is expected in individuals with biallelic
Individuals who are heterozygous for a
The offspring of an individual with autosomal recessive
In general, individuals with ARO reproduce only if successfully treated by hematopoietic stem cell transplantation.
Carrier testing for at-risk relatives requires prior identification of the
• The parents of an affected child are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Individuals who are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• The limited data available suggest that in the presence of ARO, a similar presentation of the disorder is expected in individuals with biallelic
• Individuals who are heterozygous for a
• The offspring of an individual with autosomal recessive
• In general, individuals with ARO reproduce only if successfully treated by hematopoietic stem cell transplantation.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Autosomal Dominant Inheritance – Risk to Family Members
Most individuals diagnosed with autosomal dominant
A proband with autosomal dominant
If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of parents include x-ray investigation of the skeleton and molecular genetic testing for the pathogenic variant identified in the proband. Evaluation of the parents is used to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of reduced penetrance, failure by health care professionals to recognize the syndrome, and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
If a parent of the proband is affected and/or is known to have the
If the proband has a known
If the parents have not been tested for the
• Most individuals diagnosed with autosomal dominant
• A proband with autosomal dominant
• If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of parents include x-ray investigation of the skeleton and molecular genetic testing for the pathogenic variant identified in the proband. Evaluation of the parents is used to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of reduced penetrance, failure by health care professionals to recognize the syndrome, and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the
• If the proband has a known
• If the parents have not been tested for the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
CeSER
Alexandrinenstraße 5
Germany
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•
•
•
•
•
•
• CeSER
• Alexandrinenstraße 5
• Germany
•
•
•
•
•
## Molecular Genetics
CLCN7-Related Osteopetrosis: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CLCN7-Related Osteopetrosis (
Notable
ADOII = autosomal dominant osteopetrosis type II
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Notable
ADOII = autosomal dominant osteopetrosis type II
Variants listed in the table have been provided by the authors.
## Chapter Notes
Guidelines for diagnosis, therapy, and follow up for this disorder are available
Marie-Christine de Vernejoul, MD, PhD; Hôpital Lariboisière (2007-2016)Uwe Kornak, MD, PhD (2007-present)Ansgar Schulz, MD (2007-present)Cristina Sobacchi, MS (2016-present)Anna Villa, MD, PhD (2016-present)
20 January 2022 (ha) Comprehensive update posted live
9 June 2016 (ha) Comprehensive update posted live
20 June 2013 (me) Comprehensive update posted live
14 October 2010 (me) Comprehensive update posted live
12 February 2007 (me) Review posted live
8 September 2006 (uk) Original submission
• 20 January 2022 (ha) Comprehensive update posted live
• 9 June 2016 (ha) Comprehensive update posted live
• 20 June 2013 (me) Comprehensive update posted live
• 14 October 2010 (me) Comprehensive update posted live
• 12 February 2007 (me) Review posted live
• 8 September 2006 (uk) Original submission
## Author Information
Guidelines for diagnosis, therapy, and follow up for this disorder are available
## Author History
Marie-Christine de Vernejoul, MD, PhD; Hôpital Lariboisière (2007-2016)Uwe Kornak, MD, PhD (2007-present)Ansgar Schulz, MD (2007-present)Cristina Sobacchi, MS (2016-present)Anna Villa, MD, PhD (2016-present)
## Revision History
20 January 2022 (ha) Comprehensive update posted live
9 June 2016 (ha) Comprehensive update posted live
20 June 2013 (me) Comprehensive update posted live
14 October 2010 (me) Comprehensive update posted live
12 February 2007 (me) Review posted live
8 September 2006 (uk) Original submission
• 20 January 2022 (ha) Comprehensive update posted live
• 9 June 2016 (ha) Comprehensive update posted live
• 20 June 2013 (me) Comprehensive update posted live
• 14 October 2010 (me) Comprehensive update posted live
• 12 February 2007 (me) Review posted live
• 8 September 2006 (uk) Original submission
## References
## Literature Cited
Autosomal recessive osteopetrosis radiographs
Autosomal dominant osteopetrosis type II radiographs
Reprinted from
|
[
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"R Crazzolara, K Maurer, H Schulze, B Zieger, J Zustin, AS Schulz. A new mutation in the KINDLIN-3 gene ablates integrin-dependent leukocyte, platelet, and osteoclast function in a patient with leukocyte adhesion deficiency-III.. Pediatr Blood Cancer 2015;62:1677-9",
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"A Frattini, A Pangrazio, L Susani, C Sobacchi, M Mirolo, M Abinun, M Andolina, A Flanagan, EM Horwitz, E Mihci, LD Notarangelo, U Ramenghi, A Teti, J Van Hove, D Vujic, T Young, A Albertini, PJ Orchard, P Vezzoni, A Villa. Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis.. J Bone Miner Res 2003;18:1740-7",
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"A Howaldt, S Nampoothiri, LM Quell, A Ozden, B Fischer-Zirnsak, C Collet, MC de Vernejoul, H Doneray, H Kayserili, U Kornak. Sclerosing bone dysplasias with hallmarks of dysosteosclerosis in four patients carrying mutations in SLC29A3 and TCIRG1.. Bone 2019;120:495-503",
"A Howaldt, AF Hennig, T Rolvien, U Rössler, N Stelzer, A Knaus, S Böttger, J Zustin, S Geißler, R Oheim, M Amling, HP Howaldt, U Kornak. Adult osteosclerotic metaphyseal dysplasia with progressive osteonecrosis of the jaws and abnormal bone resorption pattern due to a LRRK1 splice site mutation.. J Bone Miner Res 2020;35:1322-32",
"Y Hu, IP Chen, S de Almeida, V Tiziani, CM Do Amaral, K Gowrishankar, MR Passos-Bueno, EJ Reichenberger. A novel autosomal recessive GJA1 missense mutation linked to Craniometaphyseal dysplasia.. PLoS One. 2013;8",
"JM Hwang, IO Kim, KC Wang. Complete visual recovery in osteopetrosis by early optic nerve decompression.. Pediatr Neurosurg 2000;33:328-32",
"C Jacquemin, P Mullaney, E Svedberg. Marble brain syndrome: osteopetrosis, renal acidosis and calcification of the brain.. Neuroradiology 1998;40:662-3",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"PN Kantaputra, S Thawanaphong, W Issarangporn, P Klangsinsirikul, A Ohazama, P Sharpe, C Supanchart. Long-term survival in infantile malignant autosomal recessive osteopetrosis secondary to homozygous p.Arg526Gln mutation in CLCN7.. Am J Med Genet A. 2012;158A:909-16",
"U Kornak, D Kasper, MR Bosl, E Kaiser, M Schweizer, A Schulz, W Friedrich, G Delling, TJ Jentsch. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man.. Cell 2001;104:205-15",
"U Kornak, A Schulz, W Friedrich, S Uhlhaas, B Kremens, T Voit, C Hasan, U Bode, TJ Jentsch, C Kubisch. Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis.. Hum Mol Genet 2000;9:2059-63",
"AC Lankester, MH Albert, C Booth, AR Gennery, T Güngör, M Hönig, EC Morris, D Moshous, B Neven, A Schulz, M Slatter, P Veys. EBMT/ESID inborn errors working party guidelines for hematopoietic stem cell transplantation for inborn errors of immunity.. Bone Marrow Transplant. 2021;56:2052-62",
"L Leisle, CF Ludwig, FA Wagner, TJ Jentsch, T Stauber. ClC-7 is a slowly voltage-gated 2Cl(-)/1H(+)-exchanger and requires Ostm1 for transport activity.. EMBO J. 2011;30:2140-52",
"J Natsheh, G Drozdinsky, N Simanovsky, R Lamdan, O Erlich, N Gorelik, R Or, M Weintraub, P Stepensky. Improved outcomes of hematopoietic stem cell transplantation in patients with infantile malignant osteopetrosis using fludarabine-based conditioning.. Pediatr Blood Cancer. 2016;63:535-40",
"ER Nicoli, MR Weston, M Hackbarth, A Becerril, A Larson, WM Zein, PR Baker, JD Burke, H Dorward, M Davids, Y Huang, DR Adams, PM Zerfas, D Chen, TC Markello, C Toro, T Wood, G Elliott, M Vu. Undiagnosed Diseases Network, Zheng W, Garrett LJ, Tifft CJ, Gahl WA, Day-Salvatore DL, Mindell JA, Malicdan MCV. Lysosomal storage and albinism due to effects of a de novo CLCN7 variant on lysosomal acidification.. Am J Hum Genet. 2019;104:1127-38",
"PJ Orchard, AL Fasth, J Le Rademacher, W He, JJ Boelens, EM Horwitz, A Al-Seraihy, M Ayas, CM Bonfim, F Boulad, T Lund, DK Buchbinder, N Kapoor, TA O'Brien, MA Perez, PA Veys, M Eapen. Hematopoietic stem cell transplantation for infantile osteopetrosis.. Blood 2015;126:270-6",
"E Palagano, HC Blair, A Pangrazio, I Tourkova, D Strina, A Angius, G Cuccuru, M Oppo, P Uva, W Van Hul, E Boudin, A Superti-Furga, F Faletra, A Nocerino, MC Ferrari, G Grappiolo, M Monari, A Montanelli, P Vezzoni, A Villa, C Sobacchi. Buried in the middle but guilty: intronic mutations in the TCIRG1 gene cause human autosomal recessive osteopetrosis.. J Bone Miner Res 2015;30:1814-21",
"A Pangrazio, A Fasth, A Sbardellati, PJ Orchard, KA Kasow, J Raza, C Albayrak, D Albayrak, OM Vanakker, B De Moerloose, A Vellodi, LD Notarangelo, C Schlack, G Strauss, JS Kühl, E Caldana, NL Iacono, L Susani, U Kornak, A Schulz, P Vezzoni, A Villa, C Sobacchi. SNX10 mutations define a subgroup of human autosomal recessive osteopetrosis with variable clinical severity.. J Bone Miner Res 2013;28:1041-9",
"U Rössler, AF Hennig, N Stelzer, S Bose, J Kopp, K Søe, L Cyganek, G Zifarelli, S Ali, M von der Hagen, ET Strässler, G Hahn, M Pusch, T Stauber, Z Izsvák, M Gossen, H Stachelscheid, U Kornak. Efficient generation of osteoclasts from human induced pluripotent stem cells and functional investigations of lethal CLCN7-related osteopetrosis.. J Bone Miner Res 2021;36:1621-35",
"A Pangrazio, A Frattini, R Valli, E Maserati, L Susani, P Vezzoni, A Villa, W Al-Herz, C Sobacchi. A homozygous contiguous gene deletion in chromosome 16p13.3 leads to autosomal recessive osteopetrosis in a Jordanian patient.. Calcif Tissue Int 2012;91:250-4",
"A Pangrazio, PL Poliani, A Megarbane, G Lefranc, E Lanino, M Di Rocco, F Rucci, F Lucchini, M Ravanini, F Facchetti, M Abinun, P Vezzoni, A Villa, A Frattini. Mutations in OSTM1 (grey lethal) define a particularly severe form of autosomal recessive osteopetrosis with neural involvement.. J Bone Miner Res 2006;21:1098-105",
"A Pangrazio, M Pusch, E Caldana, A Frattini, E Lanino, PM Tamhankar, S Phadke, AG Lopez, P Orchard, E Mihci, M Abinun, M Wright, K Vettenranta, I Bariae, D Melis, I Tezcan, C Baumann, F Locatelli, M Zecca, E Horwitz, LS Mansour, M Van Roij, P Vezzoni, A Villa, C Sobacchi. Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations.. Hum Mutat 2010;31:E1071-80",
"A Pangrazio, A Puddu, M Oppo, M Valentini, L Zammataro, A Vellodi, B Gener, I Llano-Rivas, J Raza, I Atta, P Vezzoni, A Superti-Furga, A Villa, C Sobacchi. Exome sequencing identifies CTSK mutations in patients originally diagnosed as intermediate osteopetrosis.. Bone 2014;59:122-6",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"R Shroff, O Beringer, K Rao, L Hofbauer, A Schulz. Denosumab for post-transplantation hypercalcemia in osteopetrosis. N Engl J Med 2012;367:1766-7",
"C Sobacchi, A Frattini, MM Guerrini, M Abinun, A Pangrazio, L Susani, R Bredius, G Mancini, A Cant, N Bishop, P Grabowski, A Del Fattore, C Messina, G Errigo, FP Coxon, DI Scott, A Teti, MJ Rogers, P Vezzoni, MH Villa A Helfrich. Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL.. Nat Genet 2007;39:960-2",
"C Sobacchi, A Pangrazio, AG Lopez, DP Gomez, ME Caldana, L Susani, P Vezzoni, A Villa. As little as needed: the extraordinary case of a mild recessive osteopetrosis owing to a novel splicing hypomorphic mutation in the TCIRG1 gene.. J Bone Miner Res 2014;29:1646-50",
"C Sobacchi, A Schulz, FP Coxon, MH Helfrich. Osteopetrosis: genetics, treatment and new insights into osteoclast function.. Nat Rev Endocrinol. 2013;9:522-36",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"CG Steward. Neurological aspects of osteopetrosis.. Neuropathol Appl Neurobiol 2003;29:87-97",
"CG Steward, I Pellier, A Mahajan, MT Ashworth, AG Stuart, A Fasth, D Lang, A Fischer, W Friedrich, AS Schulz. Severe pulmonary hypertension: a frequent complication of stem cell transplantation for malignant infantile osteopetrosis.. Br J Haematol 2004;124:63-71",
"JP Strickland, DJ Berry. Total joint arthroplasty in patients with osteopetrosis: a report of 5 cases and review of the literature.. J Arthroplasty 2005;20:815-20",
"L Van Wesenbeeck, PR Odgren, FP Coxon, A Frattini, P Moens, B Perdu, CA MacKay, E Van Hul, JP Timmermans, F Vanhoenacker, R Jacobs, B Peruzzi, A Teti, MH Helfrich, MJ Rogers, A Villa, W Van Hul. Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans.. J Clin Invest 2007;117:919-30",
"SG Waguespack, SL Hui, LA Dimeglio, MJ Econs. Autosomal dominant osteopetrosis: clinical severity and natural history of 94 subjects with a chloride channel 7 gene mutation.. J Clin Endocrinol Metab. 2007;92:771-8",
"H Wang, M Pan, J Ni, Y Zhang, Y Zhang, S Gao, J Liu, Z Wang, R Zhang, H He, B Wu, X. Duan. ClC-7 deficiency impairs tooth development and eruption.. Sci Rep. 2016;6:19971",
"CJ Wilson, A Vellodi. Autosomal recessive osteopetrosis: diagnosis, management, and outcome.. Arch Dis Child 2000;83:449-52",
"Y Zhang, D Ji, L Li, S Yang, H Zhang. Duan. ClC-7 regulates the pattern and early development of craniofacial bone and tooth.. Theranostics. 2019;9:1387-400"
] |
12/2/2007
|
20/1/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
clpb-def
|
clpb-def
|
[
"Caseinolytic Peptidase B Deficiency",
"CLPB Defect",
"Caseinolytic Peptidase B Deficiency",
"CLPB Deficiency",
"Mitochondrial disaggregase",
"CLPB",
"CLPB Deficiency"
] |
CLPB Deficiency
|
Saskia B Wortmann, Ron A Wevers
|
Summary CLPB ( The diagnosis of CLPB deficiency is established in a proband by identification of biallelic pathogenic variants in CLPB deficiency associated with biallelic Once the
|
## Diagnosis
CLPB (
The disease spectrum of CLPB deficiency ranges from severe to mild.
Polyhydramnios, fetal contractures, intrauterine growth restriction
Microcephaly
Hyperekplexia, absence of voluntary movements, respiratory insufficiency, and swallowing problems
Hypotonia or hypertonia
Seizures
Spasticity
Ataxia, tremor and dystonia, dyskinesia
Intellectual disability
No neurologic involvement
Normal intellect
Neutropenia beginning at birth can be chronic or intermittent (especially during infections) with absolute neutrophil count ranging from severe (<0.5 per mm
Elevated urinary excretion of 3-methylglutaconic acid (3-MGA) (typically 2x-10x the reference range) has been observed in the majority of affected individuals to date. Note: Individuals with isolated neutropenia may have normal urine 3-MGA levels.
Initial brain MRI is often unremarkable; however, during infancy, progressive cerebral and cerebellar atrophy are seen on follow-up MRI in the majority of affected individuals [
The diagnosis of CLPB deficiency
Biallelic
A heterozygous
Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of CLPB deficiency, molecular genetic testing approaches can include
Note: Targeted analysis for c.803C>T, a known founder variant, can be performed first in individuals of Inuit ancestry (see
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by intellectual disability and neurologic findings and/or neutropenia
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in CLPB Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
• Polyhydramnios, fetal contractures, intrauterine growth restriction
• Microcephaly
• Hyperekplexia, absence of voluntary movements, respiratory insufficiency, and swallowing problems
• Hypotonia or hypertonia
• Seizures
• Spasticity
• Ataxia, tremor and dystonia, dyskinesia
• Intellectual disability
• No neurologic involvement
• Normal intellect
• Biallelic
• A heterozygous
• Note: Targeted analysis for c.803C>T, a known founder variant, can be performed first in individuals of Inuit ancestry (see
• For an introduction to multigene panels click
## Suggestive Findings
CLPB (
The disease spectrum of CLPB deficiency ranges from severe to mild.
Polyhydramnios, fetal contractures, intrauterine growth restriction
Microcephaly
Hyperekplexia, absence of voluntary movements, respiratory insufficiency, and swallowing problems
Hypotonia or hypertonia
Seizures
Spasticity
Ataxia, tremor and dystonia, dyskinesia
Intellectual disability
No neurologic involvement
Normal intellect
Neutropenia beginning at birth can be chronic or intermittent (especially during infections) with absolute neutrophil count ranging from severe (<0.5 per mm
Elevated urinary excretion of 3-methylglutaconic acid (3-MGA) (typically 2x-10x the reference range) has been observed in the majority of affected individuals to date. Note: Individuals with isolated neutropenia may have normal urine 3-MGA levels.
Initial brain MRI is often unremarkable; however, during infancy, progressive cerebral and cerebellar atrophy are seen on follow-up MRI in the majority of affected individuals [
• Polyhydramnios, fetal contractures, intrauterine growth restriction
• Microcephaly
• Hyperekplexia, absence of voluntary movements, respiratory insufficiency, and swallowing problems
• Hypotonia or hypertonia
• Seizures
• Spasticity
• Ataxia, tremor and dystonia, dyskinesia
• Intellectual disability
• No neurologic involvement
• Normal intellect
## Clinical Findings
The disease spectrum of CLPB deficiency ranges from severe to mild.
Polyhydramnios, fetal contractures, intrauterine growth restriction
Microcephaly
Hyperekplexia, absence of voluntary movements, respiratory insufficiency, and swallowing problems
Hypotonia or hypertonia
Seizures
Spasticity
Ataxia, tremor and dystonia, dyskinesia
Intellectual disability
No neurologic involvement
Normal intellect
• Polyhydramnios, fetal contractures, intrauterine growth restriction
• Microcephaly
• Hyperekplexia, absence of voluntary movements, respiratory insufficiency, and swallowing problems
• Hypotonia or hypertonia
• Seizures
• Spasticity
• Ataxia, tremor and dystonia, dyskinesia
• Intellectual disability
• No neurologic involvement
• Normal intellect
## Laboratory Findings
Neutropenia beginning at birth can be chronic or intermittent (especially during infections) with absolute neutrophil count ranging from severe (<0.5 per mm
Elevated urinary excretion of 3-methylglutaconic acid (3-MGA) (typically 2x-10x the reference range) has been observed in the majority of affected individuals to date. Note: Individuals with isolated neutropenia may have normal urine 3-MGA levels.
## Imaging Findings
Initial brain MRI is often unremarkable; however, during infancy, progressive cerebral and cerebellar atrophy are seen on follow-up MRI in the majority of affected individuals [
## Establishing the Diagnosis
The diagnosis of CLPB deficiency
Biallelic
A heterozygous
Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of CLPB deficiency, molecular genetic testing approaches can include
Note: Targeted analysis for c.803C>T, a known founder variant, can be performed first in individuals of Inuit ancestry (see
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by intellectual disability and neurologic findings and/or neutropenia
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in CLPB Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
• Biallelic
• A heterozygous
• Note: Targeted analysis for c.803C>T, a known founder variant, can be performed first in individuals of Inuit ancestry (see
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of CLPB deficiency, molecular genetic testing approaches can include
Note: Targeted analysis for c.803C>T, a known founder variant, can be performed first in individuals of Inuit ancestry (see
For an introduction to multigene panels click
• Note: Targeted analysis for c.803C>T, a known founder variant, can be performed first in individuals of Inuit ancestry (see
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by intellectual disability and neurologic findings and/or neutropenia
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in CLPB Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
## Clinical Characteristics
The clinical phenotype of CLPB deficiency ranges from severe to mild as determined by neurologic involvement and neutropenia. Children with neonatal onset or early-infantile onset have severe involvement and may die from complications of their disease, whereas those with late-infantile and early-childhood onset have a milder clinical presentation [
To date a total of 32 individuals from 16 families with biallelic
Autosomal dominant CLPB deficiency has been reported in 16 probands (from 16 families) with severe to mild phenotypes [
CLPB Deficiency: Frequency of Select Features
3-MGA = 3-methylglutaconic acid; AD = autosomal dominant; AR = autosomal or recessive; DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth restriction
Autosomal dominant CLPB deficiency is caused by specific heterozygous
Early demise of individuals with autosomal recessive CLPB deficiency may prevent identification of developmental delay / intellectual disability.
These infants show no motor or intellectual development, and generally die in the first months of life.
Retrospectively, many mothers of infants with the severe phenotype reported issues during the pregnancy, including decreased or increased fetal movements and intrauterine growth restriction [
Subsequent neurologic involvement varies. In many with neonatal onset, generalized hypotonia progresses during childhood to spasticity (mainly of the legs). Many have an infantile-onset progressive movement disorder that can include ataxia, dystonia, or dyskinesia of varying severity. Several individuals have epileptic seizures that can be difficult to treat. All but two have intellectual disability that ranges from mild learning disability to very limited development of all cognitive and motor functions.
Mildly affected individuals show only some clinical signs and symptoms without progression and survive without significant disease burden into adulthood.
Individuals with the most severe phenotypes often have pathogenic variants predicted to lead to the complete absence of functional protein.
Autosomal dominant CLPB deficiency has been reported in six individuals with the following pathogenic variants:
Six different heterozygous
CLPB deficiency is rare. A total of 32 individuals with autosomal recessive CLPB deficiency have been reported to date (n=14 [
In the largely Inuit population of Greenland the carrier frequency of the
## Clinical Description
The clinical phenotype of CLPB deficiency ranges from severe to mild as determined by neurologic involvement and neutropenia. Children with neonatal onset or early-infantile onset have severe involvement and may die from complications of their disease, whereas those with late-infantile and early-childhood onset have a milder clinical presentation [
To date a total of 32 individuals from 16 families with biallelic
Autosomal dominant CLPB deficiency has been reported in 16 probands (from 16 families) with severe to mild phenotypes [
CLPB Deficiency: Frequency of Select Features
3-MGA = 3-methylglutaconic acid; AD = autosomal dominant; AR = autosomal or recessive; DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth restriction
Autosomal dominant CLPB deficiency is caused by specific heterozygous
Early demise of individuals with autosomal recessive CLPB deficiency may prevent identification of developmental delay / intellectual disability.
These infants show no motor or intellectual development, and generally die in the first months of life.
Retrospectively, many mothers of infants with the severe phenotype reported issues during the pregnancy, including decreased or increased fetal movements and intrauterine growth restriction [
Subsequent neurologic involvement varies. In many with neonatal onset, generalized hypotonia progresses during childhood to spasticity (mainly of the legs). Many have an infantile-onset progressive movement disorder that can include ataxia, dystonia, or dyskinesia of varying severity. Several individuals have epileptic seizures that can be difficult to treat. All but two have intellectual disability that ranges from mild learning disability to very limited development of all cognitive and motor functions.
Mildly affected individuals show only some clinical signs and symptoms without progression and survive without significant disease burden into adulthood.
## Severe Phenotype
These infants show no motor or intellectual development, and generally die in the first months of life.
Retrospectively, many mothers of infants with the severe phenotype reported issues during the pregnancy, including decreased or increased fetal movements and intrauterine growth restriction [
## Moderate Phenotype
Subsequent neurologic involvement varies. In many with neonatal onset, generalized hypotonia progresses during childhood to spasticity (mainly of the legs). Many have an infantile-onset progressive movement disorder that can include ataxia, dystonia, or dyskinesia of varying severity. Several individuals have epileptic seizures that can be difficult to treat. All but two have intellectual disability that ranges from mild learning disability to very limited development of all cognitive and motor functions.
## Mild Phenotype
Mildly affected individuals show only some clinical signs and symptoms without progression and survive without significant disease burden into adulthood.
## Genotype-Phenotype Correlations
Individuals with the most severe phenotypes often have pathogenic variants predicted to lead to the complete absence of functional protein.
Autosomal dominant CLPB deficiency has been reported in six individuals with the following pathogenic variants:
Six different heterozygous
## Prevalence
CLPB deficiency is rare. A total of 32 individuals with autosomal recessive CLPB deficiency have been reported to date (n=14 [
In the largely Inuit population of Greenland the carrier frequency of the
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders to Consider in the Differential Diagnosis of CLPB Deficiency
AD
3-HIVA = 3-hydroxyisovaleric acid; 3-MGA = 3-methylglutaconic acid; AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; mtDNA = mitochondrial DNA; SNHL = sensorineural hearing loss; XL = X-linked
In addition to discriminative feature shown in column 1
Increased urinary excretion of 3-MGA, known as 3-methylglutaconic aciduria (3-MGA-uria), is a relatively common finding in children investigated for suspected inborn errors of metabolism [
## Management
No clinical practice guidelines for CLPB deficiency have been published.
To establish the extent of disease and needs in an individual diagnosed with CLPB deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with CLPB Deficiency
Complete physical & neurologic exam
Brain MRI
Complete eval of feeding & diet to determine need for tube feeding or gastrostomy
Eval of excessive drooling to determine if ↑ risk of aspiration &/or dehydration
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Consider IQ testing in persons diagnosed at an older age.
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; ANC = absolute neutrophil count; G-CSF = granulocyte-colony stimulating factor; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; TSH = thyroid-stimulating hormone
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment is supportive. Care is best provided by a multidisciplinary team including a metabolic pediatrician, pediatric neurologist, dietitian, and physical therapist when possible. No specific dietary or other metabolic treatment is available.
Treatment of Manifestations in Individuals with CLPB Deficiency
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ASM = anti-seizure medication; G-CSF = granulocyte-colony stimulating factor; HSCT = hematopoietic stem cell transplant; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
SB Wortmann, personal communication
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Recommended Surveillance for Individuals with CLPB Deficiency
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & mvmt disorders.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
OT = occupational therapy; PT = physical therapy; TSH = thyroid-stimulating hormone
Drugs potentially toxic to mitochondria (including chloramphenicol, aminoglycosides, linezolid, valproic acid, and nucleoside reverse transcriptase inhibitors) should be avoided.
See
Search
• Complete physical & neurologic exam
• Brain MRI
• Complete eval of feeding & diet to determine need for tube feeding or gastrostomy
• Eval of excessive drooling to determine if ↑ risk of aspiration &/or dehydration
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Consider IQ testing in persons diagnosed at an older age.
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & mvmt disorders.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CLPB deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with CLPB Deficiency
Complete physical & neurologic exam
Brain MRI
Complete eval of feeding & diet to determine need for tube feeding or gastrostomy
Eval of excessive drooling to determine if ↑ risk of aspiration &/or dehydration
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Consider IQ testing in persons diagnosed at an older age.
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; ANC = absolute neutrophil count; G-CSF = granulocyte-colony stimulating factor; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; TSH = thyroid-stimulating hormone
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Complete physical & neurologic exam
• Brain MRI
• Complete eval of feeding & diet to determine need for tube feeding or gastrostomy
• Eval of excessive drooling to determine if ↑ risk of aspiration &/or dehydration
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Consider IQ testing in persons diagnosed at an older age.
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment is supportive. Care is best provided by a multidisciplinary team including a metabolic pediatrician, pediatric neurologist, dietitian, and physical therapist when possible. No specific dietary or other metabolic treatment is available.
Treatment of Manifestations in Individuals with CLPB Deficiency
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ASM = anti-seizure medication; G-CSF = granulocyte-colony stimulating factor; HSCT = hematopoietic stem cell transplant; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
SB Wortmann, personal communication
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Surveillance
Recommended Surveillance for Individuals with CLPB Deficiency
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & mvmt disorders.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
OT = occupational therapy; PT = physical therapy; TSH = thyroid-stimulating hormone
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & mvmt disorders.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Agents/Circumstances to Avoid
Drugs potentially toxic to mitochondria (including chloramphenicol, aminoglycosides, linezolid, valproic acid, and nucleoside reverse transcriptase inhibitors) should be avoided.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
CLPB deficiency associated with biallelic
The parents of a child with biallelic
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) of pathogenic variants known to be associated with autosomal recessive CLPB deficiency are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
The clinical manifestations of CLPB deficiency are variable and may differ between sibs who inherit identical biallelic
Heterozygotes (carriers) of pathogenic variants known to be associated with autosomal recessive CLPB deficiency are asymptomatic and are not at risk of developing the disorder.
Unless an affected individual's reproductive partner also has autosomal recessive CLPB deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
The c.803C>T founder variant has a carrier frequency of 3.3% in the Inuit population of Greenland (see
All individuals reported to date with autosomal dominant CLPB deficiency have the disorder as the result of a
Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with autosomal dominant CLPB deficiency may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
The clinical manifestations of CLPB deficiency are variable and may differ between sibs who inherit a
If the
If the parents have not been tested for the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected with CLPB deficiency or are carriers (or are at risk of being carriers) of autosomal recessive CLPB deficiency.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of a child with biallelic
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) of pathogenic variants known to be associated with autosomal recessive CLPB deficiency are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• The clinical manifestations of CLPB deficiency are variable and may differ between sibs who inherit identical biallelic
• Heterozygotes (carriers) of pathogenic variants known to be associated with autosomal recessive CLPB deficiency are asymptomatic and are not at risk of developing the disorder.
• Unless an affected individual's reproductive partner also has autosomal recessive CLPB deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
• The c.803C>T founder variant has a carrier frequency of 3.3% in the Inuit population of Greenland (see
• All individuals reported to date with autosomal dominant CLPB deficiency have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with autosomal dominant CLPB deficiency may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• The clinical manifestations of CLPB deficiency are variable and may differ between sibs who inherit a
• If the
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected with CLPB deficiency or are carriers (or are at risk of being carriers) of autosomal recessive CLPB deficiency.
## Mode of Inheritance
CLPB deficiency associated with biallelic
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of a child with biallelic
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) of pathogenic variants known to be associated with autosomal recessive CLPB deficiency are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
The clinical manifestations of CLPB deficiency are variable and may differ between sibs who inherit identical biallelic
Heterozygotes (carriers) of pathogenic variants known to be associated with autosomal recessive CLPB deficiency are asymptomatic and are not at risk of developing the disorder.
Unless an affected individual's reproductive partner also has autosomal recessive CLPB deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
The c.803C>T founder variant has a carrier frequency of 3.3% in the Inuit population of Greenland (see
• The parents of a child with biallelic
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) of pathogenic variants known to be associated with autosomal recessive CLPB deficiency are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• The clinical manifestations of CLPB deficiency are variable and may differ between sibs who inherit identical biallelic
• Heterozygotes (carriers) of pathogenic variants known to be associated with autosomal recessive CLPB deficiency are asymptomatic and are not at risk of developing the disorder.
• Unless an affected individual's reproductive partner also has autosomal recessive CLPB deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
• The c.803C>T founder variant has a carrier frequency of 3.3% in the Inuit population of Greenland (see
## Autosomal Dominant Inheritance – Risk to Family Members
All individuals reported to date with autosomal dominant CLPB deficiency have the disorder as the result of a
Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with autosomal dominant CLPB deficiency may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
The clinical manifestations of CLPB deficiency are variable and may differ between sibs who inherit a
If the
If the parents have not been tested for the
• All individuals reported to date with autosomal dominant CLPB deficiency have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with autosomal dominant CLPB deficiency may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• The clinical manifestations of CLPB deficiency are variable and may differ between sibs who inherit a
• If the
• If the parents have not been tested for the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected with CLPB deficiency or are carriers (or are at risk of being carriers) of autosomal recessive CLPB deficiency.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected with CLPB deficiency or are carriers (or are at risk of being carriers) of autosomal recessive CLPB deficiency.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
• United Kingdom
•
## Molecular Genetics
CLPB Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CLPB Deficiency (
CLPB, a mitochondrial protein of poorly known function in human, is a member of the large AAA (ATPases associated with diverse cellular activities) protein superfamily. Members of this superfamily are involved in various processes, such as DNA replication and repair and protein disaggregation and refolding, and operate as part of dynein motors, as chelatases or proteases [
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
CLPB, a mitochondrial protein of poorly known function in human, is a member of the large AAA (ATPases associated with diverse cellular activities) protein superfamily. Members of this superfamily are involved in various processes, such as DNA replication and repair and protein disaggregation and refolding, and operate as part of dynein motors, as chelatases or proteases [
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
Dr SB Wortmann and Prof RA Wevers are interested in patients with elevated urinary excretion of 3-methylglutaconic acid. Combining the clinical, biochemical, and neuroradiologic findings of these patients, they are able to define homogeneous subgroups. Next-generation sequencing is then used to identify the underlying genetic disorders in these subgroups, followed by biochemical investigations to characterize the function of the affected protein.
Arjan PM de Brouwer, PhD; Radboud University Medical Center (2016-2022)Ron A Wevers, PhD (2016-present)Saskia B Wortmann, MD, PhD (2016-present)
10 March 2022 (sw) Comprehensive update posted live
22 November 2016 (bp) Review posted live
21 June 2016 (sbw) Original submission
• 10 March 2022 (sw) Comprehensive update posted live
• 22 November 2016 (bp) Review posted live
• 21 June 2016 (sbw) Original submission
## Author Notes
Dr SB Wortmann and Prof RA Wevers are interested in patients with elevated urinary excretion of 3-methylglutaconic acid. Combining the clinical, biochemical, and neuroradiologic findings of these patients, they are able to define homogeneous subgroups. Next-generation sequencing is then used to identify the underlying genetic disorders in these subgroups, followed by biochemical investigations to characterize the function of the affected protein.
## Author History
Arjan PM de Brouwer, PhD; Radboud University Medical Center (2016-2022)Ron A Wevers, PhD (2016-present)Saskia B Wortmann, MD, PhD (2016-present)
## Revision History
10 March 2022 (sw) Comprehensive update posted live
22 November 2016 (bp) Review posted live
21 June 2016 (sbw) Original submission
• 10 March 2022 (sw) Comprehensive update posted live
• 22 November 2016 (bp) Review posted live
• 21 June 2016 (sbw) Original submission
## References
## Literature Cited
|
[
"JM Capo-Chichi, S Boissel, E Brustein, S Pickles, C Fallet-Bianco, C Nassif, L Patry, S Dobrzeniecka, M Liao, D Labuda, ME Samuels, FF Hamdan, C Vande Velde, GA Rouleau, P Drapeau, JL Michaud. Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.. J Med Genet. 2015;52:303-11",
"SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"M Kanabus, R Shahni, JW Saldanha, E Murphy, V Plagnol, WV Hoff, S Heales, S Rahman. Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation.. J Inherit Metab Dis. 2015;38:211-9",
"A Kiykim, W Garncarz, E Karakoc-Aydiner, A Ozen, E Kiykim, G Yesil, K Boztug, S. Baris. Novel CLPB mutation in a patient with 3-methylglutaconic aciduria causing severe neurological involvement and congenital neutropenia.. Clin Immunol. 2016;165:1-3",
"D Mróz, H Wyszkowski, T Szablewski, K Zawieracz, R Dutkiewicz, K Bury, SB Wortmann, RA Wevers, S Ziętkiewicz. CLPB (caseinolytic peptidase B homolog), the first mitochondrial protein refoldase associated with human disease.. Biochim Biophys Acta Gen Subj. 2020;1864",
"E Pronicka, M Ropacka-Lesiak, J Trubicka, M Pajdowska, M Linke, E Ostergaard, C Saunders, S Horsch, C van Karnebeek, J Yaplito-Lee, F Distelmaier, K Õunap, S Rahman, M Castelle, J Kelleher, S Baris, K Iwanicka-Pronicka, CG Steward, E Ciara, SB Wortmann. A scoring system predicting the clinical course of CLPB defect based on the foetal and neonatal presentation of 31 patients.. J Inherit Metab Dis. 2017;40:853-60",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"O Sarig, D Goldsher, J Nousbeck, D Fuchs-Telem, K Cohen-Katsenelson, TC Iancu, I Manov, A Saada, E Sprecher, H Mandel. Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novel mutations in SERAC1.. Am J Med Genet A. 2013;161A:2204-15",
"C Saunders, L Smith, F Wibrand, K Ravn, P Bross, I Thiffault, M Christensen, A Atherton, E Farrow, N Miller, SF Kingsmore, E Ostergaard. CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.. Am J Hum Genet. 2015;96:258-65",
"J Snider, G Thibault, WA Houry. The AAA+ superfamily of functionally diverse proteins.. Genome Biol. 2008;9:216",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"JT Warren, RR Cupo, P Wattanasirakul, D Spencer, AE Locke, V Makaryan, AA Bolyard, ML Kelley, NL Kingston, J Shorter, C Bellanné-Chantelot, J Donadieu, DC Dale, DC Link. Heterozygous variants of CLPB are a cause of severe congenital neutropenia.. Blood. 2022;139:779-91",
"SB Wortmann, LA Kluijtmans, RJ Rodenburg, JO Sass, J Nouws, EP van Kaauwen, T Kleefstra, L Tranebjaerg, MC de Vries, P Isohanni, K Walter, FS Alkuraya, I Smuts, CJ Reinecke, FH van der Westhuizen, D Thorburn, JA Smeitink, E Morava, RA Wevers. 3-Methylglutaconic aciduria --lessons from 50 genes and 977 patients.. J Inherit Metab Dis. 2013;36:913-21",
"SB Wortmann, BH Kremer, A Graham, MA Willemsen, FJ Loupatty, SL Hogg, UF Engelke, LA Kluijtmans, RJ Wanders, S Illsinger, B Wilcken, JR Cruysberg, AM Das, E Morava, RA Wevers. 3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy.. Neurology. 2010;75:1079-83",
"SB Wortmann, S Ziętkiewicz, S Guerrero-Castillo, RG Feichtinger, M Wagner, J Russell, C Ellaway, D Mróz, H Wyszkowski, D Weis, I Hannibal, C von Stülpnagel, A Cabrera-Orefice, U Lichter-Konecki, J Gaesser, R Windreich, KC Myers, R Lorsbach, RC Dale, S Gersting, CE Prada, J Christodoulou, NI Wolf, H Venselaar, JA Mayr, RA Wevers. Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.. Genet Med. 2021;23:1705-14",
"SB Wortmann, S Ziętkiewicz, M Kousi, R Szklarczyk, TB Haack, SW Gersting, AC Muntau, A Rakovic, GH Renkema, RJ Rodenburg, TM Strom, T Meitinger, ME Rubio-Gozalbo, E Chrusciel, F Distelmaier, C Golzio, JH Jansen, C van Karnebeek, Y Lillquist, T Lücke, K Õunap, R Zordania, J Yaplito-Lee, H van Bokhoven, JN Spelbrink, FM Vaz, M Pras-Raves, R Ploski, E Pronicka, C Klein, MA Willemsen, AP de Brouwer, H Prokisch, N Katsanis, RA Wevers. CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.. Am J Hum Genet. 2015;96:245-57"
] |
22/11/2016
|
10/3/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
cls
|
cls
|
[
"Coffin-Lowry Syndrome",
"Ribosomal protein S6 kinase alpha-3",
"RPS6KA3",
"RPS6KA3-Related Intellectual Disability"
] |
R Curtis Rogers, Fatima E Abidi
|
Summary The phenotypic spectrum associated with The diagnosis of
|
With the current widespread use of multigene panels and comprehensive genomic testing based on an unbiased (i.e., not phenotype-driven) approach, it has become apparent that the phenotypic spectrum associated with
## Diagnosis
For the purposes of this
Other findings in some individuals:
Hypotonia
Stimulus-induced drop attacks
Progressive spasticity/paraplegia
Seizures
Kyphoscoliosis of childhood onset that is often progressive
Pectus carinatum and/or excavatum
Craniofacial features (particularly in an affected older child or adult). Widely spaced eyes with downslanted palpebral fissures; depressed nasal tip with thick alae nasi and broad columella; protruding ears; wide mouth with thick vermilion of the upper and lower lips; coarse face that may further coarsen with age (
Hand findings. Small, soft, fleshy hands; distally tapered fingers with small terminal phalanges and small nails; hyperextensible fingers (
Craniofacial features. Females may have subtle craniofacial features, and some have been reported with features similar to those seen in males.
Hand findings. Females may have mildly tapered, soft, fleshy fingers.
Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis.
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Genetic mechanisms other than monoallelic pathogenic variants in
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the diagnosis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
•
• Hypotonia
• Stimulus-induced drop attacks
• Progressive spasticity/paraplegia
• Seizures
• Hypotonia
• Stimulus-induced drop attacks
• Progressive spasticity/paraplegia
• Seizures
•
• Kyphoscoliosis of childhood onset that is often progressive
• Pectus carinatum and/or excavatum
• Kyphoscoliosis of childhood onset that is often progressive
• Pectus carinatum and/or excavatum
•
• Craniofacial features (particularly in an affected older child or adult). Widely spaced eyes with downslanted palpebral fissures; depressed nasal tip with thick alae nasi and broad columella; protruding ears; wide mouth with thick vermilion of the upper and lower lips; coarse face that may further coarsen with age (
• Hand findings. Small, soft, fleshy hands; distally tapered fingers with small terminal phalanges and small nails; hyperextensible fingers (
• Craniofacial features (particularly in an affected older child or adult). Widely spaced eyes with downslanted palpebral fissures; depressed nasal tip with thick alae nasi and broad columella; protruding ears; wide mouth with thick vermilion of the upper and lower lips; coarse face that may further coarsen with age (
• Hand findings. Small, soft, fleshy hands; distally tapered fingers with small terminal phalanges and small nails; hyperextensible fingers (
• Hypotonia
• Stimulus-induced drop attacks
• Progressive spasticity/paraplegia
• Seizures
• Kyphoscoliosis of childhood onset that is often progressive
• Pectus carinatum and/or excavatum
• Craniofacial features (particularly in an affected older child or adult). Widely spaced eyes with downslanted palpebral fissures; depressed nasal tip with thick alae nasi and broad columella; protruding ears; wide mouth with thick vermilion of the upper and lower lips; coarse face that may further coarsen with age (
• Hand findings. Small, soft, fleshy hands; distally tapered fingers with small terminal phalanges and small nails; hyperextensible fingers (
•
• Craniofacial features. Females may have subtle craniofacial features, and some have been reported with features similar to those seen in males.
• Hand findings. Females may have mildly tapered, soft, fleshy fingers.
• Craniofacial features. Females may have subtle craniofacial features, and some have been reported with features similar to those seen in males.
• Hand findings. Females may have mildly tapered, soft, fleshy fingers.
• Craniofacial features. Females may have subtle craniofacial features, and some have been reported with features similar to those seen in males.
• Hand findings. Females may have mildly tapered, soft, fleshy fingers.
## Suggestive Findings
Other findings in some individuals:
Hypotonia
Stimulus-induced drop attacks
Progressive spasticity/paraplegia
Seizures
Kyphoscoliosis of childhood onset that is often progressive
Pectus carinatum and/or excavatum
Craniofacial features (particularly in an affected older child or adult). Widely spaced eyes with downslanted palpebral fissures; depressed nasal tip with thick alae nasi and broad columella; protruding ears; wide mouth with thick vermilion of the upper and lower lips; coarse face that may further coarsen with age (
Hand findings. Small, soft, fleshy hands; distally tapered fingers with small terminal phalanges and small nails; hyperextensible fingers (
Craniofacial features. Females may have subtle craniofacial features, and some have been reported with features similar to those seen in males.
Hand findings. Females may have mildly tapered, soft, fleshy fingers.
Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis.
•
• Hypotonia
• Stimulus-induced drop attacks
• Progressive spasticity/paraplegia
• Seizures
• Hypotonia
• Stimulus-induced drop attacks
• Progressive spasticity/paraplegia
• Seizures
•
• Kyphoscoliosis of childhood onset that is often progressive
• Pectus carinatum and/or excavatum
• Kyphoscoliosis of childhood onset that is often progressive
• Pectus carinatum and/or excavatum
•
• Craniofacial features (particularly in an affected older child or adult). Widely spaced eyes with downslanted palpebral fissures; depressed nasal tip with thick alae nasi and broad columella; protruding ears; wide mouth with thick vermilion of the upper and lower lips; coarse face that may further coarsen with age (
• Hand findings. Small, soft, fleshy hands; distally tapered fingers with small terminal phalanges and small nails; hyperextensible fingers (
• Craniofacial features (particularly in an affected older child or adult). Widely spaced eyes with downslanted palpebral fissures; depressed nasal tip with thick alae nasi and broad columella; protruding ears; wide mouth with thick vermilion of the upper and lower lips; coarse face that may further coarsen with age (
• Hand findings. Small, soft, fleshy hands; distally tapered fingers with small terminal phalanges and small nails; hyperextensible fingers (
• Hypotonia
• Stimulus-induced drop attacks
• Progressive spasticity/paraplegia
• Seizures
• Kyphoscoliosis of childhood onset that is often progressive
• Pectus carinatum and/or excavatum
• Craniofacial features (particularly in an affected older child or adult). Widely spaced eyes with downslanted palpebral fissures; depressed nasal tip with thick alae nasi and broad columella; protruding ears; wide mouth with thick vermilion of the upper and lower lips; coarse face that may further coarsen with age (
• Hand findings. Small, soft, fleshy hands; distally tapered fingers with small terminal phalanges and small nails; hyperextensible fingers (
•
• Craniofacial features. Females may have subtle craniofacial features, and some have been reported with features similar to those seen in males.
• Hand findings. Females may have mildly tapered, soft, fleshy fingers.
• Craniofacial features. Females may have subtle craniofacial features, and some have been reported with features similar to those seen in males.
• Hand findings. Females may have mildly tapered, soft, fleshy fingers.
• Craniofacial features. Females may have subtle craniofacial features, and some have been reported with features similar to those seen in males.
• Hand findings. Females may have mildly tapered, soft, fleshy fingers.
## Clinical Findings
Other findings in some individuals:
Hypotonia
Stimulus-induced drop attacks
Progressive spasticity/paraplegia
Seizures
Kyphoscoliosis of childhood onset that is often progressive
Pectus carinatum and/or excavatum
Craniofacial features (particularly in an affected older child or adult). Widely spaced eyes with downslanted palpebral fissures; depressed nasal tip with thick alae nasi and broad columella; protruding ears; wide mouth with thick vermilion of the upper and lower lips; coarse face that may further coarsen with age (
Hand findings. Small, soft, fleshy hands; distally tapered fingers with small terminal phalanges and small nails; hyperextensible fingers (
Craniofacial features. Females may have subtle craniofacial features, and some have been reported with features similar to those seen in males.
Hand findings. Females may have mildly tapered, soft, fleshy fingers.
•
• Hypotonia
• Stimulus-induced drop attacks
• Progressive spasticity/paraplegia
• Seizures
• Hypotonia
• Stimulus-induced drop attacks
• Progressive spasticity/paraplegia
• Seizures
•
• Kyphoscoliosis of childhood onset that is often progressive
• Pectus carinatum and/or excavatum
• Kyphoscoliosis of childhood onset that is often progressive
• Pectus carinatum and/or excavatum
•
• Craniofacial features (particularly in an affected older child or adult). Widely spaced eyes with downslanted palpebral fissures; depressed nasal tip with thick alae nasi and broad columella; protruding ears; wide mouth with thick vermilion of the upper and lower lips; coarse face that may further coarsen with age (
• Hand findings. Small, soft, fleshy hands; distally tapered fingers with small terminal phalanges and small nails; hyperextensible fingers (
• Craniofacial features (particularly in an affected older child or adult). Widely spaced eyes with downslanted palpebral fissures; depressed nasal tip with thick alae nasi and broad columella; protruding ears; wide mouth with thick vermilion of the upper and lower lips; coarse face that may further coarsen with age (
• Hand findings. Small, soft, fleshy hands; distally tapered fingers with small terminal phalanges and small nails; hyperextensible fingers (
• Hypotonia
• Stimulus-induced drop attacks
• Progressive spasticity/paraplegia
• Seizures
• Kyphoscoliosis of childhood onset that is often progressive
• Pectus carinatum and/or excavatum
• Craniofacial features (particularly in an affected older child or adult). Widely spaced eyes with downslanted palpebral fissures; depressed nasal tip with thick alae nasi and broad columella; protruding ears; wide mouth with thick vermilion of the upper and lower lips; coarse face that may further coarsen with age (
• Hand findings. Small, soft, fleshy hands; distally tapered fingers with small terminal phalanges and small nails; hyperextensible fingers (
•
• Craniofacial features. Females may have subtle craniofacial features, and some have been reported with features similar to those seen in males.
• Hand findings. Females may have mildly tapered, soft, fleshy fingers.
• Craniofacial features. Females may have subtle craniofacial features, and some have been reported with features similar to those seen in males.
• Hand findings. Females may have mildly tapered, soft, fleshy fingers.
• Craniofacial features. Females may have subtle craniofacial features, and some have been reported with features similar to those seen in males.
• Hand findings. Females may have mildly tapered, soft, fleshy fingers.
## Imaging Findings
## Family History
Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis.
## Establishing the Diagnosis
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Genetic mechanisms other than monoallelic pathogenic variants in
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the diagnosis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Option 1
For an introduction to multigene panels click
## Option 2
When the diagnosis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
At the more severe end of the continuum of
To date, more than 200 individuals have been identified with a pathogenic variant in
+++ = high frequency; ++ = moderate frequency, + = low frequency
Based on
Relative frequencies are provided, with percentages in parentheses where those are available in the literature
In most cases, the transient loss of muscle tone occurs in the paraspinal or quadriceps muscles. Some individuals also experience myoclonic jerks or increased muscle tone due to "hyperekplexia-like" episodes with a startle response [
Onset occurs between ages four and 17 years with a mean age of 8.6 years [
SIDAs were reported in 20% (34/170) of individuals in the CLS Foundation database [
The episodes may become debilitating due to injury from falls [
See
Abnormalities of the corpus callosum, including thinning and agenesis [
Multiple focal frontal hypodensities visible on MRI. Hypodensities attributed to focal areas of cerebrospinal fluid were reported in three affected sibs by
Periventricular white matter abnormalities/cysts [
Constricted foramen magnum (decreased diameter)
Reduced gray and white matter volume without evidence of ventriculomegaly
The severity of the spinal deformity often worsens significantly over time and can lead to severe complications:
Cardiorespiratory compromise caused by kyphoscoliosis may contribute to premature death.
Neurologic compromise can also occur, and rapidly progressive kyphosis with acute paralysis has been reported in several instances.
Pectus carinatum and/or excavatum are frequently seen.
Pes planus may occur [
Other minor skeletal changes that may be seen on radiographs are of no clinical consequence.
While microcephaly is common, many individuals with CLS have a normal head circumference. Short stature, hypotonia, and decreased activity may lead to increased risk for obesity.
An audiogram may reveal sensorineural hearing loss. Mixed hearing loss has also been described [
Malformation of the labyrinth has been reported [
Clustering of hearing loss within families may occur.
Persons with CLS may have issues with intubation and/or ventilation that require careful consideration of the strategy for airway management during anesthesia [
Restrictive lung disease may occur due to kyphoscoliosis; this can be severe and go unrecognized [
Life span is reduced in some males with CLS. Of individuals reported in the literature, death occurred in 13.5% of males at a mean age of 20.5 years (range: 13-34) [
Complicating factors have included cardiac anomalies, panacinar emphysema, respiratory complications, progressive kyphoscoliosis, and seizure-associated aspiration.
The authors are aware of an individual with CLS who had life-threatening central and obstructive sleep apnea, and of another male who had a history of chronic obstructive and central sleep apnea who died from respiratory complications after surgery for jaw advancement.
One affected male died of Hodgkin disease [
Heterozygous females often manifest markedly variable clinical manifestations of
Although no strong correlation exists between phenotype and location or type of
Early authors referred to Coffin syndrome until it was recognized that the individuals reported by
Some early texts and papers confused Coffin-Siris syndrome and Coffin-Lowry syndrome.
The title of this
No estimate of the prevalence of CLS has been published. Based on the authors' experience, a rate of 1:40,000-50,000 may be reasonable – although it may underestimate the actual prevalence.
• In most cases, the transient loss of muscle tone occurs in the paraspinal or quadriceps muscles. Some individuals also experience myoclonic jerks or increased muscle tone due to "hyperekplexia-like" episodes with a startle response [
• Onset occurs between ages four and 17 years with a mean age of 8.6 years [
• SIDAs were reported in 20% (34/170) of individuals in the CLS Foundation database [
• The episodes may become debilitating due to injury from falls [
• See
• In most cases, the transient loss of muscle tone occurs in the paraspinal or quadriceps muscles. Some individuals also experience myoclonic jerks or increased muscle tone due to "hyperekplexia-like" episodes with a startle response [
• Onset occurs between ages four and 17 years with a mean age of 8.6 years [
• SIDAs were reported in 20% (34/170) of individuals in the CLS Foundation database [
• The episodes may become debilitating due to injury from falls [
• See
• Abnormalities of the corpus callosum, including thinning and agenesis [
• Multiple focal frontal hypodensities visible on MRI. Hypodensities attributed to focal areas of cerebrospinal fluid were reported in three affected sibs by
• Periventricular white matter abnormalities/cysts [
• Constricted foramen magnum (decreased diameter)
• Reduced gray and white matter volume without evidence of ventriculomegaly
• Abnormalities of the corpus callosum, including thinning and agenesis [
• Multiple focal frontal hypodensities visible on MRI. Hypodensities attributed to focal areas of cerebrospinal fluid were reported in three affected sibs by
• Periventricular white matter abnormalities/cysts [
• Constricted foramen magnum (decreased diameter)
• Reduced gray and white matter volume without evidence of ventriculomegaly
• In most cases, the transient loss of muscle tone occurs in the paraspinal or quadriceps muscles. Some individuals also experience myoclonic jerks or increased muscle tone due to "hyperekplexia-like" episodes with a startle response [
• Onset occurs between ages four and 17 years with a mean age of 8.6 years [
• SIDAs were reported in 20% (34/170) of individuals in the CLS Foundation database [
• The episodes may become debilitating due to injury from falls [
• See
• Abnormalities of the corpus callosum, including thinning and agenesis [
• Multiple focal frontal hypodensities visible on MRI. Hypodensities attributed to focal areas of cerebrospinal fluid were reported in three affected sibs by
• Periventricular white matter abnormalities/cysts [
• Constricted foramen magnum (decreased diameter)
• Reduced gray and white matter volume without evidence of ventriculomegaly
• The severity of the spinal deformity often worsens significantly over time and can lead to severe complications:
• Cardiorespiratory compromise caused by kyphoscoliosis may contribute to premature death.
• Neurologic compromise can also occur, and rapidly progressive kyphosis with acute paralysis has been reported in several instances.
• Cardiorespiratory compromise caused by kyphoscoliosis may contribute to premature death.
• Neurologic compromise can also occur, and rapidly progressive kyphosis with acute paralysis has been reported in several instances.
• Pectus carinatum and/or excavatum are frequently seen.
• Pes planus may occur [
• Other minor skeletal changes that may be seen on radiographs are of no clinical consequence.
• Cardiorespiratory compromise caused by kyphoscoliosis may contribute to premature death.
• Neurologic compromise can also occur, and rapidly progressive kyphosis with acute paralysis has been reported in several instances.
• An audiogram may reveal sensorineural hearing loss. Mixed hearing loss has also been described [
• Malformation of the labyrinth has been reported [
• Clustering of hearing loss within families may occur.
• Complicating factors have included cardiac anomalies, panacinar emphysema, respiratory complications, progressive kyphoscoliosis, and seizure-associated aspiration.
• The authors are aware of an individual with CLS who had life-threatening central and obstructive sleep apnea, and of another male who had a history of chronic obstructive and central sleep apnea who died from respiratory complications after surgery for jaw advancement.
• One affected male died of Hodgkin disease [
## Clinical Description
At the more severe end of the continuum of
To date, more than 200 individuals have been identified with a pathogenic variant in
+++ = high frequency; ++ = moderate frequency, + = low frequency
Based on
Relative frequencies are provided, with percentages in parentheses where those are available in the literature
In most cases, the transient loss of muscle tone occurs in the paraspinal or quadriceps muscles. Some individuals also experience myoclonic jerks or increased muscle tone due to "hyperekplexia-like" episodes with a startle response [
Onset occurs between ages four and 17 years with a mean age of 8.6 years [
SIDAs were reported in 20% (34/170) of individuals in the CLS Foundation database [
The episodes may become debilitating due to injury from falls [
See
Abnormalities of the corpus callosum, including thinning and agenesis [
Multiple focal frontal hypodensities visible on MRI. Hypodensities attributed to focal areas of cerebrospinal fluid were reported in three affected sibs by
Periventricular white matter abnormalities/cysts [
Constricted foramen magnum (decreased diameter)
Reduced gray and white matter volume without evidence of ventriculomegaly
The severity of the spinal deformity often worsens significantly over time and can lead to severe complications:
Cardiorespiratory compromise caused by kyphoscoliosis may contribute to premature death.
Neurologic compromise can also occur, and rapidly progressive kyphosis with acute paralysis has been reported in several instances.
Pectus carinatum and/or excavatum are frequently seen.
Pes planus may occur [
Other minor skeletal changes that may be seen on radiographs are of no clinical consequence.
While microcephaly is common, many individuals with CLS have a normal head circumference. Short stature, hypotonia, and decreased activity may lead to increased risk for obesity.
An audiogram may reveal sensorineural hearing loss. Mixed hearing loss has also been described [
Malformation of the labyrinth has been reported [
Clustering of hearing loss within families may occur.
Persons with CLS may have issues with intubation and/or ventilation that require careful consideration of the strategy for airway management during anesthesia [
Restrictive lung disease may occur due to kyphoscoliosis; this can be severe and go unrecognized [
Life span is reduced in some males with CLS. Of individuals reported in the literature, death occurred in 13.5% of males at a mean age of 20.5 years (range: 13-34) [
Complicating factors have included cardiac anomalies, panacinar emphysema, respiratory complications, progressive kyphoscoliosis, and seizure-associated aspiration.
The authors are aware of an individual with CLS who had life-threatening central and obstructive sleep apnea, and of another male who had a history of chronic obstructive and central sleep apnea who died from respiratory complications after surgery for jaw advancement.
One affected male died of Hodgkin disease [
Heterozygous females often manifest markedly variable clinical manifestations of
• In most cases, the transient loss of muscle tone occurs in the paraspinal or quadriceps muscles. Some individuals also experience myoclonic jerks or increased muscle tone due to "hyperekplexia-like" episodes with a startle response [
• Onset occurs between ages four and 17 years with a mean age of 8.6 years [
• SIDAs were reported in 20% (34/170) of individuals in the CLS Foundation database [
• The episodes may become debilitating due to injury from falls [
• See
• In most cases, the transient loss of muscle tone occurs in the paraspinal or quadriceps muscles. Some individuals also experience myoclonic jerks or increased muscle tone due to "hyperekplexia-like" episodes with a startle response [
• Onset occurs between ages four and 17 years with a mean age of 8.6 years [
• SIDAs were reported in 20% (34/170) of individuals in the CLS Foundation database [
• The episodes may become debilitating due to injury from falls [
• See
• Abnormalities of the corpus callosum, including thinning and agenesis [
• Multiple focal frontal hypodensities visible on MRI. Hypodensities attributed to focal areas of cerebrospinal fluid were reported in three affected sibs by
• Periventricular white matter abnormalities/cysts [
• Constricted foramen magnum (decreased diameter)
• Reduced gray and white matter volume without evidence of ventriculomegaly
• Abnormalities of the corpus callosum, including thinning and agenesis [
• Multiple focal frontal hypodensities visible on MRI. Hypodensities attributed to focal areas of cerebrospinal fluid were reported in three affected sibs by
• Periventricular white matter abnormalities/cysts [
• Constricted foramen magnum (decreased diameter)
• Reduced gray and white matter volume without evidence of ventriculomegaly
• In most cases, the transient loss of muscle tone occurs in the paraspinal or quadriceps muscles. Some individuals also experience myoclonic jerks or increased muscle tone due to "hyperekplexia-like" episodes with a startle response [
• Onset occurs between ages four and 17 years with a mean age of 8.6 years [
• SIDAs were reported in 20% (34/170) of individuals in the CLS Foundation database [
• The episodes may become debilitating due to injury from falls [
• See
• Abnormalities of the corpus callosum, including thinning and agenesis [
• Multiple focal frontal hypodensities visible on MRI. Hypodensities attributed to focal areas of cerebrospinal fluid were reported in three affected sibs by
• Periventricular white matter abnormalities/cysts [
• Constricted foramen magnum (decreased diameter)
• Reduced gray and white matter volume without evidence of ventriculomegaly
• The severity of the spinal deformity often worsens significantly over time and can lead to severe complications:
• Cardiorespiratory compromise caused by kyphoscoliosis may contribute to premature death.
• Neurologic compromise can also occur, and rapidly progressive kyphosis with acute paralysis has been reported in several instances.
• Cardiorespiratory compromise caused by kyphoscoliosis may contribute to premature death.
• Neurologic compromise can also occur, and rapidly progressive kyphosis with acute paralysis has been reported in several instances.
• Pectus carinatum and/or excavatum are frequently seen.
• Pes planus may occur [
• Other minor skeletal changes that may be seen on radiographs are of no clinical consequence.
• Cardiorespiratory compromise caused by kyphoscoliosis may contribute to premature death.
• Neurologic compromise can also occur, and rapidly progressive kyphosis with acute paralysis has been reported in several instances.
• An audiogram may reveal sensorineural hearing loss. Mixed hearing loss has also been described [
• Malformation of the labyrinth has been reported [
• Clustering of hearing loss within families may occur.
• Complicating factors have included cardiac anomalies, panacinar emphysema, respiratory complications, progressive kyphoscoliosis, and seizure-associated aspiration.
• The authors are aware of an individual with CLS who had life-threatening central and obstructive sleep apnea, and of another male who had a history of chronic obstructive and central sleep apnea who died from respiratory complications after surgery for jaw advancement.
• One affected male died of Hodgkin disease [
## Affected Males
+++ = high frequency; ++ = moderate frequency, + = low frequency
Based on
Relative frequencies are provided, with percentages in parentheses where those are available in the literature
In most cases, the transient loss of muscle tone occurs in the paraspinal or quadriceps muscles. Some individuals also experience myoclonic jerks or increased muscle tone due to "hyperekplexia-like" episodes with a startle response [
Onset occurs between ages four and 17 years with a mean age of 8.6 years [
SIDAs were reported in 20% (34/170) of individuals in the CLS Foundation database [
The episodes may become debilitating due to injury from falls [
See
Abnormalities of the corpus callosum, including thinning and agenesis [
Multiple focal frontal hypodensities visible on MRI. Hypodensities attributed to focal areas of cerebrospinal fluid were reported in three affected sibs by
Periventricular white matter abnormalities/cysts [
Constricted foramen magnum (decreased diameter)
Reduced gray and white matter volume without evidence of ventriculomegaly
The severity of the spinal deformity often worsens significantly over time and can lead to severe complications:
Cardiorespiratory compromise caused by kyphoscoliosis may contribute to premature death.
Neurologic compromise can also occur, and rapidly progressive kyphosis with acute paralysis has been reported in several instances.
Pectus carinatum and/or excavatum are frequently seen.
Pes planus may occur [
Other minor skeletal changes that may be seen on radiographs are of no clinical consequence.
While microcephaly is common, many individuals with CLS have a normal head circumference. Short stature, hypotonia, and decreased activity may lead to increased risk for obesity.
An audiogram may reveal sensorineural hearing loss. Mixed hearing loss has also been described [
Malformation of the labyrinth has been reported [
Clustering of hearing loss within families may occur.
Persons with CLS may have issues with intubation and/or ventilation that require careful consideration of the strategy for airway management during anesthesia [
Restrictive lung disease may occur due to kyphoscoliosis; this can be severe and go unrecognized [
Life span is reduced in some males with CLS. Of individuals reported in the literature, death occurred in 13.5% of males at a mean age of 20.5 years (range: 13-34) [
Complicating factors have included cardiac anomalies, panacinar emphysema, respiratory complications, progressive kyphoscoliosis, and seizure-associated aspiration.
The authors are aware of an individual with CLS who had life-threatening central and obstructive sleep apnea, and of another male who had a history of chronic obstructive and central sleep apnea who died from respiratory complications after surgery for jaw advancement.
One affected male died of Hodgkin disease [
• In most cases, the transient loss of muscle tone occurs in the paraspinal or quadriceps muscles. Some individuals also experience myoclonic jerks or increased muscle tone due to "hyperekplexia-like" episodes with a startle response [
• Onset occurs between ages four and 17 years with a mean age of 8.6 years [
• SIDAs were reported in 20% (34/170) of individuals in the CLS Foundation database [
• The episodes may become debilitating due to injury from falls [
• See
• In most cases, the transient loss of muscle tone occurs in the paraspinal or quadriceps muscles. Some individuals also experience myoclonic jerks or increased muscle tone due to "hyperekplexia-like" episodes with a startle response [
• Onset occurs between ages four and 17 years with a mean age of 8.6 years [
• SIDAs were reported in 20% (34/170) of individuals in the CLS Foundation database [
• The episodes may become debilitating due to injury from falls [
• See
• Abnormalities of the corpus callosum, including thinning and agenesis [
• Multiple focal frontal hypodensities visible on MRI. Hypodensities attributed to focal areas of cerebrospinal fluid were reported in three affected sibs by
• Periventricular white matter abnormalities/cysts [
• Constricted foramen magnum (decreased diameter)
• Reduced gray and white matter volume without evidence of ventriculomegaly
• Abnormalities of the corpus callosum, including thinning and agenesis [
• Multiple focal frontal hypodensities visible on MRI. Hypodensities attributed to focal areas of cerebrospinal fluid were reported in three affected sibs by
• Periventricular white matter abnormalities/cysts [
• Constricted foramen magnum (decreased diameter)
• Reduced gray and white matter volume without evidence of ventriculomegaly
• In most cases, the transient loss of muscle tone occurs in the paraspinal or quadriceps muscles. Some individuals also experience myoclonic jerks or increased muscle tone due to "hyperekplexia-like" episodes with a startle response [
• Onset occurs between ages four and 17 years with a mean age of 8.6 years [
• SIDAs were reported in 20% (34/170) of individuals in the CLS Foundation database [
• The episodes may become debilitating due to injury from falls [
• See
• Abnormalities of the corpus callosum, including thinning and agenesis [
• Multiple focal frontal hypodensities visible on MRI. Hypodensities attributed to focal areas of cerebrospinal fluid were reported in three affected sibs by
• Periventricular white matter abnormalities/cysts [
• Constricted foramen magnum (decreased diameter)
• Reduced gray and white matter volume without evidence of ventriculomegaly
• The severity of the spinal deformity often worsens significantly over time and can lead to severe complications:
• Cardiorespiratory compromise caused by kyphoscoliosis may contribute to premature death.
• Neurologic compromise can also occur, and rapidly progressive kyphosis with acute paralysis has been reported in several instances.
• Cardiorespiratory compromise caused by kyphoscoliosis may contribute to premature death.
• Neurologic compromise can also occur, and rapidly progressive kyphosis with acute paralysis has been reported in several instances.
• Pectus carinatum and/or excavatum are frequently seen.
• Pes planus may occur [
• Other minor skeletal changes that may be seen on radiographs are of no clinical consequence.
• Cardiorespiratory compromise caused by kyphoscoliosis may contribute to premature death.
• Neurologic compromise can also occur, and rapidly progressive kyphosis with acute paralysis has been reported in several instances.
• An audiogram may reveal sensorineural hearing loss. Mixed hearing loss has also been described [
• Malformation of the labyrinth has been reported [
• Clustering of hearing loss within families may occur.
• Complicating factors have included cardiac anomalies, panacinar emphysema, respiratory complications, progressive kyphoscoliosis, and seizure-associated aspiration.
• The authors are aware of an individual with CLS who had life-threatening central and obstructive sleep apnea, and of another male who had a history of chronic obstructive and central sleep apnea who died from respiratory complications after surgery for jaw advancement.
• One affected male died of Hodgkin disease [
## Heterozygous Females
Heterozygous females often manifest markedly variable clinical manifestations of
## Genotype-Phenotype Correlations
Although no strong correlation exists between phenotype and location or type of
## Nomenclature
Early authors referred to Coffin syndrome until it was recognized that the individuals reported by
Some early texts and papers confused Coffin-Siris syndrome and Coffin-Lowry syndrome.
The title of this
## Prevalence
No estimate of the prevalence of CLS has been published. Based on the authors' experience, a rate of 1:40,000-50,000 may be reasonable – although it may underestimate the actual prevalence.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders of Interest in the Differential Diagnosis of Coffin-Lowry Syndrome
Borjeson-Forssman-Lehmann syndrome (BFLS) (OMIM
AD = autosomal dominant; CLS = Coffin-Lowry syndrome; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; WBSCR = Williams-Beuren syndrome critical region; XL = X-linked
Pitt-Hopkins syndrome is caused by haploinsufficiency of
In most affected individuals, Pitt-Hopkins syndrome results from a
Most cases are
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To assess for SIDAs, changes in gait or in bowel or bladder function, & seizures or movement disorder
Consider EEG if seizures are a concern.
Gross motor & fine motor skills
Kyphoscoliosis
Pectus deformity
Contractures
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Cardiomyopathy
Valve dysfunction or other abnormalities
Small or malpositioned teeth
Advanced or delayed eruption of primary teeth
Hypodontia of secondary teeth
Premature tooth loss
To assess for obstructive sleep apnea
Refer to pulmonologist to evaluate for restrictive lung disease if severe kyphoscoliosis or concerning respiratory symptoms are present.
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for
Treatment of Manifestations in Individuals with
A trial of medication & efforts to optimize dosage may be considerations.
Awareness of SIDAs should allow early intervention to minimize occurrence of triggering stimuli & provide protection from falls.
If attacks occur w/great frequency a protective helmet may be indicated & use of a wheelchair may be required to prevent falling & injury.
Various medications have been used in an attempt to manage SIDAs; these incl benzodiazepines, ASMs, SSRIs, & tricyclic antidepressants.
While most treatments have not resulted in significant long-term control of SIDAs, improvements in selected persons have been seen w/clonazepam,
Valproic acid led to improvement in 1 persons, but this & other conventional ASMs have generally been ineffective.
Improvement of SIDAs occurred in a male after treatment of obstructive sleep apnea w/tracheostomy.
Consider need for positioning & mobility devices, disability parking placard.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Ensure appropriate nutritional & feeing support in hypotonic infants w/feeding difficulty.
Abnormal growth velocity & obesity should be assessed & treated in standard manner.
There are no data regarding safety or efficacy of growth hormone for treatment of growth deficiency in this disorder.
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ASM = anti-seizure medication; CPAP = continuous positive airway pressure; OT = occupational therapy; PT = physical therapy; SIDAs = stimulus-induced drop attacks; SSRIs = selective serotonin reuptake inhibitors
Reviewed in
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Recommended Surveillance for Individuals with
At each visit
Note: Persons w/calcifications of ligamentum flavum, particularly in cervical region, may require more careful surveillance.
Per treating orthopedist
Note: Skeletal maturity may be delayed, requiring longer than anticipated monitoring for progression.
Per treating orthopedist
Note: Persons w/calcifications of ligamentum flavum, particularly in cervical region, may require more careful surveillance.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
Note: A table containing suggested guidelines for follow up of individuals with CLS is provided in
Care should be taken to avoid specific stimuli that are known to trigger SIDAs in a given individual. Physical activity may be limited due to valvular disease as recommended by a cardiologist.
See
Search
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To assess for SIDAs, changes in gait or in bowel or bladder function, & seizures or movement disorder
• Consider EEG if seizures are a concern.
• Gross motor & fine motor skills
• Kyphoscoliosis
• Pectus deformity
• Contractures
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Cardiomyopathy
• Valve dysfunction or other abnormalities
• Small or malpositioned teeth
• Advanced or delayed eruption of primary teeth
• Hypodontia of secondary teeth
• Premature tooth loss
• To assess for obstructive sleep apnea
• Refer to pulmonologist to evaluate for restrictive lung disease if severe kyphoscoliosis or concerning respiratory symptoms are present.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• A trial of medication & efforts to optimize dosage may be considerations.
• Awareness of SIDAs should allow early intervention to minimize occurrence of triggering stimuli & provide protection from falls.
• If attacks occur w/great frequency a protective helmet may be indicated & use of a wheelchair may be required to prevent falling & injury.
• Various medications have been used in an attempt to manage SIDAs; these incl benzodiazepines, ASMs, SSRIs, & tricyclic antidepressants.
• While most treatments have not resulted in significant long-term control of SIDAs, improvements in selected persons have been seen w/clonazepam,
• Valproic acid led to improvement in 1 persons, but this & other conventional ASMs have generally been ineffective.
• Improvement of SIDAs occurred in a male after treatment of obstructive sleep apnea w/tracheostomy.
• Consider need for positioning & mobility devices, disability parking placard.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Ensure appropriate nutritional & feeing support in hypotonic infants w/feeding difficulty.
• Abnormal growth velocity & obesity should be assessed & treated in standard manner.
• There are no data regarding safety or efficacy of growth hormone for treatment of growth deficiency in this disorder.
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• At each visit
• Note: Persons w/calcifications of ligamentum flavum, particularly in cervical region, may require more careful surveillance.
• Per treating orthopedist
• Note: Skeletal maturity may be delayed, requiring longer than anticipated monitoring for progression.
• Per treating orthopedist
• Note: Persons w/calcifications of ligamentum flavum, particularly in cervical region, may require more careful surveillance.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To assess for SIDAs, changes in gait or in bowel or bladder function, & seizures or movement disorder
Consider EEG if seizures are a concern.
Gross motor & fine motor skills
Kyphoscoliosis
Pectus deformity
Contractures
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Cardiomyopathy
Valve dysfunction or other abnormalities
Small or malpositioned teeth
Advanced or delayed eruption of primary teeth
Hypodontia of secondary teeth
Premature tooth loss
To assess for obstructive sleep apnea
Refer to pulmonologist to evaluate for restrictive lung disease if severe kyphoscoliosis or concerning respiratory symptoms are present.
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To assess for SIDAs, changes in gait or in bowel or bladder function, & seizures or movement disorder
• Consider EEG if seizures are a concern.
• Gross motor & fine motor skills
• Kyphoscoliosis
• Pectus deformity
• Contractures
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Cardiomyopathy
• Valve dysfunction or other abnormalities
• Small or malpositioned teeth
• Advanced or delayed eruption of primary teeth
• Hypodontia of secondary teeth
• Premature tooth loss
• To assess for obstructive sleep apnea
• Refer to pulmonologist to evaluate for restrictive lung disease if severe kyphoscoliosis or concerning respiratory symptoms are present.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
There is no cure for
Treatment of Manifestations in Individuals with
A trial of medication & efforts to optimize dosage may be considerations.
Awareness of SIDAs should allow early intervention to minimize occurrence of triggering stimuli & provide protection from falls.
If attacks occur w/great frequency a protective helmet may be indicated & use of a wheelchair may be required to prevent falling & injury.
Various medications have been used in an attempt to manage SIDAs; these incl benzodiazepines, ASMs, SSRIs, & tricyclic antidepressants.
While most treatments have not resulted in significant long-term control of SIDAs, improvements in selected persons have been seen w/clonazepam,
Valproic acid led to improvement in 1 persons, but this & other conventional ASMs have generally been ineffective.
Improvement of SIDAs occurred in a male after treatment of obstructive sleep apnea w/tracheostomy.
Consider need for positioning & mobility devices, disability parking placard.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Ensure appropriate nutritional & feeing support in hypotonic infants w/feeding difficulty.
Abnormal growth velocity & obesity should be assessed & treated in standard manner.
There are no data regarding safety or efficacy of growth hormone for treatment of growth deficiency in this disorder.
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ASM = anti-seizure medication; CPAP = continuous positive airway pressure; OT = occupational therapy; PT = physical therapy; SIDAs = stimulus-induced drop attacks; SSRIs = selective serotonin reuptake inhibitors
Reviewed in
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• A trial of medication & efforts to optimize dosage may be considerations.
• Awareness of SIDAs should allow early intervention to minimize occurrence of triggering stimuli & provide protection from falls.
• If attacks occur w/great frequency a protective helmet may be indicated & use of a wheelchair may be required to prevent falling & injury.
• Various medications have been used in an attempt to manage SIDAs; these incl benzodiazepines, ASMs, SSRIs, & tricyclic antidepressants.
• While most treatments have not resulted in significant long-term control of SIDAs, improvements in selected persons have been seen w/clonazepam,
• Valproic acid led to improvement in 1 persons, but this & other conventional ASMs have generally been ineffective.
• Improvement of SIDAs occurred in a male after treatment of obstructive sleep apnea w/tracheostomy.
• Consider need for positioning & mobility devices, disability parking placard.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Ensure appropriate nutritional & feeing support in hypotonic infants w/feeding difficulty.
• Abnormal growth velocity & obesity should be assessed & treated in standard manner.
• There are no data regarding safety or efficacy of growth hormone for treatment of growth deficiency in this disorder.
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Neurobehavioral/Psychiatric Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Recommended Surveillance for Individuals with
At each visit
Note: Persons w/calcifications of ligamentum flavum, particularly in cervical region, may require more careful surveillance.
Per treating orthopedist
Note: Skeletal maturity may be delayed, requiring longer than anticipated monitoring for progression.
Per treating orthopedist
Note: Persons w/calcifications of ligamentum flavum, particularly in cervical region, may require more careful surveillance.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
Note: A table containing suggested guidelines for follow up of individuals with CLS is provided in
• At each visit
• Note: Persons w/calcifications of ligamentum flavum, particularly in cervical region, may require more careful surveillance.
• Per treating orthopedist
• Note: Skeletal maturity may be delayed, requiring longer than anticipated monitoring for progression.
• Per treating orthopedist
• Note: Persons w/calcifications of ligamentum flavum, particularly in cervical region, may require more careful surveillance.
## Agents/Circumstances to Avoid
Care should be taken to avoid specific stimuli that are known to trigger SIDAs in a given individual. Physical activity may be limited due to valvular disease as recommended by a cardiologist.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
The father of an affected male will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
Detailed evaluation of the parents and review of the extended family history may help distinguish male probands with a
A female proband may have inherited the
Molecular genetic testing of the mother (and possibly the father, or subsequently the father) is recommended to confirm parental genetic status and to allow reliable recurrence risk assessment.
Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If the mother of the proband has an
Males who inherit the pathogenic variant will be affected;
Females who inherit the pathogenic variant will be heterozygous and at high risk to exhibit at least some manifestations of the disorder (see Clinical Description,
Note: As expected with random X-chromosome inactivation, a mildly affected mother may have a severely affected daughter.
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
If the mother of the proband has an
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
Males with
Severely affected males typically do not reproduce.
Females with
Severely affected females typically do not reproduce.
Note: Molecular genetic testing may be able to identify the family member in whom a
Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the
Note: Females who are heterozygotes for this X-linked disorder are at high risk to exhibit at least some manifestations of
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to females who are affected, heterozygous, or at risk of being heterozygous.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• Detailed evaluation of the parents and review of the extended family history may help distinguish male probands with a
• A female proband may have inherited the
• Molecular genetic testing of the mother (and possibly the father, or subsequently the father) is recommended to confirm parental genetic status and to allow reliable recurrence risk assessment.
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If the mother of the proband has an
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygous and at high risk to exhibit at least some manifestations of the disorder (see Clinical Description,
• Note: As expected with random X-chromosome inactivation, a mildly affected mother may have a severely affected daughter.
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygous and at high risk to exhibit at least some manifestations of the disorder (see Clinical Description,
• Note: As expected with random X-chromosome inactivation, a mildly affected mother may have a severely affected daughter.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygous and at high risk to exhibit at least some manifestations of the disorder (see Clinical Description,
• Note: As expected with random X-chromosome inactivation, a mildly affected mother may have a severely affected daughter.
• If the mother of the proband has an
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Males with
• Severely affected males typically do not reproduce.
• Females with
• Severely affected females typically do not reproduce.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to females who are affected, heterozygous, or at risk of being heterozygous.
## Mode of Inheritance
## Risk to Family Members
The father of an affected male will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
Detailed evaluation of the parents and review of the extended family history may help distinguish male probands with a
A female proband may have inherited the
Molecular genetic testing of the mother (and possibly the father, or subsequently the father) is recommended to confirm parental genetic status and to allow reliable recurrence risk assessment.
Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If the mother of the proband has an
Males who inherit the pathogenic variant will be affected;
Females who inherit the pathogenic variant will be heterozygous and at high risk to exhibit at least some manifestations of the disorder (see Clinical Description,
Note: As expected with random X-chromosome inactivation, a mildly affected mother may have a severely affected daughter.
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
If the mother of the proband has an
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
Males with
Severely affected males typically do not reproduce.
Females with
Severely affected females typically do not reproduce.
Note: Molecular genetic testing may be able to identify the family member in whom a
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• Detailed evaluation of the parents and review of the extended family history may help distinguish male probands with a
• A female proband may have inherited the
• Molecular genetic testing of the mother (and possibly the father, or subsequently the father) is recommended to confirm parental genetic status and to allow reliable recurrence risk assessment.
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If the mother of the proband has an
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygous and at high risk to exhibit at least some manifestations of the disorder (see Clinical Description,
• Note: As expected with random X-chromosome inactivation, a mildly affected mother may have a severely affected daughter.
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygous and at high risk to exhibit at least some manifestations of the disorder (see Clinical Description,
• Note: As expected with random X-chromosome inactivation, a mildly affected mother may have a severely affected daughter.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygous and at high risk to exhibit at least some manifestations of the disorder (see Clinical Description,
• Note: As expected with random X-chromosome inactivation, a mildly affected mother may have a severely affected daughter.
• If the mother of the proband has an
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Males with
• Severely affected males typically do not reproduce.
• Females with
• Severely affected females typically do not reproduce.
## Heterozygote Detection
Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the
Note: Females who are heterozygotes for this X-linked disorder are at high risk to exhibit at least some manifestations of
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to females who are affected, heterozygous, or at risk of being heterozygous.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to females who are affected, heterozygous, or at risk of being heterozygous.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
PO Box 5801
Bethesda MD 20824
•
•
•
•
•
• PO Box 5801
• Bethesda MD 20824
•
## Molecular Genetics
RPS6KA3-Related Intellectual Disability: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for RPS6KA3-Related Intellectual Disability (
In general, members of the ribosomal S6 kinase family participate in cellular events such as proliferation and differentiation. Specific functions of S6K-alpha-3 include regulation of neurite formation [
Full- and partial-gene duplications have been reported.
## Molecular Pathogenesis
In general, members of the ribosomal S6 kinase family participate in cellular events such as proliferation and differentiation. Specific functions of S6K-alpha-3 include regulation of neurite formation [
Full- and partial-gene duplications have been reported.
## Chapter Notes
Contact Dr Fatima E Abidi (
Thank you to the families who have continued to be involved in patient support groups and clinical and research publications that have improved the understanding of this disorder.
Fatima E Abidi, PhD, MS, FACMG (2002-present)Alisdair GW Hunter, MD; University of Ottawa (2002-2014)R Curtis Rogers, MD (2014-present)Charles E Schwartz, PhD; Greenwood Genetic Center (2002-2009)
16 March 2023 (bp/de) Comprehensive update posted live
1 February 2018 (ha) Comprehensive update posted live
27 March 2014 (me) Comprehensive update posted live
15 January 2009 (me) Comprehensive update posted live
6 August 2007 (cd) Revision: deletion/duplication analysis available clinically
31 August 2006 (me) Comprehensive update posted live
27 December 2004 (cd) Revision: change in molecular genetic testing availability
28 June 2004 (me) Comprehensive update posted live
16 July 2002 (me) Review posted live
24 January 2002 (ah) Original submission
• 16 March 2023 (bp/de) Comprehensive update posted live
• 1 February 2018 (ha) Comprehensive update posted live
• 27 March 2014 (me) Comprehensive update posted live
• 15 January 2009 (me) Comprehensive update posted live
• 6 August 2007 (cd) Revision: deletion/duplication analysis available clinically
• 31 August 2006 (me) Comprehensive update posted live
• 27 December 2004 (cd) Revision: change in molecular genetic testing availability
• 28 June 2004 (me) Comprehensive update posted live
• 16 July 2002 (me) Review posted live
• 24 January 2002 (ah) Original submission
## Author Notes
Contact Dr Fatima E Abidi (
## Acknowledgments
Thank you to the families who have continued to be involved in patient support groups and clinical and research publications that have improved the understanding of this disorder.
## Author History
Fatima E Abidi, PhD, MS, FACMG (2002-present)Alisdair GW Hunter, MD; University of Ottawa (2002-2014)R Curtis Rogers, MD (2014-present)Charles E Schwartz, PhD; Greenwood Genetic Center (2002-2009)
## Revision History
16 March 2023 (bp/de) Comprehensive update posted live
1 February 2018 (ha) Comprehensive update posted live
27 March 2014 (me) Comprehensive update posted live
15 January 2009 (me) Comprehensive update posted live
6 August 2007 (cd) Revision: deletion/duplication analysis available clinically
31 August 2006 (me) Comprehensive update posted live
27 December 2004 (cd) Revision: change in molecular genetic testing availability
28 June 2004 (me) Comprehensive update posted live
16 July 2002 (me) Review posted live
24 January 2002 (ah) Original submission
• 16 March 2023 (bp/de) Comprehensive update posted live
• 1 February 2018 (ha) Comprehensive update posted live
• 27 March 2014 (me) Comprehensive update posted live
• 15 January 2009 (me) Comprehensive update posted live
• 6 August 2007 (cd) Revision: deletion/duplication analysis available clinically
• 31 August 2006 (me) Comprehensive update posted live
• 27 December 2004 (cd) Revision: change in molecular genetic testing availability
• 28 June 2004 (me) Comprehensive update posted live
• 16 July 2002 (me) Review posted live
• 24 January 2002 (ah) Original submission
## References
## Literature Cited
AP view of a boy age two years with CLS showing relatively fine facial features but with widely spaced eyes, mildly downslanted palpebral fissures, short nose with broad columella, and thick, slightly everted vermilion of the lips (Affected individual has a known
AP and lateral view of the same boy in
AP view of an adolescent showing relatively mild facial signs but with widely spaced eyes, mildly downslanted palpebral fissures, thick vermilion of the upper and lower lips, and small teeth. The columella is broad but nares are a good size. (Affected individual has a known
Hand of the child illustrated in
A. At age two years
B. At age five years
Hands of affected individuals with a known
A. Hand of an older child showing classic tapering and soft appearance
B. More subtle differences seen in the hand of the individual illustrated in
|
[
"MR Ammar, Y Humeau, A Hanauer, B Nieswandt, MF Bader, N Vitale. The Coffin-Lowry syndrome-associated protein RSK2 regulates neurite outgrowth through phosphorylation of phospholipase D1 (PLD1) and synthesis of phosphatidic acid.. J Neurosci 2013;33:19470-9",
"EA Arslan, S Ceylander, G Turanli. Stimulus-induced myoclonus treated effectively with clonazepam in genetically confirmed Coffin-Lowry syndrome.. Epilepsy Behav Case Rep 2014;2:196-8",
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"AG Hunter. Coffin-Lowry syndrome: a 20-year follow-up and review of long-term outcomes.. Am J Med Genet 2002;111:345-55",
"K Igari, Y Hozumi, Y Monma, H Mayanagi. A case of Coffin-Lowry syndrome with premature exfoliation of primary teeth.. Int J Paediatr Dent. 2006;16:213-7",
"G Imataka, I Nakajima, K Goto, W Konno, H Hirabayashi, O Arisaka. Drop episodes improved after tracheostomy: a case of Coffin-Lowry syndrome associated with obstructive sleep apnea syndrome.. Eur Rev Med Pharmacol Sci 2016;20:498-501",
"S Jacquot, K Merienne, S Pannetier, S Blumenfeld, A Schinzel, A Hanauer. Germline mosaicism in Coffin-Lowry syndrome.. Eur J Hum Genet 1998;6:578-82",
"D Jurkiewicz, A Jezela-Stanek, E Ciara, D Piekutowska-Abramczuk, M Kugaudo, M Gajdulewicz, K Chrzanowska, E Popowska, M. Krajewska-Walasek. Four novel RSK2 mutations in females with Coffin-Lowry syndrome.. Eur J Med Genet. 2010;53:268-73",
"SR Kesler, RJ Simensen, K Voeller, F Abidi, RE Stevenson, CE Schwartz, AL Reiss. Altered neurodevelopment associated with mutations of RSK2: a morphometric MRI study of Coffin-Lowry syndrome.. Neurogenetics 2007;8:143-7",
"HC Lim, L Xie, W Zhang, R Li, ZC Chen, GZ Wu, SS Cui, EK Tan, L Zeng. Ribosomal S6 kinase 2 (RSK2) maintains genomic stability by activating the Atm/p53-dependent DNA damage pathway.. PLoS One. 2013;8",
"RY Liu, Y Zhang, P Smolen, LJ Cleary, JH Byrne. Role of p90 ribosomal S6 kinase in long-term synaptic facilitation and enhanced neuronal excitability.. Sci Rep 2020;10:608",
"B Lowry, JR Miller, FC Fraser. A new dominant gene mental retardation syndrome. Association with small stature, tapering fingers, characteristic facies, and possible hydrocephalus.. Am J Dis Child 1971;121:496-500",
"Y Lv, L Zhu, J Zheng, D Wu, J Shao. Growth concerns in Coffin-Lowry syndrome: a case report and literature review.. Front Pediatr. 2019;6:430",
"S Manouvrier-Hanu, J Amiel, S Jacquot, K Merienne, A Moerman, A Coeslier, F Labarriere, L Vallee, MF Croquette, A Hanauer. Unreported RSK2 missense mutation in two male sibs with an unusually mild form of Coffin-Lowry syndrome.. J Med Genet 1999;36:775-8",
"P Marques Pereira, D Heron, A. Hanauer. The first large duplication of the RSK2 gene identified in a Coffin-Lowry syndrome patient.. Hum Genet. 2007;122:541-3",
"HR Martinez, MC Niu, VR Sutton, R Pignatelli, M Vatta, JL Jefferies. Coffin-Lowry syndrome and left ventricular noncompaction cardiomyopathy with a restrictive pattern.. Am J Med Genet A. 2011;155A:3030-4",
"MM Massin, MA Radermecker, A Verloes, S Jacquot, T Grenade. Cardiac involvement in Coffin-Lowry syndrome.. Acta Paediatr 1999;88:468-70",
"A Matsumoto, M Kuwajima, K Miyake, K Kojima, N Nakashima, EF Jimbo, T Kubota, MY Momoi, T Yamagata. An Xp22.12 microduplication including RPS6KA3 identified in a family with variably affected intellectual and behavioral disabilities.. J Hum Genet 2013;58:755-7",
"K Merienne, S Jacquot, S Pannetier, M Zeniou, A Bankier, J Gecz, JL Mandel, J Mulley, P Sassone-Corsi, A Hanauer. A missense mutation in RPS6KA3 (RSK2) responsible for non-specific mental retardation.. Nat Genet 1999;22:13-4",
"V Micheli, S Sestini, V Parri, M Fichera, C Romano, F Ariani, I Longo, F Mari, M Bruttini, A Renieri, I Meloni. RSK2 enzymatic assay as a second level diagnostic tool in Coffin-Lowry syndrome.. Clin Chim Acta 2007;384:35-40",
"Y Miyata, K Saida, S Kumada, N Miyake, H Mashimo, Y Nishida, I Shirai, E Kurihara, Y Nakata, N Matsumoto. Periventricular small cystic lesions in a patient with Coffin-Lowry syndrome who exhibited a novel mutation in the RPS6KA3 gene.. Brain Dev. 2018;40:566-9",
"T Morino, T Ogata, H Horiuchi, S Yamaoka, M Fukuda, H Miura. Eight years of follow-up after laminectomy of calcium pyrophosphate crystal deposition in the cervical yellow liament of patient with Coffin-Lowry syndrome: a case report.. Medicine (Baltimore) 2016;95",
"M Nakamura, T Yamagata, M Mori, MY Momoi. RSK2 gene mutations in Coffin-Lowry syndrome with drop episodes.. Brain Dev 2005;27:114-7",
"GB Nelson, JS Hahn. Stimulus-induced drop episodes in Coffin-Lowry syndrome.. Pediatrics 2003;111:e197-202",
"J Norderyd, J Aronsson. Hypoplastic root cementum and premature loss of primary teeth in Coffin-Lowry syndrome: a case report.. Int J Paediatr Dent. 2012;22:154-6",
"S O'Riordan, M Patton, F Schon. Treatment of drop episodes in Coffin-Lowry syndrome.. J Neurol 2006;253:109-10",
"PM Pereira, A Schneider, S Pannetier, D Heron, A Hanauer. Coffin-Lowry syndrome.. Eur J Hum Genet 2010;18:627-33",
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"K Rojnueangnit, JR Jones, MJ Basehore, NH Robin. Classic phenotype of Coffin-Lowry syndrome in a female with stimulus-induced drop episodes and a genotype with preserved N-terminal kinase domain.. Am J Med Genet A. 2014;164A:516-21",
"A Schneider, SM Maas, RC Hennekam, A Hanauer. Identification of the first deep intronic mutation in the RPS6KA3 gene in a patient with a severe form of Coffin-Lowry syndrome.. Eur J Med Genet 2013;56:150-2",
"RJ Simensen, F Abidi, JS Collins, CE Schwartz, RE Stevenson. Cognitive function in Coffin-Lowry syndrome.. Clin Genet 2002;61:299-304",
"P Smolen, MA Wood, DA Baxter, JH Byrne. Modeling suggests combined-drug treatments for disorders impairing synaptic plasticity via shared signaling pathways.. J Comput Neurosci. 2021;49:37-56",
"A Song, M Im, MS Kim, ES Noh, C Kim, J Jang, SM Lee, CS Ki, SY Cho, DK Jin. First Korean female child with Coffin-Lowry syndrome: a novel variant in RPS6KA3 diagnosed by exome sequencing and a literature review.. Ann Pediatr Endocrinol Metab. 2022",
"JB Stephenson, MC Hoffman, AJ Russell, J Falconer, RC Beach, JL Tolmie, RC McWilliam, SM Zuberi. The movement disorders of Coffin-Lowry syndrome.. Brain Dev 2005;27:108-13",
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"CG Tise, DR Matalon, MA Manning, HM Byers, M Grover. Short bones, renal stones, and diagnostic moans: hypercalcemia in a girl found to have Coffin-Lowry syndrome.. J Investig Med High Impact Case Rep. 2022;10",
"T Tos, MY Alp, A Aksoy, S Ceylaner, A Hanauer. A familial case of Coffin-Lowry syndrome caused by RPS6KA3 C.898C>T mutation associated with multiple abnormal brain imaging findings.. Genet Couns. 2015;26:47-52",
"M Touma Boulos, A Moukarzel, T Yammine, N Salem, M Souaid, C. Farra. Novel missense mutation c.1784A>G, p.Tyr595Cys in RPS6KA3 gene responsible for Coffin-Lowry syndrome in a family with variable features and diabetes 2.. Clin Dysmorphol. 2021;30:32-5",
"R-L Touraine, M Zeniou, A Hanauer. A syndromic form of X-linked mental retardation: the Coffin-Lowry syndrome.. Eur J Pediatr 2002;161:179-87",
"J Upadia, J Oakes, A Hamm, AC Hurst, NH Robin. Foramen magnum compression in Coffin-Lowry syndrome: a case report.. Am J Med Genet A. 2017;173:1087-9",
"MG Valdovinos, DA Napolitano, JR Zarcone, JA Hellings, DC Williams, SR Schroeder. Multimodal evaluation of risperidone for destructive behavior: functional analysis, direct observations, rating scales, and psychiatric impressions.. Exp Clin Psychopharmacol 2002;10:268-75",
"F Venter, A Evans, C Fontes, C Stewart. Severe restrictive lung disease in one of the oldest documented males with Coffin-Lowry syndrome.. J Investig Med High Impact Case Rep. 2019;7",
"T Wakami, K Yoshizawa, T Maeda, O Mori, N Tamura. Mitral valve repair and tricuspid annuloplasty for Coffin-Lowry syndrome.. Asian Cardiovasc Thorac Ann. 2022;30:1017-9",
"Y Wang, JE Martinez, GL Wilson, XY He, CM Tuck-Muller, P Maertens, W Wertelecki, TJ Chen. A novel RSK2 (RPS6KA3) gene mutation associated with abnormal brain MRI findings in a family with Coffin-Lowry syndrome.. Am J Med Genet A 2006;140:1274-9",
"M Welborn, S Farrell, P Knott, E Mayekar, S Mardjetko. The natural history of spinal deformity in patients with Coffin-Lowry syndrome.. J Child Orthop. 2018;12:70-5",
"K Yamoto, H Saitsu, Y Fujisawa, F Kato, K Matsubara, M Fukami, M Kagami, T Ogata. Coffin-Lowry syndrome in a girl with 46,XX,t(X;11)(p22;p15)dn: identification of RPS6KA3 disruption by whole genome sequencing.. Clin Case Rep. 2020;8:1076-80",
"T Yoshida, T Ohashi, M Furui, S Kageyama, N Kodani, Y Kobayashi, Y Hirai, R Sakakura. Mitral and tricuspid valve surgery for Coffin-Lowry syndrome.. Gen Thorac Cardiovasc Surg. 2015;63:290-2",
"M Zeniou-Meyer, A Béglé, MF Bader, N Vitale. The Coffin-Lowry syndrome-associated protein RSK2 controls neuroendocrine secretion through the regulation of phospholipase D1 at the exocytotic sites.. Ann N Y Acad Sci 2009;1152:201-8",
"M Zeniou-Meyer, F Gambino, MR Ammar, Y Humeau, N Vitale. The Coffin-Lowry syndrome-associated protein RSK2 and neurosecretion.. Cell Mol Neurobiol 2010;30:1401-6",
"M Zeniou-Meyer, Y Liu, A Béglé, ME Olanich, A Hanauer, U Becherer, J Rettig, MF Bader, N Vitale. The Coffin-Lowry syndrome-associated protein RSK2 is implicated in calcium-regulated exocytosis through the regulation of PLD1.. Proc Natl Acad Sci U S A 2008;105:8434-9"
] |
16/7/2002
|
16/3/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
cmd-overview
|
cmd-overview
|
[
"Collagen Type VI-Related Disorders",
"FKTN-Related Muscle Diseases",
"FKRP-Related Muscle Diseases",
"LARGE-Related Muscle Diseases",
"LAMA2-Related Muscular Dystrophy",
"LMNA-Related Muscle Diseases",
"POMGNT1-Related Muscle Diseases",
"POMT1-Related Muscle Diseases",
"POMT2-Related Muscle Diseases",
"SEPN1-Related Myopathy",
"Congenital Muscular Dystrophy due to Integrin Alpha-7 Deficiency",
"CHKB-Related Muscle Diseases",
"ISPD-Related Muscle Diseases",
"GTDC2-Related Muscle Diseases",
"Choline/ethanolamine kinase",
"Collagen alpha-1(VI) chain",
"Collagen alpha-2(VI) chain",
"Collagen alpha-3(VI) chain",
"D-ribitol-5-phosphate cytidylyltransferase",
"Fukutin",
"Fukutin-related protein",
"Laminin subunit alpha-2",
"LARGE xylosyl- and glucuronyltransferase 1",
"Nesprin-1",
"Prelamin-A/C",
"Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1",
"Protein O-mannosyl-transferase 1",
"Protein O-mannosyl-transferase 2",
"Selenoprotein N",
"CHKB",
"COL6A1",
"COL6A2",
"COL6A3",
"FKRP",
"FKTN",
"ISPD",
"LAMA2",
"LARGE1",
"LMNA",
"POMGNT1",
"POMT1",
"POMT2",
"SELENON",
"SYNE1",
"Congenital Muscular Dystrophy",
"Overview"
] |
Congenital Muscular Dystrophy Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Susan E Sparks, Susana Quijano-Roy, Amy Harper, Anne Rutkowski, Erynn Gordon, Eric P Hoffman, Elena Pegoraro
|
Summary Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of inherited muscle disorders. Muscle weakness typically presents from birth to early infancy. Affected infants typically appear "floppy" with low muscle tone and poor spontaneous movements. Affected children may present with delay or arrest of gross motor development together with joint and/or spinal rigidity. Muscle weakness may improve, worsen, or stabilize in the short term; however, with time progressive weakness and joint contractures, spinal deformities, and respiratory compromise may affect quality of life and life span. The main CMD subtypes, grouped by involved protein function and gene in which causative allelic variants occur, are laminin alpha-2 (merosin) deficiency (MDC1A), collagen VI-deficient CMD, the dystroglycanopathies (caused by mutation of The diagnosis of congenital muscular dystrophy relies on clinical findings, brain and muscle imaging, muscle biopsy histology (dystrophic features without the hallmarks of the structural changes seen in the congenital myopathies), muscle and/or skin immunohistochemical staining, and molecular genetic testing. The congenital muscular dystrophies are inherited in an autosomal recessive manner with the following exceptions: collagen VI-deficient CMD, which may be inherited in an autosomal recessive or an autosomal dominant manner; LMNA-related CMD (L-CMD), which is inherited in an autosomal dominant manner with all cases to date caused by a In autosomal recessive subtypes, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carriers are asymptomatic. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family are known. In autosomal dominant subtypes, the offspring of affected individuals have a 50% chance of being affected. The risk to sibs of an individual with an apparent
|
## Definition of CMD
The term congenital muscular dystrophy (CMD) refers to a heterogeneous group of inherited disorders in which weakness is first apparent at birth or in infancy. With the discovery of causative pathogenic variants in multiple genes in the last two decades, the concept of CMD has evolved from a narrowly defined clinical diagnosis (onset in the first months of life) and histologic diagnosis (dystrophic muscle on biopsy) to a more inclusive group of subtypes defined by genes in which causative pathogenic variants occur [
Hypotonia and muscle weakness are present at birth or during infancy. Poor or decreased motor abilities, delay or arrest of motor milestones, and joint or spinal deformities are often the presenting features of CMD. The age of onset is usually not clearly defined and often difficult to identify retrospectively. Since delay of motor skill acquisition may be a presenting symptom of CMD, onset of manifestations before age two years may be a reasonable diagnostic criterion.
Although muscle weakness of CMD may be stable in the short term, typically over time the weakness and its complications become more severe. These complications include feeding difficulties leading to poor nutrition; respiratory insufficiency; joint contractures and scoliosis; and, in some subtypes, cardiac involvement. The central nervous system, eye, and connective tissue may also be involved.
Note: The diagnosis of a child who has delay in onset of walking during the first two years of life as having CMD versus limb-girdle muscular dystrophy (LGMD) may be considered a matter of convention especially given the overlap between the CMD and LGMD phenotypes (see
## Clinical Manifestations of CMD
Hypotonia and muscle weakness are present at birth or during infancy. Poor or decreased motor abilities, delay or arrest of motor milestones, and joint or spinal deformities are often the presenting features of CMD. The age of onset is usually not clearly defined and often difficult to identify retrospectively. Since delay of motor skill acquisition may be a presenting symptom of CMD, onset of manifestations before age two years may be a reasonable diagnostic criterion.
Although muscle weakness of CMD may be stable in the short term, typically over time the weakness and its complications become more severe. These complications include feeding difficulties leading to poor nutrition; respiratory insufficiency; joint contractures and scoliosis; and, in some subtypes, cardiac involvement. The central nervous system, eye, and connective tissue may also be involved.
Note: The diagnosis of a child who has delay in onset of walking during the first two years of life as having CMD versus limb-girdle muscular dystrophy (LGMD) may be considered a matter of convention especially given the overlap between the CMD and LGMD phenotypes (see
## Subtypes of CMD
Click
The classification scheme for subtypes of CMD that is used in this
The disorders associated with mutation of the 13 genes most commonly associated with CMD are summarized in
Of note, in large cohorts of individuals with CMD causative pathogenic variants can be identified in 25%-50% of cases, underscoring the need for ongoing investigation into the genetic causes of CMD [
Congenital Muscular Dystrophies by Protein Defect and Gene
CMD = Congenital muscular dystrophy; EDMD = Emery-Dreifuss muscular dystrophy; FCMD = Fukuyama CMD; LGMD2I = Limb-girdle muscular dystrophy type 2I (no intellectual disability); LGMD2K = Limb-girdle muscular dystrophy type 2K with microcephaly, intellectual disability, normal MRI; LGMD2M = Limb-girdle muscular Dystrophy type 2M (no intellectual disability); LGMD2N = Congenital muscular dystrophy/limb-girdle muscular dystrophy type 2N (intellectual disability); MDC1A = Merosin-deficient congenital muscular dystrophy type 1A; MDC1C = Merosin-deficient congenital muscular dystrophy type 1C (with muscle hypertrophy); MDC1D = Merosin-deficient congenital muscular dystrophy type 1D (with intellectual disability and abnormal glycosylation); MEB = Muscle-eye-brain (disease); WWS = Walker-Warburg syndrome
Protein located in basement membrane (BM) or extracellular matrix (ECM)
Subtype name no longer in use; because merosin deficiency can be primary in laminin alpha-2 deficiency or secondary in the dystroglycanopathies, the term merosin deficiency is no longer sufficiently specific.
Rigid spine muscular dystrophy type 1
With time affected children develop typical myopathic facies and some develop external ophthalmoplegia and may appear to have an enlarged head with parents relaying difficulty in pulling T-shirts over the head. Of note, retrospective data on 15 children with laminin alpha-2 deficiency from one CMD center revealed that 53% had a head circumference above the 90
Cognitive abilities are normal in the majority of affected individuals. Seizures are observed in 20%-30% [
Brain MRI demonstrates diffuse white matter signal abnormalities sparing the cerebellum, corpus callosum, and internal capsule. Children may initially be misdiagnosed as having a leukodystrophy. The MRI findings can be found consistently beyond age six months. White matter changes do not regress with time. A small number of individuals have structural changes with focal cortical dysplasia that tends to involve the occipital and temporal lobes.
Nerve conduction studies show reduced velocities during disease demonstrating a peripheral neuropathy.
Inheritance is autosomal recessive.
Homozygous premature termination codon-causing pathogenic variants in the triple helix domains were associated with the early/severe phenotype and dominant
Terminology:
UCMD (first described as "scleroatonic myopathy") is characterized by congenital weakness and hypotonia along with congenital joint or spinal rigidity or deformities. The combination of proximal joint contractures and a striking hyperlaxity of the distal joints is characteristic. Some affected children have acquired the ability to walk independently; however, disease progression often results in loss of ambulation. Early and severe respiratory involvement may require ventilatory support in the first or second decade of life.
Bethlem myopathy is characterized by the combination of proximal muscle weakness and variable contractures, affecting most frequently the long finger flexors, elbows, and ankles.
Although the first reports of UCMD showed autosomal recessive transmission, most affected individuals identified in recent years have a
Several CMD phenotypes known to be dystroglycanopathies were initially described as syndromes (in descending order of severity):
Walker Warburg syndrome (WWS)
Muscle-eye-brain (MEB) disease
Fukuyama congenital muscular dystrophy (FCMD)
MDC1D
MDC1C
Eye manifestations can include either unilateral or bilateral microcornea and/or microphthalmia, hypoplastic or absent optic nerves, and colobomas that may involve the retina. Anterior chamber malformations include cataracts, iris hypoplasia or malformation, and abnormal or shallow anterior chamber angle which can result in glaucoma. Retinal dysplasia or detachment may occur. In individuals with milder manifestations of a dystroglycanopathy, high myopia or optic disc pallor may be the only ocular manifestation.
Brain MRI may demonstrate structural abnormalities (e.g., hydrocephalus, brain stem hypoplasia, cerebellar cysts) or abnormalities in neuronal migration (cobblestone lissencephaly or polymicrogyria), which are common [
Hindbrain malformations can include atrophy of the cerebellar vermis and hemispheres and flattening of the pons and brain stem [
WWS, MEB disease, and FCMD were considered separate entities long before their molecular basis was known. When clinically defined, these three disorders did not include milder phenotypes in which the brain MRI was normal or showed less severe cortical or cerebellar malformations. The spectrum of the dystroglycanopathies is now known to include the milder phenotype of limb-girdle muscle muscular dystrophy, with and without cognitive impairment.
Pathogenic variants in a number of genes (
Isoprenoid synthase (encoded by
Known glycosyltransferases (encoded by
Proteins involved in a specific glycan epitope that confers laminin binding (encoded by
Although "one gene, one syndrome" was initially postulated, it is now known that pathogenic variants in any one of the seven genes results in a broad phenotypic spectrum. The most phenotypic variability is observed with pathogenic variants in
Certain clinical findings can help direct one to the specific gene involved:
It is unclear at this time if certain central nervous system abnormalities are associated with mutation of specific genes.
Inheritance is autosomal recessive.
Findings in the α-Dystroglycanopathies
Severe congenital myopia, congenital glaucoma, pallor of the optic discs, and retinal hypoplasia
Microphthalmia, retinal detachment, retinal hypoplasia, anterior chamber malformation, cataracts
Clinical features tend to be homogeneous: cervicoaxial weakness early in life that may be associated with delay in motor milestones and development of spinal stiffness often associated with thoracic spinal lordosis and a characteristic "S"-shaped thoracic scoliosis. Progressive respiratory insufficiency is aggravated by diaphragmatic weakness. Early nocturnal hypoventilation prior to adulthood in a person who is still ambulatory is the distinct feature of this CMD subtype.
MRI shows selective involvement of the sartorius and major adductor muscles in the thigh giving a characteristic medial thigh wasting, notable on physical examination.
L-CMD can be considered as an early-onset variant of
Genetic testing has identified a number of
A number of reports describe individuals with a subtype of CMD which does not resemble the known subtypes and/or is not caused by mutation of the genes currently known to be associated with CMD subtypes.
CMD with cerebellar involvement. Cerebellar abnormalities may include cysts or other signs of cerebellar dysplasia or hypoplasia [
CMD with intellectual disability and normal MRI. Minimal ventricular dilation or minor white matter changes on MRI are observed [
CMD with no intellectual disability and normal MRI [
CMD with intellectual disability, microcephaly, cerebellar hypoplasia, feeding difficulties, and severe myoclonic epilepsy [
• UCMD (first described as "scleroatonic myopathy") is characterized by congenital weakness and hypotonia along with congenital joint or spinal rigidity or deformities. The combination of proximal joint contractures and a striking hyperlaxity of the distal joints is characteristic. Some affected children have acquired the ability to walk independently; however, disease progression often results in loss of ambulation. Early and severe respiratory involvement may require ventilatory support in the first or second decade of life.
• Bethlem myopathy is characterized by the combination of proximal muscle weakness and variable contractures, affecting most frequently the long finger flexors, elbows, and ankles.
• Walker Warburg syndrome (WWS)
• Muscle-eye-brain (MEB) disease
• Fukuyama congenital muscular dystrophy (FCMD)
• MDC1D
• MDC1C
• Isoprenoid synthase (encoded by
• Known glycosyltransferases (encoded by
• Proteins involved in a specific glycan epitope that confers laminin binding (encoded by
• CMD with cerebellar involvement. Cerebellar abnormalities may include cysts or other signs of cerebellar dysplasia or hypoplasia [
• CMD with intellectual disability and normal MRI. Minimal ventricular dilation or minor white matter changes on MRI are observed [
• CMD with no intellectual disability and normal MRI [
• CMD with intellectual disability, microcephaly, cerebellar hypoplasia, feeding difficulties, and severe myoclonic epilepsy [
## Subtypes of CMD of Known Cause
Click
The classification scheme for subtypes of CMD that is used in this
The disorders associated with mutation of the 13 genes most commonly associated with CMD are summarized in
Of note, in large cohorts of individuals with CMD causative pathogenic variants can be identified in 25%-50% of cases, underscoring the need for ongoing investigation into the genetic causes of CMD [
Congenital Muscular Dystrophies by Protein Defect and Gene
CMD = Congenital muscular dystrophy; EDMD = Emery-Dreifuss muscular dystrophy; FCMD = Fukuyama CMD; LGMD2I = Limb-girdle muscular dystrophy type 2I (no intellectual disability); LGMD2K = Limb-girdle muscular dystrophy type 2K with microcephaly, intellectual disability, normal MRI; LGMD2M = Limb-girdle muscular Dystrophy type 2M (no intellectual disability); LGMD2N = Congenital muscular dystrophy/limb-girdle muscular dystrophy type 2N (intellectual disability); MDC1A = Merosin-deficient congenital muscular dystrophy type 1A; MDC1C = Merosin-deficient congenital muscular dystrophy type 1C (with muscle hypertrophy); MDC1D = Merosin-deficient congenital muscular dystrophy type 1D (with intellectual disability and abnormal glycosylation); MEB = Muscle-eye-brain (disease); WWS = Walker-Warburg syndrome
Protein located in basement membrane (BM) or extracellular matrix (ECM)
Subtype name no longer in use; because merosin deficiency can be primary in laminin alpha-2 deficiency or secondary in the dystroglycanopathies, the term merosin deficiency is no longer sufficiently specific.
Rigid spine muscular dystrophy type 1
With time affected children develop typical myopathic facies and some develop external ophthalmoplegia and may appear to have an enlarged head with parents relaying difficulty in pulling T-shirts over the head. Of note, retrospective data on 15 children with laminin alpha-2 deficiency from one CMD center revealed that 53% had a head circumference above the 90
Cognitive abilities are normal in the majority of affected individuals. Seizures are observed in 20%-30% [
Brain MRI demonstrates diffuse white matter signal abnormalities sparing the cerebellum, corpus callosum, and internal capsule. Children may initially be misdiagnosed as having a leukodystrophy. The MRI findings can be found consistently beyond age six months. White matter changes do not regress with time. A small number of individuals have structural changes with focal cortical dysplasia that tends to involve the occipital and temporal lobes.
Nerve conduction studies show reduced velocities during disease demonstrating a peripheral neuropathy.
Inheritance is autosomal recessive.
Homozygous premature termination codon-causing pathogenic variants in the triple helix domains were associated with the early/severe phenotype and dominant
Terminology:
UCMD (first described as "scleroatonic myopathy") is characterized by congenital weakness and hypotonia along with congenital joint or spinal rigidity or deformities. The combination of proximal joint contractures and a striking hyperlaxity of the distal joints is characteristic. Some affected children have acquired the ability to walk independently; however, disease progression often results in loss of ambulation. Early and severe respiratory involvement may require ventilatory support in the first or second decade of life.
Bethlem myopathy is characterized by the combination of proximal muscle weakness and variable contractures, affecting most frequently the long finger flexors, elbows, and ankles.
Although the first reports of UCMD showed autosomal recessive transmission, most affected individuals identified in recent years have a
Several CMD phenotypes known to be dystroglycanopathies were initially described as syndromes (in descending order of severity):
Walker Warburg syndrome (WWS)
Muscle-eye-brain (MEB) disease
Fukuyama congenital muscular dystrophy (FCMD)
MDC1D
MDC1C
Eye manifestations can include either unilateral or bilateral microcornea and/or microphthalmia, hypoplastic or absent optic nerves, and colobomas that may involve the retina. Anterior chamber malformations include cataracts, iris hypoplasia or malformation, and abnormal or shallow anterior chamber angle which can result in glaucoma. Retinal dysplasia or detachment may occur. In individuals with milder manifestations of a dystroglycanopathy, high myopia or optic disc pallor may be the only ocular manifestation.
Brain MRI may demonstrate structural abnormalities (e.g., hydrocephalus, brain stem hypoplasia, cerebellar cysts) or abnormalities in neuronal migration (cobblestone lissencephaly or polymicrogyria), which are common [
Hindbrain malformations can include atrophy of the cerebellar vermis and hemispheres and flattening of the pons and brain stem [
WWS, MEB disease, and FCMD were considered separate entities long before their molecular basis was known. When clinically defined, these three disorders did not include milder phenotypes in which the brain MRI was normal or showed less severe cortical or cerebellar malformations. The spectrum of the dystroglycanopathies is now known to include the milder phenotype of limb-girdle muscle muscular dystrophy, with and without cognitive impairment.
Pathogenic variants in a number of genes (
Isoprenoid synthase (encoded by
Known glycosyltransferases (encoded by
Proteins involved in a specific glycan epitope that confers laminin binding (encoded by
Although "one gene, one syndrome" was initially postulated, it is now known that pathogenic variants in any one of the seven genes results in a broad phenotypic spectrum. The most phenotypic variability is observed with pathogenic variants in
Certain clinical findings can help direct one to the specific gene involved:
It is unclear at this time if certain central nervous system abnormalities are associated with mutation of specific genes.
Inheritance is autosomal recessive.
Findings in the α-Dystroglycanopathies
Severe congenital myopia, congenital glaucoma, pallor of the optic discs, and retinal hypoplasia
Microphthalmia, retinal detachment, retinal hypoplasia, anterior chamber malformation, cataracts
Clinical features tend to be homogeneous: cervicoaxial weakness early in life that may be associated with delay in motor milestones and development of spinal stiffness often associated with thoracic spinal lordosis and a characteristic "S"-shaped thoracic scoliosis. Progressive respiratory insufficiency is aggravated by diaphragmatic weakness. Early nocturnal hypoventilation prior to adulthood in a person who is still ambulatory is the distinct feature of this CMD subtype.
MRI shows selective involvement of the sartorius and major adductor muscles in the thigh giving a characteristic medial thigh wasting, notable on physical examination.
L-CMD can be considered as an early-onset variant of
Genetic testing has identified a number of
• UCMD (first described as "scleroatonic myopathy") is characterized by congenital weakness and hypotonia along with congenital joint or spinal rigidity or deformities. The combination of proximal joint contractures and a striking hyperlaxity of the distal joints is characteristic. Some affected children have acquired the ability to walk independently; however, disease progression often results in loss of ambulation. Early and severe respiratory involvement may require ventilatory support in the first or second decade of life.
• Bethlem myopathy is characterized by the combination of proximal muscle weakness and variable contractures, affecting most frequently the long finger flexors, elbows, and ankles.
• Walker Warburg syndrome (WWS)
• Muscle-eye-brain (MEB) disease
• Fukuyama congenital muscular dystrophy (FCMD)
• MDC1D
• MDC1C
• Isoprenoid synthase (encoded by
• Known glycosyltransferases (encoded by
• Proteins involved in a specific glycan epitope that confers laminin binding (encoded by
## Clinical Findings in the Disorders Described in
With time affected children develop typical myopathic facies and some develop external ophthalmoplegia and may appear to have an enlarged head with parents relaying difficulty in pulling T-shirts over the head. Of note, retrospective data on 15 children with laminin alpha-2 deficiency from one CMD center revealed that 53% had a head circumference above the 90
Cognitive abilities are normal in the majority of affected individuals. Seizures are observed in 20%-30% [
Brain MRI demonstrates diffuse white matter signal abnormalities sparing the cerebellum, corpus callosum, and internal capsule. Children may initially be misdiagnosed as having a leukodystrophy. The MRI findings can be found consistently beyond age six months. White matter changes do not regress with time. A small number of individuals have structural changes with focal cortical dysplasia that tends to involve the occipital and temporal lobes.
Nerve conduction studies show reduced velocities during disease demonstrating a peripheral neuropathy.
Inheritance is autosomal recessive.
Homozygous premature termination codon-causing pathogenic variants in the triple helix domains were associated with the early/severe phenotype and dominant
Terminology:
UCMD (first described as "scleroatonic myopathy") is characterized by congenital weakness and hypotonia along with congenital joint or spinal rigidity or deformities. The combination of proximal joint contractures and a striking hyperlaxity of the distal joints is characteristic. Some affected children have acquired the ability to walk independently; however, disease progression often results in loss of ambulation. Early and severe respiratory involvement may require ventilatory support in the first or second decade of life.
Bethlem myopathy is characterized by the combination of proximal muscle weakness and variable contractures, affecting most frequently the long finger flexors, elbows, and ankles.
Although the first reports of UCMD showed autosomal recessive transmission, most affected individuals identified in recent years have a
Several CMD phenotypes known to be dystroglycanopathies were initially described as syndromes (in descending order of severity):
Walker Warburg syndrome (WWS)
Muscle-eye-brain (MEB) disease
Fukuyama congenital muscular dystrophy (FCMD)
MDC1D
MDC1C
Eye manifestations can include either unilateral or bilateral microcornea and/or microphthalmia, hypoplastic or absent optic nerves, and colobomas that may involve the retina. Anterior chamber malformations include cataracts, iris hypoplasia or malformation, and abnormal or shallow anterior chamber angle which can result in glaucoma. Retinal dysplasia or detachment may occur. In individuals with milder manifestations of a dystroglycanopathy, high myopia or optic disc pallor may be the only ocular manifestation.
Brain MRI may demonstrate structural abnormalities (e.g., hydrocephalus, brain stem hypoplasia, cerebellar cysts) or abnormalities in neuronal migration (cobblestone lissencephaly or polymicrogyria), which are common [
Hindbrain malformations can include atrophy of the cerebellar vermis and hemispheres and flattening of the pons and brain stem [
WWS, MEB disease, and FCMD were considered separate entities long before their molecular basis was known. When clinically defined, these three disorders did not include milder phenotypes in which the brain MRI was normal or showed less severe cortical or cerebellar malformations. The spectrum of the dystroglycanopathies is now known to include the milder phenotype of limb-girdle muscle muscular dystrophy, with and without cognitive impairment.
Pathogenic variants in a number of genes (
Isoprenoid synthase (encoded by
Known glycosyltransferases (encoded by
Proteins involved in a specific glycan epitope that confers laminin binding (encoded by
Although "one gene, one syndrome" was initially postulated, it is now known that pathogenic variants in any one of the seven genes results in a broad phenotypic spectrum. The most phenotypic variability is observed with pathogenic variants in
Certain clinical findings can help direct one to the specific gene involved:
It is unclear at this time if certain central nervous system abnormalities are associated with mutation of specific genes.
Inheritance is autosomal recessive.
Findings in the α-Dystroglycanopathies
Severe congenital myopia, congenital glaucoma, pallor of the optic discs, and retinal hypoplasia
Microphthalmia, retinal detachment, retinal hypoplasia, anterior chamber malformation, cataracts
Clinical features tend to be homogeneous: cervicoaxial weakness early in life that may be associated with delay in motor milestones and development of spinal stiffness often associated with thoracic spinal lordosis and a characteristic "S"-shaped thoracic scoliosis. Progressive respiratory insufficiency is aggravated by diaphragmatic weakness. Early nocturnal hypoventilation prior to adulthood in a person who is still ambulatory is the distinct feature of this CMD subtype.
MRI shows selective involvement of the sartorius and major adductor muscles in the thigh giving a characteristic medial thigh wasting, notable on physical examination.
L-CMD can be considered as an early-onset variant of
Genetic testing has identified a number of
• UCMD (first described as "scleroatonic myopathy") is characterized by congenital weakness and hypotonia along with congenital joint or spinal rigidity or deformities. The combination of proximal joint contractures and a striking hyperlaxity of the distal joints is characteristic. Some affected children have acquired the ability to walk independently; however, disease progression often results in loss of ambulation. Early and severe respiratory involvement may require ventilatory support in the first or second decade of life.
• Bethlem myopathy is characterized by the combination of proximal muscle weakness and variable contractures, affecting most frequently the long finger flexors, elbows, and ankles.
• Walker Warburg syndrome (WWS)
• Muscle-eye-brain (MEB) disease
• Fukuyama congenital muscular dystrophy (FCMD)
• MDC1D
• MDC1C
• Isoprenoid synthase (encoded by
• Known glycosyltransferases (encoded by
• Proteins involved in a specific glycan epitope that confers laminin binding (encoded by
## Less Common CMD Subtypes
## CMD of Unknown Cause
A number of reports describe individuals with a subtype of CMD which does not resemble the known subtypes and/or is not caused by mutation of the genes currently known to be associated with CMD subtypes.
CMD with cerebellar involvement. Cerebellar abnormalities may include cysts or other signs of cerebellar dysplasia or hypoplasia [
CMD with intellectual disability and normal MRI. Minimal ventricular dilation or minor white matter changes on MRI are observed [
CMD with no intellectual disability and normal MRI [
CMD with intellectual disability, microcephaly, cerebellar hypoplasia, feeding difficulties, and severe myoclonic epilepsy [
• CMD with cerebellar involvement. Cerebellar abnormalities may include cysts or other signs of cerebellar dysplasia or hypoplasia [
• CMD with intellectual disability and normal MRI. Minimal ventricular dilation or minor white matter changes on MRI are observed [
• CMD with no intellectual disability and normal MRI [
• CMD with intellectual disability, microcephaly, cerebellar hypoplasia, feeding difficulties, and severe myoclonic epilepsy [
## Establishing the Diagnosis of a CMD Subtype
Establishing the specific CMD subtype can help clarify prognosis and inheritance pattern. Establishing the subtype usually involves medical history, family history, physical examination, neurologic examination, eye examination by a pediatric ophthalmologist, measurement of serum CK concentration, neuroimaging, muscle imaging, muscle and/or skin biopsy for histologic examination and immunohistochemistry, and molecular genetic testing.
In older children, medical history focuses on cognitive abilities, motor abilities, muscle weakness, disease progression, joint contractures, scoliosis and spinal deformities, nutritional status, signs of respiratory compromise, hospitalizations, and infections.
Information in the medical history that may help identify the specific CMD subtype:
Central nervous system involvement, psychomotor delay or intellectual disability: dystroglycanopathies; occasionally, laminin alpha-2 deficiency
Early signs of respiratory insufficiency:
Very severe or progressive in the first two years of life: L-CMD; some very hypotonic infants with laminin alpha-2 deficiency
Slowly progressive resulting in severe respiratory insufficiency in the first decade:
Nonambulatory: laminin alpha-2 deficiency; collagen VI-deficient CMD; L-CMD; dystroglycanopathy
Ambulatory:
Development of orthopedic complications:
Diffuse proximal and distal joint contractures and spinal stiffness and/or scoliosis: collagen VI-deficient CMD and laminin alpha-2 deficiency; late-stage L-CMD and dystroglycanopathies
Selective involvement of the spine:
The presence of joint deformities, torticollis or hip dislocation at birth: collagen VI-deficient CMD
Rapidly progressive course with loss of head control: L-CMD (dropped head syndrome)
Congenital head lag as a result of marked cervicoaxial hypotonia associated with progressive cervical stiffness:
Documentation of relevant findings in family members with congenital weakness can be accomplished through review of medical records. It is appropriate to review the medical records and any available tissue samples of sibs of the proband who have died in the newborn period.
Muscle pseudohypertrophy: dystroglycanopathies
Diffuse joint contractures: laminin alpha-2 deficiency, collagen VI-deficient CMD
Distal hyperlaxity: collagen VI-deficient CMD
Hypertrophic scars or keloid formation: collagen VI-deficient CMD
Spinal stiffness without limb joint contractures:
Axial hypotonia and weakness (poor trunk control) preceding spinal stiffness: in early laminin alpha-2 deficiency, L-CMD, and collagen VI-deficient CMD .
Cardiac involvement: rhythm disturbances in L-CMD; cardiomyopathy in dystroglycanopathies; right heart failure in any CMD subtype if chronic severe respiratory failure is untreated
Nocturnal hypoventilation or respiratory failure in a person who is ambulatory:
The type and location of spinal deformity:
Thoracic kyphosis: collagen VI-deficient CMD
Thoracic lordosis: laminin alpha-2 deficiency,
Occipital-frontal circumference (OFC): may be abnormal in laminin alpha 2 deficiency (macrocephaly) or in dystroglycanopathies (microcephaly or macrocephaly).
Muscle pseudohypertrophy (calves and tongue): dystroglycanopathies. Calf pseudohypertrophy may resemble that seen in Duchenne muscular dystrophy
CNS malformation and abnormal white matter: may be evident as:
Pyramidal signs (hyperreflexia, clonus) and cognitive involvement: dystroglycanopathies
Seizures easy to control with routine antiepileptic drugs: typical for laminin alpha-2 deficiency
Seizures refractory to polytherapy: often in MEB disease, especially those with
Intellectual disability associated with marked behavioral disturbances: suggestive of MEB disease, especially those with
In laminin alpha-2 deficiency abnormal white matter signal after age six months helps establish the diagnosis. White matter changes do not regress with time.
In the dystroglycanopathies, structural changes (including hydrocephalus, brain stem hypoplasia, cerebellar cysts) or abnormalities in neuronal migration (lissencephaly or polymicrogyria) are common [
In contrast, when multiple genes may need to be tested, as in the confirmation of the diagnosis of a dystroglycanopathy, performing immunohistochemical analysis of a muscle biopsy may identify the subtype prior to proceeding with molecular genetic testing.
For an introduction to multigene panels click
Once the pathogenic variants in an autosomal recessive disorder or the pathogenic variant in an autosomal dominant disorder is identified, molecular genetic testing of the parents is needed to clarify mode of inheritance and to provide accurate recurrence risk information to family members [
A muscle biopsy may be indicated if the diagnosis based on clinical examination remains unclear or molecular genetic testing does not confirm a diagnosis.
When testing for presence of large proteins in muscle (e.g., laminin alpha-2) it may be necessary to use more than one antibody in order to detect partial deficiencies. Partial merosin deficiency may be primary (i.e., caused by mutation of
Serum CK Concentration and Muscle Biopsy Findings in the Congenital Muscular Dystrophies Discussed in
Merosin: partial or total deficiency
Laminin alpha-5: overexpression
Variable reduction in muscle
Abnormal secretion in fibroblast culture
Deficiency difficult to detect if partial
Merosin: normal or reduced
Glycosylated alpha dystroglycan: deficient
Beta dystroglycan: normal
Merosin: normal
Alpha-dystroglycan: possible secondary abnormal expression
Normal serum CK concentration = 35-160 µ/L (may vary slightly in different laboratories)
Ideally using antibodies recognizing different regions of the protein
May need co-staining with merosin, perlecan, or other proteins to demonstrate abnormal sarcolemmal staining of collagen VI
Congenital muscular dystrophies are distinguished from other conditions in which muscle disease, anterior horn cell disease, and/or central nervous system involvement produce muscle weakness and low muscle tone [
A later-onset presentation of GSD2 may include non-progressive or slowly progressive proximal muscle weakness and spinal stiffness without major limb contractures. Progressive respiratory failure results from diaphragmatic failure. This clinical picture may overlap with other congenital muscular dystrophies associated with rigid spine syndrome and particularly
Centronuclear myopathy (
The incidence and prevalence of CMD in populations are not well documented because of limited molecular genetic confirmation of the diagnosis and use of different diagnostic classification systems in the past.
The incidence of all forms of congenital muscular dystrophies has been estimated at 1:21,500 with a prevalence of 1:125,000 in northeastern Italy [
The point prevalence (i.e., the total number of cases of a specific disease in existence in a given population at a specific point in time) ranges from 0.68 to 2.5 per 100,000. The failure to diagnosis primary muscle disease in individuals with mild muscle weakness with and without intellectual disability may continue to result in underestimation of the prevalence of CMD [
In addition, the relative frequency of CMD subtypes varies in different populations. For example, in Japan the most commonly diagnosed CMD subtype is Fukuyama CMD caused by a founder variant in
Laminin alpha-2 deficiency and collagen VI-deficient CMDs are the most common subtypes in many countries with populations of European origin.
• Central nervous system involvement, psychomotor delay or intellectual disability: dystroglycanopathies; occasionally, laminin alpha-2 deficiency
• Early signs of respiratory insufficiency:
• Very severe or progressive in the first two years of life: L-CMD; some very hypotonic infants with laminin alpha-2 deficiency
• Slowly progressive resulting in severe respiratory insufficiency in the first decade:
• Nonambulatory: laminin alpha-2 deficiency; collagen VI-deficient CMD; L-CMD; dystroglycanopathy
• Ambulatory:
• Very severe or progressive in the first two years of life: L-CMD; some very hypotonic infants with laminin alpha-2 deficiency
• Slowly progressive resulting in severe respiratory insufficiency in the first decade:
• Nonambulatory: laminin alpha-2 deficiency; collagen VI-deficient CMD; L-CMD; dystroglycanopathy
• Ambulatory:
• Nonambulatory: laminin alpha-2 deficiency; collagen VI-deficient CMD; L-CMD; dystroglycanopathy
• Ambulatory:
• Development of orthopedic complications:
• Diffuse proximal and distal joint contractures and spinal stiffness and/or scoliosis: collagen VI-deficient CMD and laminin alpha-2 deficiency; late-stage L-CMD and dystroglycanopathies
• Selective involvement of the spine:
• Diffuse proximal and distal joint contractures and spinal stiffness and/or scoliosis: collagen VI-deficient CMD and laminin alpha-2 deficiency; late-stage L-CMD and dystroglycanopathies
• Selective involvement of the spine:
• The presence of joint deformities, torticollis or hip dislocation at birth: collagen VI-deficient CMD
• Rapidly progressive course with loss of head control: L-CMD (dropped head syndrome)
• Congenital head lag as a result of marked cervicoaxial hypotonia associated with progressive cervical stiffness:
• Very severe or progressive in the first two years of life: L-CMD; some very hypotonic infants with laminin alpha-2 deficiency
• Slowly progressive resulting in severe respiratory insufficiency in the first decade:
• Nonambulatory: laminin alpha-2 deficiency; collagen VI-deficient CMD; L-CMD; dystroglycanopathy
• Ambulatory:
• Nonambulatory: laminin alpha-2 deficiency; collagen VI-deficient CMD; L-CMD; dystroglycanopathy
• Ambulatory:
• Nonambulatory: laminin alpha-2 deficiency; collagen VI-deficient CMD; L-CMD; dystroglycanopathy
• Ambulatory:
• Diffuse proximal and distal joint contractures and spinal stiffness and/or scoliosis: collagen VI-deficient CMD and laminin alpha-2 deficiency; late-stage L-CMD and dystroglycanopathies
• Selective involvement of the spine:
• Muscle pseudohypertrophy: dystroglycanopathies
• Diffuse joint contractures: laminin alpha-2 deficiency, collagen VI-deficient CMD
• Distal hyperlaxity: collagen VI-deficient CMD
• Hypertrophic scars or keloid formation: collagen VI-deficient CMD
• Spinal stiffness without limb joint contractures:
• Axial hypotonia and weakness (poor trunk control) preceding spinal stiffness: in early laminin alpha-2 deficiency, L-CMD, and collagen VI-deficient CMD .
• Cardiac involvement: rhythm disturbances in L-CMD; cardiomyopathy in dystroglycanopathies; right heart failure in any CMD subtype if chronic severe respiratory failure is untreated
• Nocturnal hypoventilation or respiratory failure in a person who is ambulatory:
• The type and location of spinal deformity:
• Thoracic kyphosis: collagen VI-deficient CMD
• Thoracic lordosis: laminin alpha-2 deficiency,
• Thoracic kyphosis: collagen VI-deficient CMD
• Thoracic lordosis: laminin alpha-2 deficiency,
• Thoracic kyphosis: collagen VI-deficient CMD
• Thoracic lordosis: laminin alpha-2 deficiency,
• Occipital-frontal circumference (OFC): may be abnormal in laminin alpha 2 deficiency (macrocephaly) or in dystroglycanopathies (microcephaly or macrocephaly).
• Muscle pseudohypertrophy (calves and tongue): dystroglycanopathies. Calf pseudohypertrophy may resemble that seen in Duchenne muscular dystrophy
• CNS malformation and abnormal white matter: may be evident as:
• Pyramidal signs (hyperreflexia, clonus) and cognitive involvement: dystroglycanopathies
• Seizures easy to control with routine antiepileptic drugs: typical for laminin alpha-2 deficiency
• Seizures refractory to polytherapy: often in MEB disease, especially those with
• Intellectual disability associated with marked behavioral disturbances: suggestive of MEB disease, especially those with
• Pyramidal signs (hyperreflexia, clonus) and cognitive involvement: dystroglycanopathies
• Seizures easy to control with routine antiepileptic drugs: typical for laminin alpha-2 deficiency
• Seizures refractory to polytherapy: often in MEB disease, especially those with
• Intellectual disability associated with marked behavioral disturbances: suggestive of MEB disease, especially those with
• Pyramidal signs (hyperreflexia, clonus) and cognitive involvement: dystroglycanopathies
• Seizures easy to control with routine antiepileptic drugs: typical for laminin alpha-2 deficiency
• Seizures refractory to polytherapy: often in MEB disease, especially those with
• Intellectual disability associated with marked behavioral disturbances: suggestive of MEB disease, especially those with
• In laminin alpha-2 deficiency abnormal white matter signal after age six months helps establish the diagnosis. White matter changes do not regress with time.
• In the dystroglycanopathies, structural changes (including hydrocephalus, brain stem hypoplasia, cerebellar cysts) or abnormalities in neuronal migration (lissencephaly or polymicrogyria) are common [
• For an introduction to multigene panels click
• Merosin: partial or total deficiency
• Laminin alpha-5: overexpression
• Variable reduction in muscle
• Abnormal secretion in fibroblast culture
• Deficiency difficult to detect if partial
• Merosin: normal or reduced
• Glycosylated alpha dystroglycan: deficient
• Beta dystroglycan: normal
• Merosin: normal
• Alpha-dystroglycan: possible secondary abnormal expression
• A later-onset presentation of GSD2 may include non-progressive or slowly progressive proximal muscle weakness and spinal stiffness without major limb contractures. Progressive respiratory failure results from diaphragmatic failure. This clinical picture may overlap with other congenital muscular dystrophies associated with rigid spine syndrome and particularly
• Centronuclear myopathy (
## Differential Diagnosis of CMD
Congenital muscular dystrophies are distinguished from other conditions in which muscle disease, anterior horn cell disease, and/or central nervous system involvement produce muscle weakness and low muscle tone [
A later-onset presentation of GSD2 may include non-progressive or slowly progressive proximal muscle weakness and spinal stiffness without major limb contractures. Progressive respiratory failure results from diaphragmatic failure. This clinical picture may overlap with other congenital muscular dystrophies associated with rigid spine syndrome and particularly
Centronuclear myopathy (
• A later-onset presentation of GSD2 may include non-progressive or slowly progressive proximal muscle weakness and spinal stiffness without major limb contractures. Progressive respiratory failure results from diaphragmatic failure. This clinical picture may overlap with other congenital muscular dystrophies associated with rigid spine syndrome and particularly
• Centronuclear myopathy (
## Prevalence of CMD
The incidence and prevalence of CMD in populations are not well documented because of limited molecular genetic confirmation of the diagnosis and use of different diagnostic classification systems in the past.
The incidence of all forms of congenital muscular dystrophies has been estimated at 1:21,500 with a prevalence of 1:125,000 in northeastern Italy [
The point prevalence (i.e., the total number of cases of a specific disease in existence in a given population at a specific point in time) ranges from 0.68 to 2.5 per 100,000. The failure to diagnosis primary muscle disease in individuals with mild muscle weakness with and without intellectual disability may continue to result in underestimation of the prevalence of CMD [
In addition, the relative frequency of CMD subtypes varies in different populations. For example, in Japan the most commonly diagnosed CMD subtype is Fukuyama CMD caused by a founder variant in
Laminin alpha-2 deficiency and collagen VI-deficient CMDs are the most common subtypes in many countries with populations of European origin.
## Genetic Counseling
The congenital muscular dystrophies are inherited in an autosomal recessive manner with the exception of collagen VI-deficient CMD, which can be inherited in an autosomal dominant or autosomal recessive manner [
The parents of an affected child are obligate heterozygotes and therefore carry a single copy of a pathogenic variant.
Heterozygotes (carriers) are asymptomatic.
At conception, each sib of an individual with autosomal recessive CMD has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
If individuals with autosomal recessive congenital muscular dystrophy reproduce, all of the offspring are obligate carriers.
Because the general population carrier frequency is low, the risk to offspring of an individual with autosomal recessive CMD of being affected is greater than the risk to the general population but less than 1%.
Carrier detection using molecular genetic techniques is possible if the pathogenic variants in the family are known.
A CMD BioBank, part of the NIGMS repository at Coriell Medical Institute, offers DNA banking as well as banking or cell lines.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
• The parents of an affected child are obligate heterozygotes and therefore carry a single copy of a pathogenic variant.
• Heterozygotes (carriers) are asymptomatic.
• At conception, each sib of an individual with autosomal recessive CMD has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.
• If individuals with autosomal recessive congenital muscular dystrophy reproduce, all of the offspring are obligate carriers.
• Because the general population carrier frequency is low, the risk to offspring of an individual with autosomal recessive CMD of being affected is greater than the risk to the general population but less than 1%.
## Mode of Inheritance
The congenital muscular dystrophies are inherited in an autosomal recessive manner with the exception of collagen VI-deficient CMD, which can be inherited in an autosomal dominant or autosomal recessive manner [
## Risk to Family Members — Autosomal Recessive CMD
The parents of an affected child are obligate heterozygotes and therefore carry a single copy of a pathogenic variant.
Heterozygotes (carriers) are asymptomatic.
At conception, each sib of an individual with autosomal recessive CMD has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
If individuals with autosomal recessive congenital muscular dystrophy reproduce, all of the offspring are obligate carriers.
Because the general population carrier frequency is low, the risk to offspring of an individual with autosomal recessive CMD of being affected is greater than the risk to the general population but less than 1%.
• The parents of an affected child are obligate heterozygotes and therefore carry a single copy of a pathogenic variant.
• Heterozygotes (carriers) are asymptomatic.
• At conception, each sib of an individual with autosomal recessive CMD has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.
• If individuals with autosomal recessive congenital muscular dystrophy reproduce, all of the offspring are obligate carriers.
• Because the general population carrier frequency is low, the risk to offspring of an individual with autosomal recessive CMD of being affected is greater than the risk to the general population but less than 1%.
## Carrier Detection
Carrier detection using molecular genetic techniques is possible if the pathogenic variants in the family are known.
## Risk to Family Members — Autosomal Dominant CMD
## Related Genetic Counseling Issues
A CMD BioBank, part of the NIGMS repository at Coriell Medical Institute, offers DNA banking as well as banking or cell lines.
## Prenatal Testing and Preimplantation Genetic Testing
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
## Resources
19401 South Vermont Avenue
Suite J100
Torrance CA 90502
Lt Gen van Heutszlaan 6
3743 JN Baarn
Netherlands
222 South Riverside Plaza
Suite 1500
Chicago IL 60606
61A Great Suffolk Street
London SE1 0BU
United Kingdom
19401 South Vermont Avenue
Suite J100
Torrance CA 90502
•
• 19401 South Vermont Avenue
• Suite J100
• Torrance CA 90502
•
•
• Lt Gen van Heutszlaan 6
• 3743 JN Baarn
• Netherlands
•
•
• 222 South Riverside Plaza
• Suite 1500
• Chicago IL 60606
•
•
• 61A Great Suffolk Street
• London SE1 0BU
• United Kingdom
•
•
•
• 19401 South Vermont Avenue
• Suite J100
• Torrance CA 90502
•
## Management
To establish the extent of disease in an individual diagnosed with congenital muscular dystrophy, the following evaluations are recommended:
Neurologic examination
Assessment of respiratory function with baseline pulmonary function tests, including forced vital capacity (FVC) in sitting and supine positions and blood gas exchange
Polysomnography to identify individuals with nocturnal hypoventilation, to evaluate individuals with symptoms of hypercapnea (daytime headache, restless sleep, loss of concentration), and to evaluate individuals with reduced forced vital capacity, particularly those with CMD subtypes associated with a rigid spine, axial weakness, and/or signs of diaphragmatic weakness (detected by a drop in FVC from sitting to supine). Additional indications for polysomnography include testing in the very young or those with developmental delay in whom reliable, consistent pulmonary function testing can be difficult to obtain.
Sleep-disordered breathing can be seen with FVC of less than 60%, while nocturnal hypoventilation correlates with FVC of less than 40% [
Radiologic examinations if spinal deformity is observed. Assessment of spine and joint deformities by physiatrists and orthopedists
Feeding and nutritional assessment, weight and height measurement, serum vitamin D concentration and calculation of body mass index (BMI)
Assessment of strength and joint contractures by an occupational therapist and physical therapist
Assessment of cardiac function in those with a dystroglycanopathy or L-CMD, with particular awareness that cardiomyopathy and/or arrhythmia can occur in the absence of severe muscle disease
Evaluation for pulmonary hypertension and/or secondary right heart failure in those with significant respiratory involvement (mechanical ventilation, severe respiratory failure)
Complete eye examination in those with a dystroglycanopathy or if clinically indicated
No definitive treatments exist for the congenital muscular dystrophies; however, multidisciplinary medical care improves quality of life and longevity. Management should be tailored to each individual, their specific CMD subtype, and rate of progression.
Respiratory therapy and use of respiratory aids including assisted cough and hyperinsufflation devices, Percussionaire
Physical therapy and stretching exercises help promote mobility and prevent contractures. Mechanical assistive devices including canes, walkers, orthotics, and wheelchairs can be used as needed to help ambulation and mobility. Posture in vertical, sitting, and supine positions has to be evaluated and assisted if necessary as improved posture may positively affect chest expansion.
Surgical intervention may be needed for orthopedic complications such as foot deformity, joint contractures, and scoliosis. Pros and cons of surgery for hip dislocation or joint contractures need to be considered given that any functional benefit may be insignificant compared to the high risk of pain and rapid relapse. Proactive trunk bracing (plexidur Garchois brace) is used in some countries to reduce the degree of deformity and to slow the progression of scoliosis in order to delay consideration of surgical intervention until puberty [
Speech therapy may be indicated.
Close attention to oral hygiene is indicated.
Assistance in education (school technical aide) and social and emotional support and stimulation can improve the sense of social involvement and productivity and can reduce the sense of social isolation common in those with CMD [
Steroid treatment using dosages based upon guidelines used in the treatment of
The following are appropriate:
Stretching exercises to prevent contractures
Positive-pressure hyperinsufflation pulmonary exercises to enhance thoracic growth and reduce thoracic cage rigidity and contractures
Medications such as laxatives to prevent constipation, medication for gastroesophageal reflux (GER), and oral caloric supplements as required
Trunk bracing in those with severe axial or cervical hypotonia with spinal collapse to prevent severe spinal deformities and to allow a stable and comfortable position when sitting or standing (during use of an upright stander). Of note, when such bracing is used, pulmonary assessment is needed to monitor for evidence of secondary respiratory compromise or complications.
Surveillance includes the following:
Monitoring of respiratory function using pulmonary function testing or spirometry with measurements in sitting and supine positions to detect diaphragmatic involvement that increases the risk of nocturnal hypoventilation. When the forced vital capacity in the supine position is less than 60% of normal values, respiratory function should be monitored by pulse oximetry and/or arterial blood gases and, where available, polysomnography.
Clinical examination and x-rays as needed to monitor for orthopedic complications such as foot deformity, joint contractures, and spinal deformity (scoliosis, thoracic lordosis or kyphosis, lumbar hyperlordosis)
Monitoring of cardiac function every six to 12 months (by echocardiography, ECG, 24-hour Holter-ECG recording) in those individuals with respiratory insufficiency with or without mechanical ventilation and/or CMD subtypes prone to cardiomyopathy (L-CMD, dystroglycanopathies) and cardiac rhythm disturbances (L-CMD)
Monitoring of neurologic function and EEG in those with CMD subtypes associated with seizures or if clinically indicated
Routine complete eye examinations in those with dystroglycanopathies to monitor for changes in vision and/or changes that suggest development of cataracts and/or evidence of retinal detachment
Note: In those with laminin alpha-2 deficiency the white matter changes do not require follow-up brain MRI.
See
Search
• Neurologic examination
• Assessment of respiratory function with baseline pulmonary function tests, including forced vital capacity (FVC) in sitting and supine positions and blood gas exchange
• Polysomnography to identify individuals with nocturnal hypoventilation, to evaluate individuals with symptoms of hypercapnea (daytime headache, restless sleep, loss of concentration), and to evaluate individuals with reduced forced vital capacity, particularly those with CMD subtypes associated with a rigid spine, axial weakness, and/or signs of diaphragmatic weakness (detected by a drop in FVC from sitting to supine). Additional indications for polysomnography include testing in the very young or those with developmental delay in whom reliable, consistent pulmonary function testing can be difficult to obtain.
• Sleep-disordered breathing can be seen with FVC of less than 60%, while nocturnal hypoventilation correlates with FVC of less than 40% [
• Radiologic examinations if spinal deformity is observed. Assessment of spine and joint deformities by physiatrists and orthopedists
• Feeding and nutritional assessment, weight and height measurement, serum vitamin D concentration and calculation of body mass index (BMI)
• Assessment of strength and joint contractures by an occupational therapist and physical therapist
• Assessment of cardiac function in those with a dystroglycanopathy or L-CMD, with particular awareness that cardiomyopathy and/or arrhythmia can occur in the absence of severe muscle disease
• Evaluation for pulmonary hypertension and/or secondary right heart failure in those with significant respiratory involvement (mechanical ventilation, severe respiratory failure)
• Complete eye examination in those with a dystroglycanopathy or if clinically indicated
• Stretching exercises to prevent contractures
• Positive-pressure hyperinsufflation pulmonary exercises to enhance thoracic growth and reduce thoracic cage rigidity and contractures
• Medications such as laxatives to prevent constipation, medication for gastroesophageal reflux (GER), and oral caloric supplements as required
• Trunk bracing in those with severe axial or cervical hypotonia with spinal collapse to prevent severe spinal deformities and to allow a stable and comfortable position when sitting or standing (during use of an upright stander). Of note, when such bracing is used, pulmonary assessment is needed to monitor for evidence of secondary respiratory compromise or complications.
• Monitoring of respiratory function using pulmonary function testing or spirometry with measurements in sitting and supine positions to detect diaphragmatic involvement that increases the risk of nocturnal hypoventilation. When the forced vital capacity in the supine position is less than 60% of normal values, respiratory function should be monitored by pulse oximetry and/or arterial blood gases and, where available, polysomnography.
• Clinical examination and x-rays as needed to monitor for orthopedic complications such as foot deformity, joint contractures, and spinal deformity (scoliosis, thoracic lordosis or kyphosis, lumbar hyperlordosis)
• Monitoring of cardiac function every six to 12 months (by echocardiography, ECG, 24-hour Holter-ECG recording) in those individuals with respiratory insufficiency with or without mechanical ventilation and/or CMD subtypes prone to cardiomyopathy (L-CMD, dystroglycanopathies) and cardiac rhythm disturbances (L-CMD)
• Monitoring of neurologic function and EEG in those with CMD subtypes associated with seizures or if clinically indicated
• Routine complete eye examinations in those with dystroglycanopathies to monitor for changes in vision and/or changes that suggest development of cataracts and/or evidence of retinal detachment
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with congenital muscular dystrophy, the following evaluations are recommended:
Neurologic examination
Assessment of respiratory function with baseline pulmonary function tests, including forced vital capacity (FVC) in sitting and supine positions and blood gas exchange
Polysomnography to identify individuals with nocturnal hypoventilation, to evaluate individuals with symptoms of hypercapnea (daytime headache, restless sleep, loss of concentration), and to evaluate individuals with reduced forced vital capacity, particularly those with CMD subtypes associated with a rigid spine, axial weakness, and/or signs of diaphragmatic weakness (detected by a drop in FVC from sitting to supine). Additional indications for polysomnography include testing in the very young or those with developmental delay in whom reliable, consistent pulmonary function testing can be difficult to obtain.
Sleep-disordered breathing can be seen with FVC of less than 60%, while nocturnal hypoventilation correlates with FVC of less than 40% [
Radiologic examinations if spinal deformity is observed. Assessment of spine and joint deformities by physiatrists and orthopedists
Feeding and nutritional assessment, weight and height measurement, serum vitamin D concentration and calculation of body mass index (BMI)
Assessment of strength and joint contractures by an occupational therapist and physical therapist
Assessment of cardiac function in those with a dystroglycanopathy or L-CMD, with particular awareness that cardiomyopathy and/or arrhythmia can occur in the absence of severe muscle disease
Evaluation for pulmonary hypertension and/or secondary right heart failure in those with significant respiratory involvement (mechanical ventilation, severe respiratory failure)
Complete eye examination in those with a dystroglycanopathy or if clinically indicated
• Neurologic examination
• Assessment of respiratory function with baseline pulmonary function tests, including forced vital capacity (FVC) in sitting and supine positions and blood gas exchange
• Polysomnography to identify individuals with nocturnal hypoventilation, to evaluate individuals with symptoms of hypercapnea (daytime headache, restless sleep, loss of concentration), and to evaluate individuals with reduced forced vital capacity, particularly those with CMD subtypes associated with a rigid spine, axial weakness, and/or signs of diaphragmatic weakness (detected by a drop in FVC from sitting to supine). Additional indications for polysomnography include testing in the very young or those with developmental delay in whom reliable, consistent pulmonary function testing can be difficult to obtain.
• Sleep-disordered breathing can be seen with FVC of less than 60%, while nocturnal hypoventilation correlates with FVC of less than 40% [
• Radiologic examinations if spinal deformity is observed. Assessment of spine and joint deformities by physiatrists and orthopedists
• Feeding and nutritional assessment, weight and height measurement, serum vitamin D concentration and calculation of body mass index (BMI)
• Assessment of strength and joint contractures by an occupational therapist and physical therapist
• Assessment of cardiac function in those with a dystroglycanopathy or L-CMD, with particular awareness that cardiomyopathy and/or arrhythmia can occur in the absence of severe muscle disease
• Evaluation for pulmonary hypertension and/or secondary right heart failure in those with significant respiratory involvement (mechanical ventilation, severe respiratory failure)
• Complete eye examination in those with a dystroglycanopathy or if clinically indicated
## Treatment of Manifestations
No definitive treatments exist for the congenital muscular dystrophies; however, multidisciplinary medical care improves quality of life and longevity. Management should be tailored to each individual, their specific CMD subtype, and rate of progression.
Respiratory therapy and use of respiratory aids including assisted cough and hyperinsufflation devices, Percussionaire
Physical therapy and stretching exercises help promote mobility and prevent contractures. Mechanical assistive devices including canes, walkers, orthotics, and wheelchairs can be used as needed to help ambulation and mobility. Posture in vertical, sitting, and supine positions has to be evaluated and assisted if necessary as improved posture may positively affect chest expansion.
Surgical intervention may be needed for orthopedic complications such as foot deformity, joint contractures, and scoliosis. Pros and cons of surgery for hip dislocation or joint contractures need to be considered given that any functional benefit may be insignificant compared to the high risk of pain and rapid relapse. Proactive trunk bracing (plexidur Garchois brace) is used in some countries to reduce the degree of deformity and to slow the progression of scoliosis in order to delay consideration of surgical intervention until puberty [
Speech therapy may be indicated.
Close attention to oral hygiene is indicated.
Assistance in education (school technical aide) and social and emotional support and stimulation can improve the sense of social involvement and productivity and can reduce the sense of social isolation common in those with CMD [
Steroid treatment using dosages based upon guidelines used in the treatment of
## Prevention of Secondary Complications
The following are appropriate:
Stretching exercises to prevent contractures
Positive-pressure hyperinsufflation pulmonary exercises to enhance thoracic growth and reduce thoracic cage rigidity and contractures
Medications such as laxatives to prevent constipation, medication for gastroesophageal reflux (GER), and oral caloric supplements as required
Trunk bracing in those with severe axial or cervical hypotonia with spinal collapse to prevent severe spinal deformities and to allow a stable and comfortable position when sitting or standing (during use of an upright stander). Of note, when such bracing is used, pulmonary assessment is needed to monitor for evidence of secondary respiratory compromise or complications.
• Stretching exercises to prevent contractures
• Positive-pressure hyperinsufflation pulmonary exercises to enhance thoracic growth and reduce thoracic cage rigidity and contractures
• Medications such as laxatives to prevent constipation, medication for gastroesophageal reflux (GER), and oral caloric supplements as required
• Trunk bracing in those with severe axial or cervical hypotonia with spinal collapse to prevent severe spinal deformities and to allow a stable and comfortable position when sitting or standing (during use of an upright stander). Of note, when such bracing is used, pulmonary assessment is needed to monitor for evidence of secondary respiratory compromise or complications.
## Surveillance
Surveillance includes the following:
Monitoring of respiratory function using pulmonary function testing or spirometry with measurements in sitting and supine positions to detect diaphragmatic involvement that increases the risk of nocturnal hypoventilation. When the forced vital capacity in the supine position is less than 60% of normal values, respiratory function should be monitored by pulse oximetry and/or arterial blood gases and, where available, polysomnography.
Clinical examination and x-rays as needed to monitor for orthopedic complications such as foot deformity, joint contractures, and spinal deformity (scoliosis, thoracic lordosis or kyphosis, lumbar hyperlordosis)
Monitoring of cardiac function every six to 12 months (by echocardiography, ECG, 24-hour Holter-ECG recording) in those individuals with respiratory insufficiency with or without mechanical ventilation and/or CMD subtypes prone to cardiomyopathy (L-CMD, dystroglycanopathies) and cardiac rhythm disturbances (L-CMD)
Monitoring of neurologic function and EEG in those with CMD subtypes associated with seizures or if clinically indicated
Routine complete eye examinations in those with dystroglycanopathies to monitor for changes in vision and/or changes that suggest development of cataracts and/or evidence of retinal detachment
Note: In those with laminin alpha-2 deficiency the white matter changes do not require follow-up brain MRI.
• Monitoring of respiratory function using pulmonary function testing or spirometry with measurements in sitting and supine positions to detect diaphragmatic involvement that increases the risk of nocturnal hypoventilation. When the forced vital capacity in the supine position is less than 60% of normal values, respiratory function should be monitored by pulse oximetry and/or arterial blood gases and, where available, polysomnography.
• Clinical examination and x-rays as needed to monitor for orthopedic complications such as foot deformity, joint contractures, and spinal deformity (scoliosis, thoracic lordosis or kyphosis, lumbar hyperlordosis)
• Monitoring of cardiac function every six to 12 months (by echocardiography, ECG, 24-hour Holter-ECG recording) in those individuals with respiratory insufficiency with or without mechanical ventilation and/or CMD subtypes prone to cardiomyopathy (L-CMD, dystroglycanopathies) and cardiac rhythm disturbances (L-CMD)
• Monitoring of neurologic function and EEG in those with CMD subtypes associated with seizures or if clinically indicated
• Routine complete eye examinations in those with dystroglycanopathies to monitor for changes in vision and/or changes that suggest development of cataracts and/or evidence of retinal detachment
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## References
## Literature Cited
## Chapter Notes
Erynn Gordon, MS, CGC (2003-present) Amy Harper, MD (2011-present)Eric P Hoffman, PhD (2001-present) Elena Pegoraro, MD, PhD (2001-present) Susana Quijano-Roy, MD, PhD (2011-present)Anne Rutkowski, MD (2011-present)Cheryl Scacheri, MS; GeneDx, Inc (2001-2003)Susan E Sparks, MD, PhD (2011-present)
18 October 2018 (ma) Chapter retired: outdated
23 August 2012 (cd) Revision: sequence analysis for
24 May 2012 (cd) Revision: sequence analysis for
4 January 2011 (me) Comprehensive update posted live
22 December 2006 (cd) Revision: clinical testing, carrier testing, and prenatal testing available for CMD with early spine rigidity; clinical testing and carrier testing available for CMD with merosin deficiency
13 January 2006 (me) Comprehensive update posted live
25 March 2005 (cd) Revision: Clinical testing available for MDC1D
26 July 2004 (eh) Revision: Bethlem and Ullrich CMD
2 January 2004 (cd) Revision: test availability
22 September 2003 (cd) Revision: test availability, prenatal testing
19 June 2003 (ca) Comprehensive update posted live
22 January 2001 (me) Overview posted live
20 April 2000 (eh) Original submission
• 18 October 2018 (ma) Chapter retired: outdated
• 23 August 2012 (cd) Revision: sequence analysis for
• 24 May 2012 (cd) Revision: sequence analysis for
• 4 January 2011 (me) Comprehensive update posted live
• 22 December 2006 (cd) Revision: clinical testing, carrier testing, and prenatal testing available for CMD with early spine rigidity; clinical testing and carrier testing available for CMD with merosin deficiency
• 13 January 2006 (me) Comprehensive update posted live
• 25 March 2005 (cd) Revision: Clinical testing available for MDC1D
• 26 July 2004 (eh) Revision: Bethlem and Ullrich CMD
• 2 January 2004 (cd) Revision: test availability
• 22 September 2003 (cd) Revision: test availability, prenatal testing
• 19 June 2003 (ca) Comprehensive update posted live
• 22 January 2001 (me) Overview posted live
• 20 April 2000 (eh) Original submission
## Author History
Erynn Gordon, MS, CGC (2003-present) Amy Harper, MD (2011-present)Eric P Hoffman, PhD (2001-present) Elena Pegoraro, MD, PhD (2001-present) Susana Quijano-Roy, MD, PhD (2011-present)Anne Rutkowski, MD (2011-present)Cheryl Scacheri, MS; GeneDx, Inc (2001-2003)Susan E Sparks, MD, PhD (2011-present)
## Revision History
18 October 2018 (ma) Chapter retired: outdated
23 August 2012 (cd) Revision: sequence analysis for
24 May 2012 (cd) Revision: sequence analysis for
4 January 2011 (me) Comprehensive update posted live
22 December 2006 (cd) Revision: clinical testing, carrier testing, and prenatal testing available for CMD with early spine rigidity; clinical testing and carrier testing available for CMD with merosin deficiency
13 January 2006 (me) Comprehensive update posted live
25 March 2005 (cd) Revision: Clinical testing available for MDC1D
26 July 2004 (eh) Revision: Bethlem and Ullrich CMD
2 January 2004 (cd) Revision: test availability
22 September 2003 (cd) Revision: test availability, prenatal testing
19 June 2003 (ca) Comprehensive update posted live
22 January 2001 (me) Overview posted live
20 April 2000 (eh) Original submission
• 18 October 2018 (ma) Chapter retired: outdated
• 23 August 2012 (cd) Revision: sequence analysis for
• 24 May 2012 (cd) Revision: sequence analysis for
• 4 January 2011 (me) Comprehensive update posted live
• 22 December 2006 (cd) Revision: clinical testing, carrier testing, and prenatal testing available for CMD with early spine rigidity; clinical testing and carrier testing available for CMD with merosin deficiency
• 13 January 2006 (me) Comprehensive update posted live
• 25 March 2005 (cd) Revision: Clinical testing available for MDC1D
• 26 July 2004 (eh) Revision: Bethlem and Ullrich CMD
• 2 January 2004 (cd) Revision: test availability
• 22 September 2003 (cd) Revision: test availability, prenatal testing
• 19 June 2003 (ca) Comprehensive update posted live
• 22 January 2001 (me) Overview posted live
• 20 April 2000 (eh) Original submission
|
[
"V Allamand, L Merlini, K Bushby. Consortium for Collagen VI-Related Myopathies. 166th ENMC International Workshop on Collagen type VI-related Myopathies, 22-24 May 2009, Naarden, The Netherlands.. Neuromuscul Disord. 2010;20:346-54",
"CG Bönnemann, A Rutkowski, E Mercuri, F Muntoni. 173rd ENMC International Workshop: congenital muscular dystrophy outcome measures 5-7 March 2010, Naarden, The Netherlands.. Neuromuscul Disord. 2011;21:513-22",
"L Briñas, P Richard, S Quijano-Roy, C Gartioux, C Ledeuil, E Lacène, S Makri, A Ferreiro, S Maugenre, H Topaloglu, G Haliloglu, I Pénisson-Besnier, PY Jeannet, L Merlini, C Navarro, A Toutain, D Chaigne, I Desguerre, C de Die-Smulders, M Dunand, B Echenne, B Eymard, T Kuntzer, K Maincent, M Mayer, G Plessis, F Rivier, F Roelens, T Stojkovic, A Lía Taratuto, F Lubieniecki, S Monges, C Tranchant, L Viollet, NB Romero, B Estournet, P Guicheney, V Allamand. Early onset collagen VI myopathies: Genetic and clinical correlations.. Ann Neurol. 2010;68:511-20",
"N Darin, E Kimber, AK Kroksmark, M Tulinius. Multiple congenital contractures: birth prevalence, etiology, and outcome.. J Pediatr 2002;140:61-7",
"S Eggers, M Zatz. Social adjustment in adult males affected with progressive muscular dystrophy.. Am J Med Genet 1998;81:4-12",
"C Godfrey, D Escolar, M Brockington, EM Clement, R Mein, C Jimenez-Mallebrera, S Torelli, L Feng, SC Brown, CA Sewry, M Rutherford, Y Shapira, S Abbs, F Muntoni. Fukutin gene mutations in steroid-responsive limb girdle muscular dystrophy.. Ann Neurol. 2006;60:603-10",
"J Kirschner, CG Bönnemann. The congenital and limb-girdle muscular dystrophies: sharpening the focus, blurring the boundaries.. Arch Neurol 2004;61:189-99",
"A Klein, E Clement, E Mercuri, F Muntoni. Differential diagnosis of congenital muscular dystrophies.. Eur J Paediatr Neurol. 2008;12:371-7",
"N Louhichi, C Triki, S Quijano-Roy, P Richard, S Makri, M Méziou, B Estournet, S Mrad, NB Romero, H Ayadi, P Guicheney, F Fakhfakh. New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families.. Neurogenetics. 2004;5:27-34",
"E Mercuri, S Messina, C Bruno, M Mora, E Pegoraro, GP Comi, A D'Amico, C Aiello, R Biancheri, A Berardinelli, P Boffi, D Cassandrini, A Laverda, M Moggio, L Morandi, I Moroni, M Pane, R Pezzani, A Pichiecchio, A Pini, C Minetti, T Mongini, E Mottarelli, E Ricci, A Ruggieri, S Saredi, C Scuderi, A Tessa, A Toscano, G Tortorella, CP Trevisan, C Uggetti, G Vasco, FM Santorelli, E Bertini. Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study.. Neurology. 2009;72:1802-9",
"E Mercuri, H Topaloglu, M Brockington, A Berardinelli, A Pichiecchio, F Santorelli, M Rutherford, B Talim, E Ricci, T Voit, F Muntoni. Spectrum of brain changes in patients with congenital muscular dystrophy and FKRP gene mutations.. Arch Neurol. 2006;63:251-7",
"S Messina, G Tortorella, D Concolino, M Spanò, A D'Amico, C Bruno, FM Santorelli, E Mercuri, E Bertini. Congenital muscular dystrophy with defective alpha-dystroglycan, cerebellar hypoplasia, and epilepsy.. Neurology. 2009;73:1599-601",
"S Mitsuhashi, A Ohkuma, B Talim, M Karahashi, T Koumura, C Aoyama, M Kurihara, R Quinlivan, C Sewry, H Mitsuhashi, K Goto, B Koksal, G Kale, K Ikeda, R Taguchi, S Noguchi, YK Hayashi, I Nonaka, RB Sher, H Sugimoto, Y Nakagawa, GA Cox, H Topaloglu, I Nishino. A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de novo phosphatidylcholine biosynthesis.. Am J Hum Genet. 2011;88:845-51",
"ML Mostacciuolo, M Miorin, F Martinello, C Angelini, P Perini, CP Trevisan. Genetic epidemiology of congenital muscular dystrophy in a sample from north-east Italy.. Hum Genet 1996;97:277-9",
"F Muntoni, T Voit. The congenital muscular dystrophies in 2004: a century of exciting progress.. Neuromuscul Disord 2004;14:635-49",
"FL Norwood, C Harling, PF Chinnery, M Eagle, K Bushby, V Straub. Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population.. Brain. 2009;132:3175-86",
"M Okada, G Kawahara, S Noguchi, K Sugie, K Murayama, I Nonaka, YK Hayashi, I Nishino. Primary collagen VI deficiency is the second most common congenital muscular dystrophy in Japan.. Neurology. 2007;69:1035-42",
"TC Pan, RZ Zhang, DG Sudano, SK Marie, CG Bönnemann, ML Chu. New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype.. Am J Hum Genet 2003;73:355-69",
"RA Peat, JM Smith, AG Compton, NL Baker, RA Pace, DJ Burkin, SJ Kaufman, SR Lamande, KN North. Diagnosis and etiology of congenital muscular dystrophy.. Neurology 2008;71:312-21",
"S Quijano-Roy, B Mbieleu, CG Bönnemann, PY Jeannet, J Colomer, NF Clarke, JM Cuisset, H Roper, L De Meirleir, A D'Amico, R Ben Yaou, A Nascimento, A Barois, L Demay, E Bertini, A Ferreiro, CA Sewry, NB Romero, M Ryan, F Muntoni, P Guicheney, P Richard, G Bonne, B Estournet. De novo LMNA mutations cause a new form of congenital muscular dystrophy.. Ann Neurol. 2008;64:177-86",
"N Shahrizaila, WJ Kinnear, AJ Wills. Respiratory involvement in inherited primary muscle conditions.. J Neurol Neurosurg Psychiatry. 2006;77:1108-15",
"M Tétreault, A Duquette, I Thiffault, C Bherer, J Jarry, L Loisel, B Banwell, G D'Anjou, J Mathieu, Y Robitaille, M Vanasse, B Brais. A new form of congenital muscular dystrophy with joint hyperlaxity maps to 3p23-21.. Brain. 2006;129:2077-84",
"M Vainzof, P Richard, R Herrmann, C Jimenez-Mallebrera, B Talim, LU Yamamoto, C Ledeuil, R Mein, S Abbs, M Brockington, NB Romero, M Zatz, H Topaloglu, T Voit, C Sewry, F Muntoni, P Guicheney, FM Tome. Prenatal diagnosis in laminin alpha2 chain (merosin)-deficient congenital muscular dystrophy: a collective experience of five international centers.. Neuromuscul Disord 2005;15:588-94",
"C Wallgren-Pettersson, K Bushby, U Mellies, A Simonds. ENMC. 117th ENMC workshop: ventilatory support in congenital neuromuscular disorders -- congenital myopathies, congenital muscular dystrophies, congenital myotonic dystrophy and SMA (II).. Neuromuscul Disord. 2004;14:56-69",
"CH Wang, CG Bönnemann, A Rutkowski, T Sejersen, J Bellini, V Battista, JM Florence, U Schara, PM Schuler, K Wahbi, A Aloysius, RO Bash, C Béroud, E Bertini, K Bushby, RD Cohn, AM Connolly, N Deconinck, I Desguerre, M Eagle, B Estournet-Mathiaud, A Ferreiro, A Fujak, N Goemans, ST Iannaccone, P Jouinot, M Main, P Melacini, W Mueller-Felber, F Muntoni, LL Nelson, J Rahbek, S Quijano-Roy, C Sewry, K Storhaug, A Simonds, B Tseng, J Vajsar, A Vianello, R Zeller. Consensus statement on standard of care for congenital muscular dystrophies.. J Child Neurol. 2010;25:1559-81",
"T Willer, H Lee, M Lommel, T Yoshida-Moriguchi, DB de Bernabe, D Venzke, S Cirak, H Schachter, J Vajsar, T Voit, F Muntoni, AS Loder, WB Dobyns, TL Winder, S Strahl, KD Mathews, SF Nelson, SA Moore, KP Campbell. ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome.. Nat Genet 2012;44:575-80"
] |
22/1/2001
|
4/1/2011
|
23/8/2012
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cmr
|
cmr
|
[
"Anderson Disease",
"Anderson Disease",
"Small COPII coat GTPase SAR1B",
"SAR1B",
"Chylomicron Retention Disease"
] |
Chylomicron Retention Disease
|
John R Burnett, Amanda J Hooper, Robert A Hegele
|
Summary Chylomicron retention disease (CMRD), characterized by the inability to secrete chylomicrons from the enterocytes following the ingestion of fat, typically presents in infancy with failure to thrive, diarrhea, vomiting, abdominal distention, and malabsorption of fat. This leads to steatorrhea – the severity of which relates to the fat content of the diet – and in some cases, hepatomegaly. Organ systems outside of the gastrointestinal tract may also be affected (often due to malnutrition and deficiencies of fat-soluble vitamins), including neuromuscular abnormalities (typically in the first or second decade of life) secondary to vitamin E deficiency, poor bone mineralization and delayed bone maturation due to vitamin D deficiency, prolonged international normalized ratio (INR) due to vitamin K deficiency, mild ophthalmologic issues (e.g., micronystagmus, delayed dark adaptation, abnormal visual evoked potentials, and abnormal scotopic electroretinograms), and (in a small proportion of adults) cardiomyopathy with decreased ejection fraction. Affected individuals typically have marked hypocholesterolemia, low plasma apolipoprotein B levels, normal-to-low plasma triglyceride levels, and low serum concentrations of fat-soluble vitamins (A, D, E, and K). Endoscopy typically demonstrates a The molecular diagnosis of CMRD is established in a proband with suggestive findings and biallelic pathogenic variants in CMRD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
No consensus clinical diagnostic criteria for chylomicron retention disease (CMRD) have been published.
CMRD
Failure to thrive, with diarrhea
Fat malabsorption with steatorrhea
Vomiting
Abdominal distention
Marked hypocholesterolemia:
Plasma total cholesterol level ~60 mg/dL (1.5 mmol/L)
HDL cholesterol ~20 mg/dL (0.5 mmol/L)
LDL cholesterol ~30 mg/dL (0.7 mmol/L)
Low plasma apolipoprotein B level (<0.5 g/L)
Normal-to-low plasma triglyceride level
Low serum concentrations of fat-soluble vitamins (A, D, and E) and prolonged international normalized ratio (due to vitamin K deficiency)
High plasma creatine kinase (1.5 to 4x the upper reference limit)
The molecular diagnosis of CMRD
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
When the phenotypic and laboratory findings suggest the diagnosis of CMRD, molecular genetic testing approaches can include
If only one or no pathogenic variant is identified, consider gene-targeted deletion/duplication testing.
For an introduction to multigene panels click
Molecular Genetic Testing Used in Chylomicron Retention Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Failure to thrive, with diarrhea
• Fat malabsorption with steatorrhea
• Vomiting
• Abdominal distention
• Marked hypocholesterolemia:
• Plasma total cholesterol level ~60 mg/dL (1.5 mmol/L)
• HDL cholesterol ~20 mg/dL (0.5 mmol/L)
• LDL cholesterol ~30 mg/dL (0.7 mmol/L)
• Plasma total cholesterol level ~60 mg/dL (1.5 mmol/L)
• HDL cholesterol ~20 mg/dL (0.5 mmol/L)
• LDL cholesterol ~30 mg/dL (0.7 mmol/L)
• Low plasma apolipoprotein B level (<0.5 g/L)
• Normal-to-low plasma triglyceride level
• Low serum concentrations of fat-soluble vitamins (A, D, and E) and prolonged international normalized ratio (due to vitamin K deficiency)
• High plasma creatine kinase (1.5 to 4x the upper reference limit)
• Plasma total cholesterol level ~60 mg/dL (1.5 mmol/L)
• HDL cholesterol ~20 mg/dL (0.5 mmol/L)
• LDL cholesterol ~30 mg/dL (0.7 mmol/L)
• If only one or no pathogenic variant is identified, consider gene-targeted deletion/duplication testing.
• For an introduction to multigene panels click
## Suggestive Findings
CMRD
Failure to thrive, with diarrhea
Fat malabsorption with steatorrhea
Vomiting
Abdominal distention
Marked hypocholesterolemia:
Plasma total cholesterol level ~60 mg/dL (1.5 mmol/L)
HDL cholesterol ~20 mg/dL (0.5 mmol/L)
LDL cholesterol ~30 mg/dL (0.7 mmol/L)
Low plasma apolipoprotein B level (<0.5 g/L)
Normal-to-low plasma triglyceride level
Low serum concentrations of fat-soluble vitamins (A, D, and E) and prolonged international normalized ratio (due to vitamin K deficiency)
High plasma creatine kinase (1.5 to 4x the upper reference limit)
• Failure to thrive, with diarrhea
• Fat malabsorption with steatorrhea
• Vomiting
• Abdominal distention
• Marked hypocholesterolemia:
• Plasma total cholesterol level ~60 mg/dL (1.5 mmol/L)
• HDL cholesterol ~20 mg/dL (0.5 mmol/L)
• LDL cholesterol ~30 mg/dL (0.7 mmol/L)
• Plasma total cholesterol level ~60 mg/dL (1.5 mmol/L)
• HDL cholesterol ~20 mg/dL (0.5 mmol/L)
• LDL cholesterol ~30 mg/dL (0.7 mmol/L)
• Low plasma apolipoprotein B level (<0.5 g/L)
• Normal-to-low plasma triglyceride level
• Low serum concentrations of fat-soluble vitamins (A, D, and E) and prolonged international normalized ratio (due to vitamin K deficiency)
• High plasma creatine kinase (1.5 to 4x the upper reference limit)
• Plasma total cholesterol level ~60 mg/dL (1.5 mmol/L)
• HDL cholesterol ~20 mg/dL (0.5 mmol/L)
• LDL cholesterol ~30 mg/dL (0.7 mmol/L)
## Establishing the Diagnosis
The molecular diagnosis of CMRD
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
When the phenotypic and laboratory findings suggest the diagnosis of CMRD, molecular genetic testing approaches can include
If only one or no pathogenic variant is identified, consider gene-targeted deletion/duplication testing.
For an introduction to multigene panels click
Molecular Genetic Testing Used in Chylomicron Retention Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• If only one or no pathogenic variant is identified, consider gene-targeted deletion/duplication testing.
• For an introduction to multigene panels click
## Clinical Characteristics
To date, approximately 40 individuals have been identified with biallelic pathogenic variants in
Chylomicron retention disease (CMRD) typically presents in infancy as failure to thrive, diarrhea, vomiting, abdominal distention, and malabsorption of fat [
Chylomicron Retention Disease: Frequency of Select Features in Untreated Individuals
Malabsorptive diarrhea, with vomiting and abdominal distention, is often present.
As affected individuals age, they learn to avoid dietary fat, which improves steatorrhea. Symptoms often improve within days or weeks of initiating a low-fat diet (see
Global caloric deficiency is associated with delayed growth trajectory, with both height and weight typically below the tenth centile without intervention.
Fat-soluble vitamin malabsorption is severe and, if untreated, can lead to irreversible systemic features that affect the eyes (see
Hepatomegaly and steatosis may develop in late childhood in some affected individuals.
Note: While hepatomegaly is present in about 20% of affected individuals, cirrhosis of the liver, which has been described in individuals with
Mild acanthocytosis, defined as irregularly speculated erythrocytes, has only rarely been reported.
Prolonged international normalized ratio due to vitamin K deficiency may occur.
Micronystagmus;
Delayed dark adaptation;
Abnormal visual evoked potentials;
Abnormal scotopic electroretinograms.
Progressive loss of deep tendon reflexes, vibratory sense, and proprioception;
Electromyographic abnormalities;
Muscle pain and cramps.
Ataxia, myopathy, and sensory neuropathy may be seen in adults. The neuromuscular manifestations can be arrested (but not reversed) with vitamin supplementation, and can be averted altogether with early diagnosis and treatment.
No genotype-phenotype correlations for
CMRD is very rare; approximately 40 individuals have been reported in the literature.
• Malabsorptive diarrhea, with vomiting and abdominal distention, is often present.
• As affected individuals age, they learn to avoid dietary fat, which improves steatorrhea. Symptoms often improve within days or weeks of initiating a low-fat diet (see
• Global caloric deficiency is associated with delayed growth trajectory, with both height and weight typically below the tenth centile without intervention.
• Fat-soluble vitamin malabsorption is severe and, if untreated, can lead to irreversible systemic features that affect the eyes (see
• As affected individuals age, they learn to avoid dietary fat, which improves steatorrhea. Symptoms often improve within days or weeks of initiating a low-fat diet (see
• Global caloric deficiency is associated with delayed growth trajectory, with both height and weight typically below the tenth centile without intervention.
• Fat-soluble vitamin malabsorption is severe and, if untreated, can lead to irreversible systemic features that affect the eyes (see
• Hepatomegaly and steatosis may develop in late childhood in some affected individuals.
• Note: While hepatomegaly is present in about 20% of affected individuals, cirrhosis of the liver, which has been described in individuals with
• As affected individuals age, they learn to avoid dietary fat, which improves steatorrhea. Symptoms often improve within days or weeks of initiating a low-fat diet (see
• Global caloric deficiency is associated with delayed growth trajectory, with both height and weight typically below the tenth centile without intervention.
• Fat-soluble vitamin malabsorption is severe and, if untreated, can lead to irreversible systemic features that affect the eyes (see
• Mild acanthocytosis, defined as irregularly speculated erythrocytes, has only rarely been reported.
• Prolonged international normalized ratio due to vitamin K deficiency may occur.
• Micronystagmus;
• Delayed dark adaptation;
• Abnormal visual evoked potentials;
• Abnormal scotopic electroretinograms.
• Progressive loss of deep tendon reflexes, vibratory sense, and proprioception;
• Electromyographic abnormalities;
• Muscle pain and cramps.
## Clinical Description
To date, approximately 40 individuals have been identified with biallelic pathogenic variants in
Chylomicron retention disease (CMRD) typically presents in infancy as failure to thrive, diarrhea, vomiting, abdominal distention, and malabsorption of fat [
Chylomicron Retention Disease: Frequency of Select Features in Untreated Individuals
Malabsorptive diarrhea, with vomiting and abdominal distention, is often present.
As affected individuals age, they learn to avoid dietary fat, which improves steatorrhea. Symptoms often improve within days or weeks of initiating a low-fat diet (see
Global caloric deficiency is associated with delayed growth trajectory, with both height and weight typically below the tenth centile without intervention.
Fat-soluble vitamin malabsorption is severe and, if untreated, can lead to irreversible systemic features that affect the eyes (see
Hepatomegaly and steatosis may develop in late childhood in some affected individuals.
Note: While hepatomegaly is present in about 20% of affected individuals, cirrhosis of the liver, which has been described in individuals with
Mild acanthocytosis, defined as irregularly speculated erythrocytes, has only rarely been reported.
Prolonged international normalized ratio due to vitamin K deficiency may occur.
Micronystagmus;
Delayed dark adaptation;
Abnormal visual evoked potentials;
Abnormal scotopic electroretinograms.
Progressive loss of deep tendon reflexes, vibratory sense, and proprioception;
Electromyographic abnormalities;
Muscle pain and cramps.
Ataxia, myopathy, and sensory neuropathy may be seen in adults. The neuromuscular manifestations can be arrested (but not reversed) with vitamin supplementation, and can be averted altogether with early diagnosis and treatment.
• Malabsorptive diarrhea, with vomiting and abdominal distention, is often present.
• As affected individuals age, they learn to avoid dietary fat, which improves steatorrhea. Symptoms often improve within days or weeks of initiating a low-fat diet (see
• Global caloric deficiency is associated with delayed growth trajectory, with both height and weight typically below the tenth centile without intervention.
• Fat-soluble vitamin malabsorption is severe and, if untreated, can lead to irreversible systemic features that affect the eyes (see
• As affected individuals age, they learn to avoid dietary fat, which improves steatorrhea. Symptoms often improve within days or weeks of initiating a low-fat diet (see
• Global caloric deficiency is associated with delayed growth trajectory, with both height and weight typically below the tenth centile without intervention.
• Fat-soluble vitamin malabsorption is severe and, if untreated, can lead to irreversible systemic features that affect the eyes (see
• Hepatomegaly and steatosis may develop in late childhood in some affected individuals.
• Note: While hepatomegaly is present in about 20% of affected individuals, cirrhosis of the liver, which has been described in individuals with
• As affected individuals age, they learn to avoid dietary fat, which improves steatorrhea. Symptoms often improve within days or weeks of initiating a low-fat diet (see
• Global caloric deficiency is associated with delayed growth trajectory, with both height and weight typically below the tenth centile without intervention.
• Fat-soluble vitamin malabsorption is severe and, if untreated, can lead to irreversible systemic features that affect the eyes (see
• Mild acanthocytosis, defined as irregularly speculated erythrocytes, has only rarely been reported.
• Prolonged international normalized ratio due to vitamin K deficiency may occur.
• Micronystagmus;
• Delayed dark adaptation;
• Abnormal visual evoked potentials;
• Abnormal scotopic electroretinograms.
• Progressive loss of deep tendon reflexes, vibratory sense, and proprioception;
• Electromyographic abnormalities;
• Muscle pain and cramps.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations for
## Prevalence
CMRD is very rare; approximately 40 individuals have been reported in the literature.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Chylomicron Retention Disease
AD = autosomal dominant; AR = autosomal recessive; CMRD = chylomicron retention disease; DiffDx = differential diagnosis; MOI = mode of inheritance
## Management
Clinical practice guidelines for chylomicron retention disease (CMRD) have been published based primarily on expert opinion [
To establish the extent of disease and needs in an individual diagnosed with CMRD, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Chylomicron Retention Disease
Total cholesterol
LDL cholesterol
HDL cholesterol
Triglyceride
Apo B
Apo A-I
To evaluate visual acuity & for baseline fundus exam
Consider visual evoked potential & electroretinography in those w/concerning symptoms.
To evaluate cardiac function & assess ejection fraction
Cardiomyopathy is uncommon.
Consider referral to cardiologist.
To evaluate bone density
Consider referral to endocrinologist if abnormal.
ALT = alanine aminotransferase; Apo = apolipoprotein; AST = aspartate aminotransferase; CBC = complete blood count; CK = creatine kinase; CMRD = chylomicron retention disease; DXA = dual-energy x-ray absorptiometry; GGT = gamma-glutamyl transferase; HDL = high-density lipoprotein; LDL = low-density lipoprotein; INR = international normalized ratio; MOI = mode of inheritance
Cardiomyopathy and decreased ejection fraction has not been reported in those younger than age 20 years [
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There are no specific recommendations for the treatment of CMRD, with therapeutic regimens currently based on those recommended for abetalipoproteinemia, namely, a low-fat diet supplemented with essential fatty acids [
Treatment of Manifestations in Individuals with Chylomicron Retention Disease
Vitamin E (hydrosoluble form
Vitamin A: 15,000 IU/d (adjust according to serum levels)
Vitamin D: 800-1200 IU/d OR 100,000 IU every 2 mos if age <5 yrs; 600,000 IU every 2 mos if age ≥5 yrs
Vitamin K: 15 mg/wk (adjust per INR & plasma levels)
Intralipid 20%: 2 g/kg as single infusion 1x/mo
Vitamin E: 4-6 mg/kg as single infusion 1x/mo
Vitamin A: 500 IU/kg as single infusion 1x/mo
INR = international normalized ratio; IV = intravenous; OT = occupational therapy; PT = physical therapy
For young children, milk preparations that contain medium-chain triglycerides can correct malnutrition and improve diarrhea, although some affected individuals do not tolerate this. In older children, a regimen low in long-chain fatty acids is often sufficient to improve symptoms [
To prevent neurologic complications, alpha-tocopherol in either lipid or aqueous form is the most effective formulation [
The use of IV vitamin supplementation in those who are late to diagnosis with neurologic complications has not been proven to be beneficial.
As outlined in
Recommended Surveillance for Individuals with Chylomicron Retention Disease
Measurement of growth parameters
Eval of digestive & neurologic symptoms
Eval of dietary fat content & compliance
Lipid profile
Liver function tests (AST, ALT, GGT, total bilirubin, alkaline phosphatase)
Vitamins A, D, & E; INR
CBC
Liver ultrasound
Neurologic: clinical exam, creatine kinase, electromyography
Ophthalmologic: eval of fundus, assessment of color vision, visual evoked potentials, & electroretinography
DXA scan (whole-body bone mineral content)
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBC = complete blood count; DXA = dual-energy x-ray absorptiometry; GGT = gamma-glutamyl transferase; INR = international normalized ratio
Surveillance of CMRD is based on that recommended for
To include total, LDL, and HDL cholesterol levels and measurement of triglycerides
Avoid fatty foods, particularly those rich in long-chain fatty acids.
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include:
A full lipid profile, including apolipoprotein B and apolipoprotein A-I concentrations;
Molecular genetic testing for the
See
Vitamin A excess can be harmful to the developing fetus. Therefore, affected women who are pregnant or who are planning to become pregnant should reduce their vitamin A supplement dose by 50%. Additionally, close monitoring of serum vitamin A levels throughout pregnancy is recommended, since its absorption is impaired as a fundamental feature of the condition.
However, because vitamin A is an essential vitamin, vitamin A supplementation for affected women should not be discontinued during pregnancy. Vitamin A deficiency can lead to maternal morbidity.
See
Search
• Total cholesterol
• LDL cholesterol
• HDL cholesterol
• Triglyceride
• Apo B
• Apo A-I
• To evaluate visual acuity & for baseline fundus exam
• Consider visual evoked potential & electroretinography in those w/concerning symptoms.
• To evaluate cardiac function & assess ejection fraction
• Cardiomyopathy is uncommon.
• Consider referral to cardiologist.
• To evaluate bone density
• Consider referral to endocrinologist if abnormal.
• Vitamin E (hydrosoluble form
• Vitamin A: 15,000 IU/d (adjust according to serum levels)
• Vitamin D: 800-1200 IU/d OR 100,000 IU every 2 mos if age <5 yrs; 600,000 IU every 2 mos if age ≥5 yrs
• Vitamin K: 15 mg/wk (adjust per INR & plasma levels)
• Intralipid 20%: 2 g/kg as single infusion 1x/mo
• Vitamin E: 4-6 mg/kg as single infusion 1x/mo
• Vitamin A: 500 IU/kg as single infusion 1x/mo
• Measurement of growth parameters
• Eval of digestive & neurologic symptoms
• Eval of dietary fat content & compliance
• Lipid profile
• Liver function tests (AST, ALT, GGT, total bilirubin, alkaline phosphatase)
• Vitamins A, D, & E; INR
• CBC
• Liver ultrasound
• Neurologic: clinical exam, creatine kinase, electromyography
• Ophthalmologic: eval of fundus, assessment of color vision, visual evoked potentials, & electroretinography
• DXA scan (whole-body bone mineral content)
• A full lipid profile, including apolipoprotein B and apolipoprotein A-I concentrations;
• Molecular genetic testing for the
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CMRD, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Chylomicron Retention Disease
Total cholesterol
LDL cholesterol
HDL cholesterol
Triglyceride
Apo B
Apo A-I
To evaluate visual acuity & for baseline fundus exam
Consider visual evoked potential & electroretinography in those w/concerning symptoms.
To evaluate cardiac function & assess ejection fraction
Cardiomyopathy is uncommon.
Consider referral to cardiologist.
To evaluate bone density
Consider referral to endocrinologist if abnormal.
ALT = alanine aminotransferase; Apo = apolipoprotein; AST = aspartate aminotransferase; CBC = complete blood count; CK = creatine kinase; CMRD = chylomicron retention disease; DXA = dual-energy x-ray absorptiometry; GGT = gamma-glutamyl transferase; HDL = high-density lipoprotein; LDL = low-density lipoprotein; INR = international normalized ratio; MOI = mode of inheritance
Cardiomyopathy and decreased ejection fraction has not been reported in those younger than age 20 years [
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Total cholesterol
• LDL cholesterol
• HDL cholesterol
• Triglyceride
• Apo B
• Apo A-I
• To evaluate visual acuity & for baseline fundus exam
• Consider visual evoked potential & electroretinography in those w/concerning symptoms.
• To evaluate cardiac function & assess ejection fraction
• Cardiomyopathy is uncommon.
• Consider referral to cardiologist.
• To evaluate bone density
• Consider referral to endocrinologist if abnormal.
## Treatment of Manifestations
There are no specific recommendations for the treatment of CMRD, with therapeutic regimens currently based on those recommended for abetalipoproteinemia, namely, a low-fat diet supplemented with essential fatty acids [
Treatment of Manifestations in Individuals with Chylomicron Retention Disease
Vitamin E (hydrosoluble form
Vitamin A: 15,000 IU/d (adjust according to serum levels)
Vitamin D: 800-1200 IU/d OR 100,000 IU every 2 mos if age <5 yrs; 600,000 IU every 2 mos if age ≥5 yrs
Vitamin K: 15 mg/wk (adjust per INR & plasma levels)
Intralipid 20%: 2 g/kg as single infusion 1x/mo
Vitamin E: 4-6 mg/kg as single infusion 1x/mo
Vitamin A: 500 IU/kg as single infusion 1x/mo
INR = international normalized ratio; IV = intravenous; OT = occupational therapy; PT = physical therapy
For young children, milk preparations that contain medium-chain triglycerides can correct malnutrition and improve diarrhea, although some affected individuals do not tolerate this. In older children, a regimen low in long-chain fatty acids is often sufficient to improve symptoms [
To prevent neurologic complications, alpha-tocopherol in either lipid or aqueous form is the most effective formulation [
The use of IV vitamin supplementation in those who are late to diagnosis with neurologic complications has not been proven to be beneficial.
• Vitamin E (hydrosoluble form
• Vitamin A: 15,000 IU/d (adjust according to serum levels)
• Vitamin D: 800-1200 IU/d OR 100,000 IU every 2 mos if age <5 yrs; 600,000 IU every 2 mos if age ≥5 yrs
• Vitamin K: 15 mg/wk (adjust per INR & plasma levels)
• Intralipid 20%: 2 g/kg as single infusion 1x/mo
• Vitamin E: 4-6 mg/kg as single infusion 1x/mo
• Vitamin A: 500 IU/kg as single infusion 1x/mo
## Prevention of Primary Manifestations
As outlined in
## Surveillance
Recommended Surveillance for Individuals with Chylomicron Retention Disease
Measurement of growth parameters
Eval of digestive & neurologic symptoms
Eval of dietary fat content & compliance
Lipid profile
Liver function tests (AST, ALT, GGT, total bilirubin, alkaline phosphatase)
Vitamins A, D, & E; INR
CBC
Liver ultrasound
Neurologic: clinical exam, creatine kinase, electromyography
Ophthalmologic: eval of fundus, assessment of color vision, visual evoked potentials, & electroretinography
DXA scan (whole-body bone mineral content)
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBC = complete blood count; DXA = dual-energy x-ray absorptiometry; GGT = gamma-glutamyl transferase; INR = international normalized ratio
Surveillance of CMRD is based on that recommended for
To include total, LDL, and HDL cholesterol levels and measurement of triglycerides
• Measurement of growth parameters
• Eval of digestive & neurologic symptoms
• Eval of dietary fat content & compliance
• Lipid profile
• Liver function tests (AST, ALT, GGT, total bilirubin, alkaline phosphatase)
• Vitamins A, D, & E; INR
• CBC
• Liver ultrasound
• Neurologic: clinical exam, creatine kinase, electromyography
• Ophthalmologic: eval of fundus, assessment of color vision, visual evoked potentials, & electroretinography
• DXA scan (whole-body bone mineral content)
## Agents/Circumstances to Avoid
Avoid fatty foods, particularly those rich in long-chain fatty acids.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include:
A full lipid profile, including apolipoprotein B and apolipoprotein A-I concentrations;
Molecular genetic testing for the
See
• A full lipid profile, including apolipoprotein B and apolipoprotein A-I concentrations;
• Molecular genetic testing for the
## Pregnancy Management
Vitamin A excess can be harmful to the developing fetus. Therefore, affected women who are pregnant or who are planning to become pregnant should reduce their vitamin A supplement dose by 50%. Additionally, close monitoring of serum vitamin A levels throughout pregnancy is recommended, since its absorption is impaired as a fundamental feature of the condition.
However, because vitamin A is an essential vitamin, vitamin A supplementation for affected women should not be discontinued during pregnancy. Vitamin A deficiency can lead to maternal morbidity.
See
## Therapies Under Investigation
Search
## Genetic Counseling
Chylomicron retention disease (CMRD) is inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygous for a
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A large deletion (i.e., a copy number variation) in the proband was not detected by sequence analysis and resulted in the artifactual appearance of homozygosity.
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for a
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A large deletion (i.e., a copy number variation) in the proband was not detected by sequence analysis and resulted in the artifactual appearance of homozygosity.
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• A large deletion (i.e., a copy number variation) in the proband was not detected by sequence analysis and resulted in the artifactual appearance of homozygosity.
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A large deletion (i.e., a copy number variation) in the proband was not detected by sequence analysis and resulted in the artifactual appearance of homozygosity.
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Chylomicron retention disease (CMRD) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for a
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A large deletion (i.e., a copy number variation) in the proband was not detected by sequence analysis and resulted in the artifactual appearance of homozygosity.
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are presumed to be heterozygous for a
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A large deletion (i.e., a copy number variation) in the proband was not detected by sequence analysis and resulted in the artifactual appearance of homozygosity.
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• A large deletion (i.e., a copy number variation) in the proband was not detected by sequence analysis and resulted in the artifactual appearance of homozygosity.
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A large deletion (i.e., a copy number variation) in the proband was not detected by sequence analysis and resulted in the artifactual appearance of homozygosity.
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
Chylomicron Retention Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Chylomicron Retention Disease (
Chylomicron retention disease (CMRD) is caused by biallelic pathogenic variants in
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Chylomicron retention disease (CMRD) is caused by biallelic pathogenic variants in
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
RAH is supported by the Jacob J Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Research Chair, and the Martha G Blackburn Chair in Cardiovascular Research. RAH holds operating grants from the Canadian Institutes of Health Research (Foundation award), the Heart and Stroke Foundation of Ontario (G-21-0031455).
24 March 2022 (ma) Review posted live
27 September 2021 (jrb) Original submission
• 24 March 2022 (ma) Review posted live
• 27 September 2021 (jrb) Original submission
## Acknowledgments
RAH is supported by the Jacob J Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Research Chair, and the Martha G Blackburn Chair in Cardiovascular Research. RAH holds operating grants from the Canadian Institutes of Health Research (Foundation award), the Heart and Stroke Foundation of Ontario (G-21-0031455).
## Revision History
24 March 2022 (ma) Review posted live
27 September 2021 (jrb) Original submission
• 24 March 2022 (ma) Review posted live
• 27 September 2021 (jrb) Original submission
## References
## Literature Cited
|
[] |
24/3/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
cms
|
cms
|
[
"Congenital Myasthenia",
"Congenital Myasthenia",
"43 kDa receptor-associated protein of the synapse",
"Acetylcholine receptor subunit alpha",
"Acetylcholine receptor subunit beta",
"Acetylcholine receptor subunit delta",
"Acetylcholine receptor subunit epsilon",
"Acetylcholinesterase collagenic tail peptide",
"Agrin",
"Alpha-1,3/1,6-mannosyltransferase ALG2",
"Choline O-acetyltransferase",
"Collagen alpha-1(XIII) chain",
"Glutamine--fructose-6-phosphate aminotransferase [isomerizing] 1",
"High affinity choline transporter 1",
"Laminin subunit beta-2",
"Low-density lipoprotein receptor-related protein 4",
"Mannose-1-phosphate guanylyltransferase catalytic subunit beta",
"Muscle, skeletal receptor tyrosine-protein kinase",
"Plectin",
"Prolyl endopeptidase-like",
"Protein Dok-7",
"Sodium channel protein type 4 subunit alpha",
"Synaptosomal-associated protein 25",
"Synaptotagmin-2",
"Tricarboxylate transport protein, mitochondrial",
"UDP-N-acetylglucosamine transferase subunit ALG14",
"UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferase",
"Unconventional myosin-IXa",
"AGRN",
"ALG14",
"ALG2",
"CHAT",
"CHRNA1",
"CHRNB1",
"CHRND",
"CHRNE",
"COL13A1",
"COLQ",
"DOK7",
"DPAGT1",
"GFPT1",
"GMPPB",
"LAMB2",
"LRP4",
"MUSK",
"MYO9A",
"PLEC",
"PREPL",
"RAPSN",
"SCN4A",
"SLC25A1",
"SLC5A7",
"SNAP25",
"SYT2",
"Congenital Myasthenic Syndromes",
"Overview"
] |
Congenital Myasthenic Syndromes Overview
|
Angela Abicht, Juliane S Müller, Hanns Lochmüller
|
Summary The purpose of this overview is to: Briefly describe the Review the Review the Provide an Review Inform
|
## Clinical Characteristics of Congenital Myasthenic Syndromes
An individual with a congenital myasthenic syndrome (CMS) typically presents with a history of fatigable weakness involving ocular, bulbar, and limb muscles with onset at or shortly after birth or in early childhood, usually in the first two years. Rarely, onset is in the second to third decade of life [
In its classic presentation, CMS is limited to weakness of the skeletal muscles. Cardiac and smooth muscle are not involved. Cognitive skills, coordination, sensation, and tendon reflexes are normal. However, in some newly identified CMS subtypes, myasthenia is only one element of a more severe and complex clinical spectrum.
Severity and course of disease are highly variable, ranging from minor symptoms to progressive disabling weakness. In some subtypes of CMS, myasthenic symptoms may be mild, but sudden severe exacerbations of weakness or even sudden episodes of respiratory insufficiency may be precipitated by fever, infections, or excitement.
An absence of major pathology is noted on skeletal muscle biopsy despite considerable muscle weakness ‒ except for
Respiratory insufficiency with sudden, episodic apnea and cyanosis are common findings in neonates.
Neonates with CMS can have multiple joint contractures (often described as arthrogryposis multiplex congenita) resulting from a lack of fetal movement in utero.
Other major findings in the neonatal period may include feeding difficulties, poor suck and cry, choking spells, eyelid ptosis, and facial, bulbar, and generalized weakness. Stridor in infancy may be an important clue to CMS.
In some individuals, long face, narrow jaw, and a high-arched palate have been reported.
Motor milestones may be delayed.
Affected individuals present with fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness. Ptosis may involve one or both eyelids.
Facial and bulbar weakness with nasal speech and difficulties in coughing and swallowing may be present.
Spinal deformity or muscle atrophy may occur.
Serum creatine kinase (CK) concentration may be normal or slightly elevated (usually ≤10-fold normal value). CK levels may be higher only in
Anti-AChR and anti-MuSK antibody testing (serum) is negative.
Note: (1) Absence of anti-AChR, anti-MuSK, and anti-LRP4 antibodies in serum can help distinguish CMS from myasthenia gravis (MG), but does not exclude seronegative types of MG which lack those antibodies.
With the exception of
In the majority of CMS subtypes, a decremental EMG response of the compound muscle action potential (CMAP) can be evoked on low-frequency (2-3 Hz) stimulation.
Generally, individuals should be tested for a decremental EMG response of CMAP on low-frequency (2- to 3-Hz) stimulation.
In some cases, 2- to 3-Hz stimulation elicits no decremental response from rested non-weak muscle, but elicits a significant decremental response after five to ten minutes of stimulation at 10 Hz.
If CMAP amplitude is normal in two distal and two proximal muscles, facial muscles should be tested.
Alternatively, or in addition, a single-fiber EMG is a good determinant of a neuromuscular transmission defect.
A single nerve stimulus may elicit a repetitive CMAP (the "double response to single nerve stimulus") in individuals with endplate acetylcholinesterase (AChE) deficiency or slow-channel CMS, or in those taking high doses of AChE inhibitors.
By contrast with the majority of CMS, some presynaptic subtypes (e.g.,
• Respiratory insufficiency with sudden, episodic apnea and cyanosis are common findings in neonates.
• Neonates with CMS can have multiple joint contractures (often described as arthrogryposis multiplex congenita) resulting from a lack of fetal movement in utero.
• Other major findings in the neonatal period may include feeding difficulties, poor suck and cry, choking spells, eyelid ptosis, and facial, bulbar, and generalized weakness. Stridor in infancy may be an important clue to CMS.
• In some individuals, long face, narrow jaw, and a high-arched palate have been reported.
• Motor milestones may be delayed.
• Affected individuals present with fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness. Ptosis may involve one or both eyelids.
• Facial and bulbar weakness with nasal speech and difficulties in coughing and swallowing may be present.
• Spinal deformity or muscle atrophy may occur.
• Serum creatine kinase (CK) concentration may be normal or slightly elevated (usually ≤10-fold normal value). CK levels may be higher only in
• Anti-AChR and anti-MuSK antibody testing (serum) is negative.
• Note: (1) Absence of anti-AChR, anti-MuSK, and anti-LRP4 antibodies in serum can help distinguish CMS from myasthenia gravis (MG), but does not exclude seronegative types of MG which lack those antibodies.
• With the exception of
• In the majority of CMS subtypes, a decremental EMG response of the compound muscle action potential (CMAP) can be evoked on low-frequency (2-3 Hz) stimulation.
• Generally, individuals should be tested for a decremental EMG response of CMAP on low-frequency (2- to 3-Hz) stimulation.
• In some cases, 2- to 3-Hz stimulation elicits no decremental response from rested non-weak muscle, but elicits a significant decremental response after five to ten minutes of stimulation at 10 Hz.
• If CMAP amplitude is normal in two distal and two proximal muscles, facial muscles should be tested.
• Alternatively, or in addition, a single-fiber EMG is a good determinant of a neuromuscular transmission defect.
• A single nerve stimulus may elicit a repetitive CMAP (the "double response to single nerve stimulus") in individuals with endplate acetylcholinesterase (AChE) deficiency or slow-channel CMS, or in those taking high doses of AChE inhibitors.
• Generally, individuals should be tested for a decremental EMG response of CMAP on low-frequency (2- to 3-Hz) stimulation.
• In some cases, 2- to 3-Hz stimulation elicits no decremental response from rested non-weak muscle, but elicits a significant decremental response after five to ten minutes of stimulation at 10 Hz.
• If CMAP amplitude is normal in two distal and two proximal muscles, facial muscles should be tested.
• Alternatively, or in addition, a single-fiber EMG is a good determinant of a neuromuscular transmission defect.
• A single nerve stimulus may elicit a repetitive CMAP (the "double response to single nerve stimulus") in individuals with endplate acetylcholinesterase (AChE) deficiency or slow-channel CMS, or in those taking high doses of AChE inhibitors.
• By contrast with the majority of CMS, some presynaptic subtypes (e.g.,
• Generally, individuals should be tested for a decremental EMG response of CMAP on low-frequency (2- to 3-Hz) stimulation.
• In some cases, 2- to 3-Hz stimulation elicits no decremental response from rested non-weak muscle, but elicits a significant decremental response after five to ten minutes of stimulation at 10 Hz.
• If CMAP amplitude is normal in two distal and two proximal muscles, facial muscles should be tested.
• Alternatively, or in addition, a single-fiber EMG is a good determinant of a neuromuscular transmission defect.
• A single nerve stimulus may elicit a repetitive CMAP (the "double response to single nerve stimulus") in individuals with endplate acetylcholinesterase (AChE) deficiency or slow-channel CMS, or in those taking high doses of AChE inhibitors.
## Clinical Features
An individual with a congenital myasthenic syndrome (CMS) typically presents with a history of fatigable weakness involving ocular, bulbar, and limb muscles with onset at or shortly after birth or in early childhood, usually in the first two years. Rarely, onset is in the second to third decade of life [
In its classic presentation, CMS is limited to weakness of the skeletal muscles. Cardiac and smooth muscle are not involved. Cognitive skills, coordination, sensation, and tendon reflexes are normal. However, in some newly identified CMS subtypes, myasthenia is only one element of a more severe and complex clinical spectrum.
Severity and course of disease are highly variable, ranging from minor symptoms to progressive disabling weakness. In some subtypes of CMS, myasthenic symptoms may be mild, but sudden severe exacerbations of weakness or even sudden episodes of respiratory insufficiency may be precipitated by fever, infections, or excitement.
An absence of major pathology is noted on skeletal muscle biopsy despite considerable muscle weakness ‒ except for
Respiratory insufficiency with sudden, episodic apnea and cyanosis are common findings in neonates.
Neonates with CMS can have multiple joint contractures (often described as arthrogryposis multiplex congenita) resulting from a lack of fetal movement in utero.
Other major findings in the neonatal period may include feeding difficulties, poor suck and cry, choking spells, eyelid ptosis, and facial, bulbar, and generalized weakness. Stridor in infancy may be an important clue to CMS.
In some individuals, long face, narrow jaw, and a high-arched palate have been reported.
Motor milestones may be delayed.
Affected individuals present with fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness. Ptosis may involve one or both eyelids.
Facial and bulbar weakness with nasal speech and difficulties in coughing and swallowing may be present.
Spinal deformity or muscle atrophy may occur.
• Respiratory insufficiency with sudden, episodic apnea and cyanosis are common findings in neonates.
• Neonates with CMS can have multiple joint contractures (often described as arthrogryposis multiplex congenita) resulting from a lack of fetal movement in utero.
• Other major findings in the neonatal period may include feeding difficulties, poor suck and cry, choking spells, eyelid ptosis, and facial, bulbar, and generalized weakness. Stridor in infancy may be an important clue to CMS.
• In some individuals, long face, narrow jaw, and a high-arched palate have been reported.
• Motor milestones may be delayed.
• Affected individuals present with fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness. Ptosis may involve one or both eyelids.
• Facial and bulbar weakness with nasal speech and difficulties in coughing and swallowing may be present.
• Spinal deformity or muscle atrophy may occur.
## Laboratory and Test Findings
Serum creatine kinase (CK) concentration may be normal or slightly elevated (usually ≤10-fold normal value). CK levels may be higher only in
Anti-AChR and anti-MuSK antibody testing (serum) is negative.
Note: (1) Absence of anti-AChR, anti-MuSK, and anti-LRP4 antibodies in serum can help distinguish CMS from myasthenia gravis (MG), but does not exclude seronegative types of MG which lack those antibodies.
With the exception of
In the majority of CMS subtypes, a decremental EMG response of the compound muscle action potential (CMAP) can be evoked on low-frequency (2-3 Hz) stimulation.
Generally, individuals should be tested for a decremental EMG response of CMAP on low-frequency (2- to 3-Hz) stimulation.
In some cases, 2- to 3-Hz stimulation elicits no decremental response from rested non-weak muscle, but elicits a significant decremental response after five to ten minutes of stimulation at 10 Hz.
If CMAP amplitude is normal in two distal and two proximal muscles, facial muscles should be tested.
Alternatively, or in addition, a single-fiber EMG is a good determinant of a neuromuscular transmission defect.
A single nerve stimulus may elicit a repetitive CMAP (the "double response to single nerve stimulus") in individuals with endplate acetylcholinesterase (AChE) deficiency or slow-channel CMS, or in those taking high doses of AChE inhibitors.
By contrast with the majority of CMS, some presynaptic subtypes (e.g.,
• Serum creatine kinase (CK) concentration may be normal or slightly elevated (usually ≤10-fold normal value). CK levels may be higher only in
• Anti-AChR and anti-MuSK antibody testing (serum) is negative.
• Note: (1) Absence of anti-AChR, anti-MuSK, and anti-LRP4 antibodies in serum can help distinguish CMS from myasthenia gravis (MG), but does not exclude seronegative types of MG which lack those antibodies.
• With the exception of
• In the majority of CMS subtypes, a decremental EMG response of the compound muscle action potential (CMAP) can be evoked on low-frequency (2-3 Hz) stimulation.
• Generally, individuals should be tested for a decremental EMG response of CMAP on low-frequency (2- to 3-Hz) stimulation.
• In some cases, 2- to 3-Hz stimulation elicits no decremental response from rested non-weak muscle, but elicits a significant decremental response after five to ten minutes of stimulation at 10 Hz.
• If CMAP amplitude is normal in two distal and two proximal muscles, facial muscles should be tested.
• Alternatively, or in addition, a single-fiber EMG is a good determinant of a neuromuscular transmission defect.
• A single nerve stimulus may elicit a repetitive CMAP (the "double response to single nerve stimulus") in individuals with endplate acetylcholinesterase (AChE) deficiency or slow-channel CMS, or in those taking high doses of AChE inhibitors.
• Generally, individuals should be tested for a decremental EMG response of CMAP on low-frequency (2- to 3-Hz) stimulation.
• In some cases, 2- to 3-Hz stimulation elicits no decremental response from rested non-weak muscle, but elicits a significant decremental response after five to ten minutes of stimulation at 10 Hz.
• If CMAP amplitude is normal in two distal and two proximal muscles, facial muscles should be tested.
• Alternatively, or in addition, a single-fiber EMG is a good determinant of a neuromuscular transmission defect.
• A single nerve stimulus may elicit a repetitive CMAP (the "double response to single nerve stimulus") in individuals with endplate acetylcholinesterase (AChE) deficiency or slow-channel CMS, or in those taking high doses of AChE inhibitors.
• By contrast with the majority of CMS, some presynaptic subtypes (e.g.,
• Generally, individuals should be tested for a decremental EMG response of CMAP on low-frequency (2- to 3-Hz) stimulation.
• In some cases, 2- to 3-Hz stimulation elicits no decremental response from rested non-weak muscle, but elicits a significant decremental response after five to ten minutes of stimulation at 10 Hz.
• If CMAP amplitude is normal in two distal and two proximal muscles, facial muscles should be tested.
• Alternatively, or in addition, a single-fiber EMG is a good determinant of a neuromuscular transmission defect.
• A single nerve stimulus may elicit a repetitive CMAP (the "double response to single nerve stimulus") in individuals with endplate acetylcholinesterase (AChE) deficiency or slow-channel CMS, or in those taking high doses of AChE inhibitors.
## Subtypes and Genetic Causes of Congenital Myasthenic Syndromes
Congenital Myasthenic Syndromes: CMS Subtypes and Distinguishing Clinical Features
Early onset
Mild to severe
Ptosis, EOP; bulbar, arm, leg weakness
Selective severe neck, wrist, finger extensor weakness
Childhood to adult onset
Mild to severe
Progressive ventilatory insufficiency; may require assisted ventilation
Hypotonia, respiratory failure at birth
Episodic apnea
Arthrogryposis multiplex congenita
Mild to severe
Limb weakness in adolescence or adulthood; as in seronegative myasthenia gravis
Prenatal onset w/fetal akinesia deformation sequence
Early onset w/ophthalmoplegia & respiratory failure
Isolated vocal cord paralysis
Late-onset limb girdle weakness
Fatigable proximal myopathy & ptosis
W/or w/o skin blistering
Often severe
In some w/C-terminal missense pathogenic variants: later presentation, milder clinical course
EOP
General muscle weakness / severe involvement of axial muscles
Slow pupillary light response
At birth, respiratory distress & dysphagia; may resolve
Recurrent apnea triggered by infections
In adulthood, bilateral nonfatigable ptosis & marked axial weakness
Sometimes improvement of muscle weakness by adulthood
Early-onset or late-onset phenotype
Persons w/late onset may present w/distal muscle weakness & wasting in addition to myasthenia
Hypotonia, respiratory failure at birth
Episodic apnea
Improvement w/age
Early onset
More severe than
Arthrogryposis/joint contractures, apneic crisis at birth, marked ptosis, ophthalmoplegia, & muscle fatigability
Some have limited survival, some have milder phenotypes.
Some w/learning difficulties
Developmental & epileptic encephalopathy of infancy & childhood w/diverse clinical manifestations
Severe ID, cerebellar ataxia, brain atrophy
Early-onset phenotype w/severe congenital hypotonia & muscle weakness, feeding difficulties, delayed motor development, ophthalmoparesis.
May have joint contractures or joint laxity
May have respiratory insufficiency
AR: Severe congenital-onset hypotonia & weakness, w/variable degrees of respiratory involvement; mimics severe congenital myopathy
AD: Mimics distal hereditary motor neuropathy, slowly progressive distal motor neuropathy, & myasthenic syndrome
Congenital hypotonia, feeding difficulties, ptosis, & proximal muscle weakness
Growth hormone deficiency
See footnote 7.
Early onset, ptosis, ophthalmoplegia & moderate global weakness, bulbar involvement, respiratory crises
Addl CNS symptoms: ID or learning difficulties, nystagmus, oculomotor apraxia
Relatively mild CMS phenotype w/ID
Subtle mitochondrial abnormalities
"Limb-girdle" pattern of weakness w/predominantly proximal weakness but usually no ptosis or EOP; tubular aggregates on muscle biopsy in some
ID may occur in
ACh = acetylcholine; AChE = acetylcholinesterase; AD = autosomal dominant; AR = autosomal recessive; CDG = congenital disorders of glycosylation; CNS = central nervous system; EOP = external ophthalmoplegia; ID = intellectual disability
CMS subtypes are grouped by site of defect and mechanism of neuromuscular junction defect.
Additional genes are published as CMS genes or genes with an underlying pathology of the neuromuscular junction, but to date have been reported in only one or two studies. These genes include: postsynaptic proteins
No or limited data; small number of reported individuals
Additional non-myasthenic features (cystinuria, learning difficulties, endocrinologic defects, hyperphagia with tendency to obesity) may be associated with homozygous deletions of the two contiguous genes
• Early onset
• Mild to severe
• Ptosis, EOP; bulbar, arm, leg weakness
• Selective severe neck, wrist, finger extensor weakness
• Childhood to adult onset
• Mild to severe
• Progressive ventilatory insufficiency; may require assisted ventilation
• Hypotonia, respiratory failure at birth
• Episodic apnea
• Arthrogryposis multiplex congenita
• Mild to severe
• Limb weakness in adolescence or adulthood; as in seronegative myasthenia gravis
• Prenatal onset w/fetal akinesia deformation sequence
• Early onset w/ophthalmoplegia & respiratory failure
• Isolated vocal cord paralysis
• Late-onset limb girdle weakness
• Fatigable proximal myopathy & ptosis
• W/or w/o skin blistering
• Often severe
• In some w/C-terminal missense pathogenic variants: later presentation, milder clinical course
• EOP
• General muscle weakness / severe involvement of axial muscles
• Slow pupillary light response
• At birth, respiratory distress & dysphagia; may resolve
• Recurrent apnea triggered by infections
• In adulthood, bilateral nonfatigable ptosis & marked axial weakness
• Sometimes improvement of muscle weakness by adulthood
• Early-onset or late-onset phenotype
• Persons w/late onset may present w/distal muscle weakness & wasting in addition to myasthenia
• Hypotonia, respiratory failure at birth
• Episodic apnea
• Improvement w/age
• Early onset
• More severe than
• Arthrogryposis/joint contractures, apneic crisis at birth, marked ptosis, ophthalmoplegia, & muscle fatigability
• Some have limited survival, some have milder phenotypes.
• Some w/learning difficulties
• Developmental & epileptic encephalopathy of infancy & childhood w/diverse clinical manifestations
• Severe ID, cerebellar ataxia, brain atrophy
• Early-onset phenotype w/severe congenital hypotonia & muscle weakness, feeding difficulties, delayed motor development, ophthalmoparesis.
• May have joint contractures or joint laxity
• May have respiratory insufficiency
• AR: Severe congenital-onset hypotonia & weakness, w/variable degrees of respiratory involvement; mimics severe congenital myopathy
• AD: Mimics distal hereditary motor neuropathy, slowly progressive distal motor neuropathy, & myasthenic syndrome
• Congenital hypotonia, feeding difficulties, ptosis, & proximal muscle weakness
• Growth hormone deficiency
• See footnote 7.
• Early onset, ptosis, ophthalmoplegia & moderate global weakness, bulbar involvement, respiratory crises
• Addl CNS symptoms: ID or learning difficulties, nystagmus, oculomotor apraxia
• Relatively mild CMS phenotype w/ID
• Subtle mitochondrial abnormalities
• "Limb-girdle" pattern of weakness w/predominantly proximal weakness but usually no ptosis or EOP; tubular aggregates on muscle biopsy in some
• ID may occur in
## Differential Diagnosis of Congenital Myasthenic Syndromes
Spinal muscular atrophy with respiratory distress 1 (SMARD1) (OMIM
Congenital muscular dystrophies (See
Congenital myopathies including
Congenital
Mitochondrial myopathies (See
Moebius syndrome (OMIM
Additional considerations include infantile botulism and brain stem anomalies.
Motor neuron disease including
Limb-girdle muscular dystrophy (OMIM
Mitochondrial myopathy and chronic progressive external ophthalmoplegia (See
Autosomal dominant progressive external ophthalmoplegia, caused by pathogenic variants in
•
• Spinal muscular atrophy with respiratory distress 1 (SMARD1) (OMIM
• Congenital muscular dystrophies (See
• Congenital myopathies including
• Congenital
• Mitochondrial myopathies (See
•
• Moebius syndrome (OMIM
• Motor neuron disease including
• Limb-girdle muscular dystrophy (OMIM
•
• Mitochondrial myopathy and chronic progressive external ophthalmoplegia (See
• Autosomal dominant progressive external ophthalmoplegia, caused by pathogenic variants in
## Evaluation Strategies to Identify the Genetic Cause of a Congenital Myasthenic Syndrome in a Proband
Establishing a specific genetic cause of a congenital myasthenic syndrome (CMS):
Can aid in discussions of prognosis (which are beyond the scope of this
Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Congenital Myasthenic Syndromes: Genes and Frequency
CMS = congenital myasthenic syndromes
Genes are listed alphabetically.
• Can aid in discussions of prognosis (which are beyond the scope of this
• Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Management
While there are no recent published consensus guidelines for the management of congenital myasthenic syndromes (CMS),
This section provides information regarding recommendations for evaluations following initial diagnosis (
To establish the extent of disease and needs in an individual diagnosed with a CMS, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with a Congenital Myasthenic Syndrome
Baseline pulmonary function tests incl forced vital capacity in sitting & supine positions & blood gas exchange
Polysomnography to identify persons w/nocturnal hypoventilation
Review of history for symptoms of hypercapnia: daytime headache, restless sleep, loss of concentration, snoring, recurrent respiratory infections, weight loss
Assessment of feeding abilities (sucking, swallowing, gastroesophageal reflux)
Eval of growth parameters to determine need for feeding interventions incl gavage feeding or gastrostomy insertion
Assessment by physiatrist &/or orthopedist
Radiologic exam if spinal curvature noted
Community or
Social work involvement for parental support;
Home nursing referral.
CMS = congenital myasthenic syndromes; MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
The choice of medication varies with the CMS subtype [
Side effects of drugs used to treat myasthenic symptoms should be carefully monitored. If necessary, individual doses should be adjusted or treatment stopped.
Congenital Myasthenic Syndromes: Medication Recommendations for Certain Genetic Causes and Subtypes
For a detailed summary of treatment options in rare CMS subtypes see
Fluoxetine may induce suicidal ideation; thus, caution is strongly suggested in its use in childhood.
Quinidine has some major side effects including
In addition to medication therapy, a multidisciplinary approach to the clinical management of the affected individual greatly improves quality of life and can influence survival. Management should be tailored to the individual, the specific CMS subtype, and the rate of progression.
Depending on the individual clinical situation, clinical management may include the following:
Physical and occupational therapy
Speech therapy
Orthotics or a wheelchair
A percutaneous gastrostomy tube
Ventilatory support
Sudden respiratory insufficiency or apneic attacks provoked by fever or infections are common in individuals with pathogenic variants in
Note: Less frequently, acute respiratory events may also occur in other CMS subtypes. Parents of infants are advised to use apnea monitors and be trained in CPR.
Regular surveillance of muscle strength and respiratory function is recommended, usually at least every six months in children and every 12 months in adults. In some individuals, especially those with
A number of drugs are known to affect neuromuscular transmission and therefore exacerbate symptoms of myasthenia gravis (e.g., ciprofloxacin, chloroquine, procaine, lithium, phenytoin, beta-blockers, procainamide, and quinidine). These drugs are not absolutely contraindicated and may be used with caution in CMS. See
It is appropriate to evaluate apparently asymptomatic at-risk relatives of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures ‒ especially newborns or young children, who could benefit from early treatment to prevent sudden respiratory failure. Evaluations can include:
Molecular genetic testing if the pathogenic variant(s) in the family are known;
Neurologic/neuropediatric examination and electrophysiologic testing (repetitive nerve stimulation) if the pathogenic variant(s) in the family are not known.
See
Data on pregnancies in CMS are limited. Seventeen pregnancies were reported in eight French individuals with CMS [
Search
• Baseline pulmonary function tests incl forced vital capacity in sitting & supine positions & blood gas exchange
• Polysomnography to identify persons w/nocturnal hypoventilation
• Review of history for symptoms of hypercapnia: daytime headache, restless sleep, loss of concentration, snoring, recurrent respiratory infections, weight loss
• Assessment of feeding abilities (sucking, swallowing, gastroesophageal reflux)
• Eval of growth parameters to determine need for feeding interventions incl gavage feeding or gastrostomy insertion
• Assessment by physiatrist &/or orthopedist
• Radiologic exam if spinal curvature noted
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Physical and occupational therapy
• Speech therapy
• Orthotics or a wheelchair
• A percutaneous gastrostomy tube
• Ventilatory support
• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Neurologic/neuropediatric examination and electrophysiologic testing (repetitive nerve stimulation) if the pathogenic variant(s) in the family are not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a CMS, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with a Congenital Myasthenic Syndrome
Baseline pulmonary function tests incl forced vital capacity in sitting & supine positions & blood gas exchange
Polysomnography to identify persons w/nocturnal hypoventilation
Review of history for symptoms of hypercapnia: daytime headache, restless sleep, loss of concentration, snoring, recurrent respiratory infections, weight loss
Assessment of feeding abilities (sucking, swallowing, gastroesophageal reflux)
Eval of growth parameters to determine need for feeding interventions incl gavage feeding or gastrostomy insertion
Assessment by physiatrist &/or orthopedist
Radiologic exam if spinal curvature noted
Community or
Social work involvement for parental support;
Home nursing referral.
CMS = congenital myasthenic syndromes; MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Baseline pulmonary function tests incl forced vital capacity in sitting & supine positions & blood gas exchange
• Polysomnography to identify persons w/nocturnal hypoventilation
• Review of history for symptoms of hypercapnia: daytime headache, restless sleep, loss of concentration, snoring, recurrent respiratory infections, weight loss
• Assessment of feeding abilities (sucking, swallowing, gastroesophageal reflux)
• Eval of growth parameters to determine need for feeding interventions incl gavage feeding or gastrostomy insertion
• Assessment by physiatrist &/or orthopedist
• Radiologic exam if spinal curvature noted
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
The choice of medication varies with the CMS subtype [
Side effects of drugs used to treat myasthenic symptoms should be carefully monitored. If necessary, individual doses should be adjusted or treatment stopped.
Congenital Myasthenic Syndromes: Medication Recommendations for Certain Genetic Causes and Subtypes
For a detailed summary of treatment options in rare CMS subtypes see
Fluoxetine may induce suicidal ideation; thus, caution is strongly suggested in its use in childhood.
Quinidine has some major side effects including
In addition to medication therapy, a multidisciplinary approach to the clinical management of the affected individual greatly improves quality of life and can influence survival. Management should be tailored to the individual, the specific CMS subtype, and the rate of progression.
Depending on the individual clinical situation, clinical management may include the following:
Physical and occupational therapy
Speech therapy
Orthotics or a wheelchair
A percutaneous gastrostomy tube
Ventilatory support
• Physical and occupational therapy
• Speech therapy
• Orthotics or a wheelchair
• A percutaneous gastrostomy tube
• Ventilatory support
## Medications Used in CMS
The choice of medication varies with the CMS subtype [
Side effects of drugs used to treat myasthenic symptoms should be carefully monitored. If necessary, individual doses should be adjusted or treatment stopped.
Congenital Myasthenic Syndromes: Medication Recommendations for Certain Genetic Causes and Subtypes
For a detailed summary of treatment options in rare CMS subtypes see
Fluoxetine may induce suicidal ideation; thus, caution is strongly suggested in its use in childhood.
Quinidine has some major side effects including
## Non-Pharmaceutical Treatment
In addition to medication therapy, a multidisciplinary approach to the clinical management of the affected individual greatly improves quality of life and can influence survival. Management should be tailored to the individual, the specific CMS subtype, and the rate of progression.
Depending on the individual clinical situation, clinical management may include the following:
Physical and occupational therapy
Speech therapy
Orthotics or a wheelchair
A percutaneous gastrostomy tube
Ventilatory support
• Physical and occupational therapy
• Speech therapy
• Orthotics or a wheelchair
• A percutaneous gastrostomy tube
• Ventilatory support
## Prevention of Primary Manifestations
Sudden respiratory insufficiency or apneic attacks provoked by fever or infections are common in individuals with pathogenic variants in
Note: Less frequently, acute respiratory events may also occur in other CMS subtypes. Parents of infants are advised to use apnea monitors and be trained in CPR.
## Surveillance
Regular surveillance of muscle strength and respiratory function is recommended, usually at least every six months in children and every 12 months in adults. In some individuals, especially those with
## Agents/Circumstances to Avoid
A number of drugs are known to affect neuromuscular transmission and therefore exacerbate symptoms of myasthenia gravis (e.g., ciprofloxacin, chloroquine, procaine, lithium, phenytoin, beta-blockers, procainamide, and quinidine). These drugs are not absolutely contraindicated and may be used with caution in CMS. See
## Evaluation of Relatives at Risk
It is appropriate to evaluate apparently asymptomatic at-risk relatives of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures ‒ especially newborns or young children, who could benefit from early treatment to prevent sudden respiratory failure. Evaluations can include:
Molecular genetic testing if the pathogenic variant(s) in the family are known;
Neurologic/neuropediatric examination and electrophysiologic testing (repetitive nerve stimulation) if the pathogenic variant(s) in the family are not known.
See
• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Neurologic/neuropediatric examination and electrophysiologic testing (repetitive nerve stimulation) if the pathogenic variant(s) in the family are not known.
## Pregnancy Management
Data on pregnancies in CMS are limited. Seventeen pregnancies were reported in eight French individuals with CMS [
## Therapies Under Investigation
Search
## Genetic Counseling
Congenital myasthenic syndromes (CMS) are typically inherited in an autosomal recessive manner. Less commonly, CMS is inherited in an autosomal dominant manner (
Congenital Myasthenic Syndromes: Mode of Inheritance
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Heterozygous gain-of-function variants result in autosomal dominant slow-channel CMS. Biallelic loss-of-function variants result in autosomal recessive CMS.
Heterozygous missense variants result in autosomal dominant CMS. Biallelic loss-of-function variants result in autosomal recessive CMS.
The parents of a child with autosomal recessive congenital myasthenic syndrome (ARCMS) are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history).
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CMS-causing pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A large deletion (i.e., a copy number variation) in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband [
Heterozygotes (carriers) are clinically asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an ARCMS-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are clinically asymptomatic and are not at risk of developing the disorder.
Unless an affected individual's reproductive partner also has ARCMS or is a carrier, offspring will be obligate heterozygotes (carriers) for an ARCMS-causing pathogenic variant.
In populations with a high carrier rate and/or a high rate of consanguineous marriages, the risk to the offspring of an affected individual of being affected is increased.
Some individuals diagnosed with autosomal dominant congenital myasthenic syndrome (ADCMS) have an affected parent.
A proband with ADCMS may have the disorder as the result of a
If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with ADCMS may appear to be negative because of failure to recognize the disorder in affected family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Reduced penetrance is unlikely to be a factor in ADCMS with severe clinical presentation at birth but may be taken into account when considering the family history of a proband with a milder late-onset form.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known ADCMS-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk, are carriers, or are at risk of being carriers.
Once the CMS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of a child with autosomal recessive congenital myasthenic syndrome (ARCMS) are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history).
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CMS-causing pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A large deletion (i.e., a copy number variation) in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband [
• A large deletion (i.e., a copy number variation) in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband [
• Heterozygotes (carriers) are clinically asymptomatic and are not at risk of developing the disorder.
• A large deletion (i.e., a copy number variation) in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband [
• If both parents are known to be heterozygous for an ARCMS-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are clinically asymptomatic and are not at risk of developing the disorder.
• Unless an affected individual's reproductive partner also has ARCMS or is a carrier, offspring will be obligate heterozygotes (carriers) for an ARCMS-causing pathogenic variant.
• In populations with a high carrier rate and/or a high rate of consanguineous marriages, the risk to the offspring of an affected individual of being affected is increased.
• Some individuals diagnosed with autosomal dominant congenital myasthenic syndrome (ADCMS) have an affected parent.
• A proband with ADCMS may have the disorder as the result of a
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with ADCMS may appear to be negative because of failure to recognize the disorder in affected family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Reduced penetrance is unlikely to be a factor in ADCMS with severe clinical presentation at birth but may be taken into account when considering the family history of a proband with a milder late-onset form.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known ADCMS-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Congenital myasthenic syndromes (CMS) are typically inherited in an autosomal recessive manner. Less commonly, CMS is inherited in an autosomal dominant manner (
Congenital Myasthenic Syndromes: Mode of Inheritance
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Heterozygous gain-of-function variants result in autosomal dominant slow-channel CMS. Biallelic loss-of-function variants result in autosomal recessive CMS.
Heterozygous missense variants result in autosomal dominant CMS. Biallelic loss-of-function variants result in autosomal recessive CMS.
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of a child with autosomal recessive congenital myasthenic syndrome (ARCMS) are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history).
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CMS-causing pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A large deletion (i.e., a copy number variation) in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband [
Heterozygotes (carriers) are clinically asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an ARCMS-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are clinically asymptomatic and are not at risk of developing the disorder.
Unless an affected individual's reproductive partner also has ARCMS or is a carrier, offspring will be obligate heterozygotes (carriers) for an ARCMS-causing pathogenic variant.
In populations with a high carrier rate and/or a high rate of consanguineous marriages, the risk to the offspring of an affected individual of being affected is increased.
• The parents of a child with autosomal recessive congenital myasthenic syndrome (ARCMS) are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history).
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CMS-causing pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A large deletion (i.e., a copy number variation) in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband [
• A large deletion (i.e., a copy number variation) in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband [
• Heterozygotes (carriers) are clinically asymptomatic and are not at risk of developing the disorder.
• A large deletion (i.e., a copy number variation) in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband [
• If both parents are known to be heterozygous for an ARCMS-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are clinically asymptomatic and are not at risk of developing the disorder.
• Unless an affected individual's reproductive partner also has ARCMS or is a carrier, offspring will be obligate heterozygotes (carriers) for an ARCMS-causing pathogenic variant.
• In populations with a high carrier rate and/or a high rate of consanguineous marriages, the risk to the offspring of an affected individual of being affected is increased.
## Autosomal Dominant Inheritance – Risk to Family Members
Some individuals diagnosed with autosomal dominant congenital myasthenic syndrome (ADCMS) have an affected parent.
A proband with ADCMS may have the disorder as the result of a
If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with ADCMS may appear to be negative because of failure to recognize the disorder in affected family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Reduced penetrance is unlikely to be a factor in ADCMS with severe clinical presentation at birth but may be taken into account when considering the family history of a proband with a milder late-onset form.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known ADCMS-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
• Some individuals diagnosed with autosomal dominant congenital myasthenic syndrome (ADCMS) have an affected parent.
• A proband with ADCMS may have the disorder as the result of a
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with ADCMS may appear to be negative because of failure to recognize the disorder in affected family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Reduced penetrance is unlikely to be a factor in ADCMS with severe clinical presentation at birth but may be taken into account when considering the family history of a proband with a milder late-onset form.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known ADCMS-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the CMS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
PO Box 5801
Bethesda MD 20824
Canada
United Kingdom
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• PO Box 5801
• Bethesda MD 20824
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• Canada
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• United Kingdom
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## Chapter Notes
Dr Hanns Lochmüller's lab website:
23 December 2021 (ha) Comprehensive update posted live; scope changed to overview
14 July 2016 (ha) Comprehensive update posted live
22 March 2012 (me) Comprehensive update posted live
8 August 2005 (me) Comprehensive update posted live
9 May 2003 (me) Review posted live
30 January 2003 (aa) Original submission
• 23 December 2021 (ha) Comprehensive update posted live; scope changed to overview
• 14 July 2016 (ha) Comprehensive update posted live
• 22 March 2012 (me) Comprehensive update posted live
• 8 August 2005 (me) Comprehensive update posted live
• 9 May 2003 (me) Review posted live
• 30 January 2003 (aa) Original submission
## Author Notes
Dr Hanns Lochmüller's lab website:
## Revision History
23 December 2021 (ha) Comprehensive update posted live; scope changed to overview
14 July 2016 (ha) Comprehensive update posted live
22 March 2012 (me) Comprehensive update posted live
8 August 2005 (me) Comprehensive update posted live
9 May 2003 (me) Review posted live
30 January 2003 (aa) Original submission
• 23 December 2021 (ha) Comprehensive update posted live; scope changed to overview
• 14 July 2016 (ha) Comprehensive update posted live
• 22 March 2012 (me) Comprehensive update posted live
• 8 August 2005 (me) Comprehensive update posted live
• 9 May 2003 (me) Review posted live
• 30 January 2003 (aa) Original submission
## References
## Literature Cited
|
[] |
9/5/2003
|
23/12/2021
|
28/6/2012
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cmt-4a
|
cmt-4a
|
[
"GDAP1-HMSN",
"GDAP1-Related Charcot-Marie-Tooth Neuropathy",
"GDAP1-HMSN",
"GDAP1-Related Charcot-Marie-Tooth Neuropathy",
"Ganglioside-induced differentiation-associated protein 1",
"GDAP1",
"GDAP1-Related Hereditary Motor and Sensory Neuropathy"
] |
Thomas D Bird
|
Summary Diagnosis of Prenatal testing for pregnancies at increased risk for
|
AD = autosomal dominant; AR = autosomal recessive; CMT = Charcot-Marie-Tooth neuropathy; CMTRIA = Charcot-Marie-Tooth Neuropathy, recessive intermediate A
MOI = mode of inheritance
Hereditary motor and sensory neuropathy is also referred to as "Charcot-Marie-Tooth neuropathy"; see
## Diagnosis
Early onset of peripheral neuropathy, presenting especially with foot deformities, muscle wasting, and involvement of the sensory nerves resulting in decreased appreciation of touch, pain, and vibration. Proximal weakness usually comes later.
Disability within the first and second decade of life consisting of foot deformity, difficulty walking and claw hand deformity.
Vocal cord paresis manifest as a hoarse voice
Mild-to-moderate scoliosis
Occasional involvement of cranial nerves sometimes resulting in facial weakness.
Most commonly are consistent with an axonal neuropathy with normal NCVs and reduced amplitudes [
Occasionally are consistent with either a demyelinating neuropathy with slowed NCVs (<38 m/s) [
The diagnosis of HMSN
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
When the phenotypic and laboratory findings suggest the diagnosis of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other hereditary motor and sensory neuropathies, molecular genetic testing approaches can include
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Pathogenic variants in
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Early onset of peripheral neuropathy, presenting especially with foot deformities, muscle wasting, and involvement of the sensory nerves resulting in decreased appreciation of touch, pain, and vibration. Proximal weakness usually comes later.
• Disability within the first and second decade of life consisting of foot deformity, difficulty walking and claw hand deformity.
• Vocal cord paresis manifest as a hoarse voice
• Mild-to-moderate scoliosis
• Occasional involvement of cranial nerves sometimes resulting in facial weakness.
•
• Most commonly are consistent with an axonal neuropathy with normal NCVs and reduced amplitudes [
• Occasionally are consistent with either a demyelinating neuropathy with slowed NCVs (<38 m/s) [
• Most commonly are consistent with an axonal neuropathy with normal NCVs and reduced amplitudes [
• Occasionally are consistent with either a demyelinating neuropathy with slowed NCVs (<38 m/s) [
• Most commonly are consistent with an axonal neuropathy with normal NCVs and reduced amplitudes [
• Occasionally are consistent with either a demyelinating neuropathy with slowed NCVs (<38 m/s) [
• For an introduction to multigene panels click
## Suggestive Findings
Early onset of peripheral neuropathy, presenting especially with foot deformities, muscle wasting, and involvement of the sensory nerves resulting in decreased appreciation of touch, pain, and vibration. Proximal weakness usually comes later.
Disability within the first and second decade of life consisting of foot deformity, difficulty walking and claw hand deformity.
Vocal cord paresis manifest as a hoarse voice
Mild-to-moderate scoliosis
Occasional involvement of cranial nerves sometimes resulting in facial weakness.
Most commonly are consistent with an axonal neuropathy with normal NCVs and reduced amplitudes [
Occasionally are consistent with either a demyelinating neuropathy with slowed NCVs (<38 m/s) [
• Early onset of peripheral neuropathy, presenting especially with foot deformities, muscle wasting, and involvement of the sensory nerves resulting in decreased appreciation of touch, pain, and vibration. Proximal weakness usually comes later.
• Disability within the first and second decade of life consisting of foot deformity, difficulty walking and claw hand deformity.
• Vocal cord paresis manifest as a hoarse voice
• Mild-to-moderate scoliosis
• Occasional involvement of cranial nerves sometimes resulting in facial weakness.
•
• Most commonly are consistent with an axonal neuropathy with normal NCVs and reduced amplitudes [
• Occasionally are consistent with either a demyelinating neuropathy with slowed NCVs (<38 m/s) [
• Most commonly are consistent with an axonal neuropathy with normal NCVs and reduced amplitudes [
• Occasionally are consistent with either a demyelinating neuropathy with slowed NCVs (<38 m/s) [
• Most commonly are consistent with an axonal neuropathy with normal NCVs and reduced amplitudes [
• Occasionally are consistent with either a demyelinating neuropathy with slowed NCVs (<38 m/s) [
## Establishing the Diagnosis
The diagnosis of HMSN
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
When the phenotypic and laboratory findings suggest the diagnosis of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other hereditary motor and sensory neuropathies, molecular genetic testing approaches can include
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Pathogenic variants in
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other hereditary motor and sensory neuropathies, molecular genetic testing approaches can include
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Pathogenic variants in
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Clinical Characteristics
Comparison of Autosomal Recessive and Autosomal Dominant
CMT = Charcot-Marie-Tooth neuropathy; CMTRIA = Charcot-Marie-Tooth Neuropathy, recessive intermediate A; HMSN = hereditary motor and sensory neuropathy; also referred to as "Charcot-Marie-Tooth neuropathy." See
When onset of motor nerve involvement is in utero, affected newborns are hypotonic (i.e., a "floppy infant"). Onset can be in infancy, often before age two years. Affected children can show delayed achievement of motor milestones, including walking.
Initial manifestations are typically in the distal lower extremities, including the following:
Foot deformities (high arch; hammertoe;
Muscle wasting
Areflexia
Sensory loss
Most authors describe early involvement of the upper extremities with distal muscle weakness and wasting and finger contractures (claw hands).
Sensory involvement leads to decreased appreciation in distal upper and lower limbs of touch, pain, vibration, and joint position.
In the majority of persons with AR
As the neuropathy progresses the voice becomes hoarse as a result of vocal cord paresis [
Rare manifestations of AR
Spinal deformities [
Facial weakness [
Painless lower-leg ulcers [
Progression of the neuropathy leads to disability of the lower and upper extremities. At the end of the second decade, most individuals are wheelchair bound. Phrenic nerve paresis has sometimes led to restrictive respiratory function [
Although persons with AR
Intrafamilial variability in disease progression was observed in one family in which the proband was wheelchair bound by age 20 years and his sister remained ambulatory with a crutch at age 26 years [
Heterozygotes in families with AR
AD
Three Spanish families. In two families segregating the variant
Eight families (in which 3 demonstrated reduced penetrance) with four different missense variants, including three families with the variant
Onset varies from childhood to late adulthood. Difficulty with walking is the most common initial manifestation. Weakness and atrophy are usually restricted to distal muscles of the upper and lower limbs. Vocal cord paresis and thoracic scoliosis are uncommon. Disease progression is slow; affected persons generally remain ambulatory.
Possible genotype-phenotype correlations have been reported but are not common enough to be confirmed. An exception is the founder variant in eastern Europe,
The
Reduced penetrance has been reported in AD
Hereditary motor and sensory neuropathy is most commonly referred to by the eponymous name, "Charcot-Marie-Tooth (CMT) neuropathy" or "Charcot-Marie-Tooth disease."
Based on an older classification system in which subtypes were defined by clinical parameters such as mode of inheritance, clinical findings, neuropathy type (defined by electrophysiologic findings), and involved gene,
CMT4A, autosomal recessive, demyelinating HMSN
CMT2H, autosomal recessive, axonal HMSN
CMTRIA, autosomal recessive, intermediate HMSN
CMT2K, autosomal dominant, axonal HMSN
However, classification using these clinically defined parameters becomes difficult when pathogenic variants in a single gene (e.g.,
Currently, autosomal recessive
Molecular genetic testing has shown the following proportion of individuals with HMSN (also known as CMT) with
Three of 69 (4.3%) unrelated Czech individuals with autosomal recessive CMT [
Eight of 197 (5.4%) individuals in an Italian population with CMT [
Five of 174 (2.8%) families from Europe with autosomal recessive CMT screened for thirteen genes known to be associated with AR-HMSN [
1% of 1000 individuals with an inherited peripheral neuropathy in Japan [
• Foot deformities (high arch; hammertoe;
• Muscle wasting
• Areflexia
• Sensory loss
• Spinal deformities [
• Facial weakness [
• Painless lower-leg ulcers [
• Three Spanish families. In two families segregating the variant
• Eight families (in which 3 demonstrated reduced penetrance) with four different missense variants, including three families with the variant
• CMT4A, autosomal recessive, demyelinating HMSN
• CMT2H, autosomal recessive, axonal HMSN
• CMTRIA, autosomal recessive, intermediate HMSN
• CMT2K, autosomal dominant, axonal HMSN
• Three of 69 (4.3%) unrelated Czech individuals with autosomal recessive CMT [
• Eight of 197 (5.4%) individuals in an Italian population with CMT [
• Five of 174 (2.8%) families from Europe with autosomal recessive CMT screened for thirteen genes known to be associated with AR-HMSN [
• 1% of 1000 individuals with an inherited peripheral neuropathy in Japan [
## Clinical Description
Comparison of Autosomal Recessive and Autosomal Dominant
CMT = Charcot-Marie-Tooth neuropathy; CMTRIA = Charcot-Marie-Tooth Neuropathy, recessive intermediate A; HMSN = hereditary motor and sensory neuropathy; also referred to as "Charcot-Marie-Tooth neuropathy." See
When onset of motor nerve involvement is in utero, affected newborns are hypotonic (i.e., a "floppy infant"). Onset can be in infancy, often before age two years. Affected children can show delayed achievement of motor milestones, including walking.
Initial manifestations are typically in the distal lower extremities, including the following:
Foot deformities (high arch; hammertoe;
Muscle wasting
Areflexia
Sensory loss
Most authors describe early involvement of the upper extremities with distal muscle weakness and wasting and finger contractures (claw hands).
Sensory involvement leads to decreased appreciation in distal upper and lower limbs of touch, pain, vibration, and joint position.
In the majority of persons with AR
As the neuropathy progresses the voice becomes hoarse as a result of vocal cord paresis [
Rare manifestations of AR
Spinal deformities [
Facial weakness [
Painless lower-leg ulcers [
Progression of the neuropathy leads to disability of the lower and upper extremities. At the end of the second decade, most individuals are wheelchair bound. Phrenic nerve paresis has sometimes led to restrictive respiratory function [
Although persons with AR
Intrafamilial variability in disease progression was observed in one family in which the proband was wheelchair bound by age 20 years and his sister remained ambulatory with a crutch at age 26 years [
Heterozygotes in families with AR
AD
Three Spanish families. In two families segregating the variant
Eight families (in which 3 demonstrated reduced penetrance) with four different missense variants, including three families with the variant
Onset varies from childhood to late adulthood. Difficulty with walking is the most common initial manifestation. Weakness and atrophy are usually restricted to distal muscles of the upper and lower limbs. Vocal cord paresis and thoracic scoliosis are uncommon. Disease progression is slow; affected persons generally remain ambulatory.
• Foot deformities (high arch; hammertoe;
• Muscle wasting
• Areflexia
• Sensory loss
• Spinal deformities [
• Facial weakness [
• Painless lower-leg ulcers [
• Three Spanish families. In two families segregating the variant
• Eight families (in which 3 demonstrated reduced penetrance) with four different missense variants, including three families with the variant
## Autosomal Recessive (AR)
When onset of motor nerve involvement is in utero, affected newborns are hypotonic (i.e., a "floppy infant"). Onset can be in infancy, often before age two years. Affected children can show delayed achievement of motor milestones, including walking.
Initial manifestations are typically in the distal lower extremities, including the following:
Foot deformities (high arch; hammertoe;
Muscle wasting
Areflexia
Sensory loss
Most authors describe early involvement of the upper extremities with distal muscle weakness and wasting and finger contractures (claw hands).
Sensory involvement leads to decreased appreciation in distal upper and lower limbs of touch, pain, vibration, and joint position.
In the majority of persons with AR
As the neuropathy progresses the voice becomes hoarse as a result of vocal cord paresis [
Rare manifestations of AR
Spinal deformities [
Facial weakness [
Painless lower-leg ulcers [
Progression of the neuropathy leads to disability of the lower and upper extremities. At the end of the second decade, most individuals are wheelchair bound. Phrenic nerve paresis has sometimes led to restrictive respiratory function [
Although persons with AR
Intrafamilial variability in disease progression was observed in one family in which the proband was wheelchair bound by age 20 years and his sister remained ambulatory with a crutch at age 26 years [
Heterozygotes in families with AR
• Foot deformities (high arch; hammertoe;
• Muscle wasting
• Areflexia
• Sensory loss
• Spinal deformities [
• Facial weakness [
• Painless lower-leg ulcers [
## Autosomal Dominant (AD)
AD
Three Spanish families. In two families segregating the variant
Eight families (in which 3 demonstrated reduced penetrance) with four different missense variants, including three families with the variant
Onset varies from childhood to late adulthood. Difficulty with walking is the most common initial manifestation. Weakness and atrophy are usually restricted to distal muscles of the upper and lower limbs. Vocal cord paresis and thoracic scoliosis are uncommon. Disease progression is slow; affected persons generally remain ambulatory.
• Three Spanish families. In two families segregating the variant
• Eight families (in which 3 demonstrated reduced penetrance) with four different missense variants, including three families with the variant
## Genotype-Phenotype Correlations
Possible genotype-phenotype correlations have been reported but are not common enough to be confirmed. An exception is the founder variant in eastern Europe,
The
## Penetrance
Reduced penetrance has been reported in AD
## Nomenclature
Hereditary motor and sensory neuropathy is most commonly referred to by the eponymous name, "Charcot-Marie-Tooth (CMT) neuropathy" or "Charcot-Marie-Tooth disease."
Based on an older classification system in which subtypes were defined by clinical parameters such as mode of inheritance, clinical findings, neuropathy type (defined by electrophysiologic findings), and involved gene,
CMT4A, autosomal recessive, demyelinating HMSN
CMT2H, autosomal recessive, axonal HMSN
CMTRIA, autosomal recessive, intermediate HMSN
CMT2K, autosomal dominant, axonal HMSN
However, classification using these clinically defined parameters becomes difficult when pathogenic variants in a single gene (e.g.,
• CMT4A, autosomal recessive, demyelinating HMSN
• CMT2H, autosomal recessive, axonal HMSN
• CMTRIA, autosomal recessive, intermediate HMSN
• CMT2K, autosomal dominant, axonal HMSN
## Prevalence
Currently, autosomal recessive
Molecular genetic testing has shown the following proportion of individuals with HMSN (also known as CMT) with
Three of 69 (4.3%) unrelated Czech individuals with autosomal recessive CMT [
Eight of 197 (5.4%) individuals in an Italian population with CMT [
Five of 174 (2.8%) families from Europe with autosomal recessive CMT screened for thirteen genes known to be associated with AR-HMSN [
1% of 1000 individuals with an inherited peripheral neuropathy in Japan [
• Three of 69 (4.3%) unrelated Czech individuals with autosomal recessive CMT [
• Eight of 197 (5.4%) individuals in an Italian population with CMT [
• Five of 174 (2.8%) families from Europe with autosomal recessive CMT screened for thirteen genes known to be associated with AR-HMSN [
• 1% of 1000 individuals with an inherited peripheral neuropathy in Japan [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
See
Vocal cord paresis, which is often seen in autosomal recessive
While AR
## Management
To establish the extent of disease and needs in an individual diagnosed with a
Neurologic examination to determine extent of weakness and atrophy,
Physical therapy and occupational therapy assessments regarding muscle weakness and gait and need for ankle foot orthoses, walking aids, and/or a wheelchair [
Speech therapy assessment if hoarseness is present or vocal cord paresis is suspected
Consultation with a clinical geneticist and/or genetic counselor
Individuals with
Daily heel cord stretching exercises to prevent Achilles tendon shortening.
Exercise within the affected individual's capability
Note: (1) Fatigue may improve with exercise; (2) unconfirmed anecdotal observations suggest benefit from the stimulant modafinil [
Ankle/foot orthoses (AFOs) to correct foot drop and aid walking [
Orthopedic surgery to correct severe
Forearm crutches or canes for gait stability
Wheelchair for mobility because of gait instability
Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory drugs [
Treatment of neuropathic pain with tricyclic antidepressants or drugs such as carbamazepine or gabapentin [
Weight control to avoid obesity, which has a negative effect on gait and balance
Career and employment counseling because of persistent weakness of hands and/or feet
Individual psychotherapy, group therapy, and/or antidepressant medication for depression [
Treatment may require involvement of specialists to evaluate and manage potential complications, including the following:
Lower urinary tract involvement [
Obstructive sleep apnea and restless legs [
Pulmonary compromise and/or phrenic nerve involvement [
Vocal cord paresis
Hip dysplasia [
Note: No special diet (including supplements with essential fatty acids, vitamin E, or creatine) has been shown to be beneficial [
Regular evaluations to determine:
Neurologic status and need for treatment (or change in treatment) for musculoskeletal and/or neuropathic pain;
Functional disability and need for change in physical therapy regime and/or augmentative devices for activities of daily living and mobility;
Need for change in diet to control weight;
Need to involve specialists to evaluate and treat potential complications.
The following should be avoided:
Obesity because of its negative effect on gait and balance
Medications that are toxic or potentially toxic to persons with HMSN (CMT) ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from prompt initiation of treatment and knowledge about
See
Search
• Neurologic examination to determine extent of weakness and atrophy,
• Physical therapy and occupational therapy assessments regarding muscle weakness and gait and need for ankle foot orthoses, walking aids, and/or a wheelchair [
• Speech therapy assessment if hoarseness is present or vocal cord paresis is suspected
• Consultation with a clinical geneticist and/or genetic counselor
• Daily heel cord stretching exercises to prevent Achilles tendon shortening.
• Exercise within the affected individual's capability
• Note: (1) Fatigue may improve with exercise; (2) unconfirmed anecdotal observations suggest benefit from the stimulant modafinil [
• Ankle/foot orthoses (AFOs) to correct foot drop and aid walking [
• Orthopedic surgery to correct severe
• Forearm crutches or canes for gait stability
• Wheelchair for mobility because of gait instability
• Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory drugs [
• Treatment of neuropathic pain with tricyclic antidepressants or drugs such as carbamazepine or gabapentin [
• Weight control to avoid obesity, which has a negative effect on gait and balance
• Career and employment counseling because of persistent weakness of hands and/or feet
• Individual psychotherapy, group therapy, and/or antidepressant medication for depression [
• Lower urinary tract involvement [
• Obstructive sleep apnea and restless legs [
• Pulmonary compromise and/or phrenic nerve involvement [
• Vocal cord paresis
• Hip dysplasia [
• Neurologic status and need for treatment (or change in treatment) for musculoskeletal and/or neuropathic pain;
• Functional disability and need for change in physical therapy regime and/or augmentative devices for activities of daily living and mobility;
• Need for change in diet to control weight;
• Need to involve specialists to evaluate and treat potential complications.
• Obesity because of its negative effect on gait and balance
• Medications that are toxic or potentially toxic to persons with HMSN (CMT) ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a
Neurologic examination to determine extent of weakness and atrophy,
Physical therapy and occupational therapy assessments regarding muscle weakness and gait and need for ankle foot orthoses, walking aids, and/or a wheelchair [
Speech therapy assessment if hoarseness is present or vocal cord paresis is suspected
Consultation with a clinical geneticist and/or genetic counselor
• Neurologic examination to determine extent of weakness and atrophy,
• Physical therapy and occupational therapy assessments regarding muscle weakness and gait and need for ankle foot orthoses, walking aids, and/or a wheelchair [
• Speech therapy assessment if hoarseness is present or vocal cord paresis is suspected
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Individuals with
Daily heel cord stretching exercises to prevent Achilles tendon shortening.
Exercise within the affected individual's capability
Note: (1) Fatigue may improve with exercise; (2) unconfirmed anecdotal observations suggest benefit from the stimulant modafinil [
Ankle/foot orthoses (AFOs) to correct foot drop and aid walking [
Orthopedic surgery to correct severe
Forearm crutches or canes for gait stability
Wheelchair for mobility because of gait instability
Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory drugs [
Treatment of neuropathic pain with tricyclic antidepressants or drugs such as carbamazepine or gabapentin [
Weight control to avoid obesity, which has a negative effect on gait and balance
Career and employment counseling because of persistent weakness of hands and/or feet
Individual psychotherapy, group therapy, and/or antidepressant medication for depression [
Treatment may require involvement of specialists to evaluate and manage potential complications, including the following:
Lower urinary tract involvement [
Obstructive sleep apnea and restless legs [
Pulmonary compromise and/or phrenic nerve involvement [
Vocal cord paresis
Hip dysplasia [
Note: No special diet (including supplements with essential fatty acids, vitamin E, or creatine) has been shown to be beneficial [
• Daily heel cord stretching exercises to prevent Achilles tendon shortening.
• Exercise within the affected individual's capability
• Note: (1) Fatigue may improve with exercise; (2) unconfirmed anecdotal observations suggest benefit from the stimulant modafinil [
• Ankle/foot orthoses (AFOs) to correct foot drop and aid walking [
• Orthopedic surgery to correct severe
• Forearm crutches or canes for gait stability
• Wheelchair for mobility because of gait instability
• Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory drugs [
• Treatment of neuropathic pain with tricyclic antidepressants or drugs such as carbamazepine or gabapentin [
• Weight control to avoid obesity, which has a negative effect on gait and balance
• Career and employment counseling because of persistent weakness of hands and/or feet
• Individual psychotherapy, group therapy, and/or antidepressant medication for depression [
• Lower urinary tract involvement [
• Obstructive sleep apnea and restless legs [
• Pulmonary compromise and/or phrenic nerve involvement [
• Vocal cord paresis
• Hip dysplasia [
## Surveillance
Regular evaluations to determine:
Neurologic status and need for treatment (or change in treatment) for musculoskeletal and/or neuropathic pain;
Functional disability and need for change in physical therapy regime and/or augmentative devices for activities of daily living and mobility;
Need for change in diet to control weight;
Need to involve specialists to evaluate and treat potential complications.
• Neurologic status and need for treatment (or change in treatment) for musculoskeletal and/or neuropathic pain;
• Functional disability and need for change in physical therapy regime and/or augmentative devices for activities of daily living and mobility;
• Need for change in diet to control weight;
• Need to involve specialists to evaluate and treat potential complications.
## Agents/Circumstances to Avoid
The following should be avoided:
Obesity because of its negative effect on gait and balance
Medications that are toxic or potentially toxic to persons with HMSN (CMT) ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
• Obesity because of its negative effect on gait and balance
• Medications that are toxic or potentially toxic to persons with HMSN (CMT) ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from prompt initiation of treatment and knowledge about
See
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of a child with AR
Heterozygotes are typically asymptomatic (see
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not heterozygous.
The phenotype is generally consistent among family members with the same genotype; however, intrafamilial variability has been observed in one family with AR
Heterozygotes are typically asymptomatic (see
Carrier testing for at-risk relatives requires prior identification of the
Most individuals diagnosed with AD
The proportion of cases caused by a
Molecular genetic testing of the parents for the
If the
If a parent of the proband has the
If the
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of a child with AR
• Heterozygotes are typically asymptomatic (see
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not heterozygous.
• The phenotype is generally consistent among family members with the same genotype; however, intrafamilial variability has been observed in one family with AR
• Heterozygotes are typically asymptomatic (see
• Most individuals diagnosed with AD
• The proportion of cases caused by a
• Molecular genetic testing of the parents for the
• If the
• If a parent of the proband has the
• If the
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of a child with AR
Heterozygotes are typically asymptomatic (see
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not heterozygous.
The phenotype is generally consistent among family members with the same genotype; however, intrafamilial variability has been observed in one family with AR
Heterozygotes are typically asymptomatic (see
Carrier testing for at-risk relatives requires prior identification of the
• The parents of a child with AR
• Heterozygotes are typically asymptomatic (see
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not heterozygous.
• The phenotype is generally consistent among family members with the same genotype; however, intrafamilial variability has been observed in one family with AR
• Heterozygotes are typically asymptomatic (see
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Autosomal Dominant Inheritance – Risk to Family Members
Most individuals diagnosed with AD
The proportion of cases caused by a
Molecular genetic testing of the parents for the
If the
If a parent of the proband has the
If the
• Most individuals diagnosed with AD
• The proportion of cases caused by a
• Molecular genetic testing of the parents for the
• If the
• If a parent of the proband has the
• If the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
France
Department of Molecular Genetics
University of Antwerp
Antwerp Antwerpen B-2610
Belgium
Institute of Translational and Clinical Research
University of Newcastle upon Tyne
International Centre for Life
Newcastle upon Tyne NE1 3BZ
United Kingdom
France
Netherlands
•
• France
•
•
•
•
• Department of Molecular Genetics
• University of Antwerp
• Antwerp Antwerpen B-2610
• Belgium
•
•
•
•
•
•
•
• Institute of Translational and Clinical Research
• University of Newcastle upon Tyne
• International Centre for Life
• Newcastle upon Tyne NE1 3BZ
• United Kingdom
•
•
• France
•
•
• Netherlands
•
•
•
## Molecular Genetics
GDAP1-Related Hereditary Motor and Sensory Neuropathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GDAP1-Related Hereditary Motor and Sensory Neuropathy (
The following variants have been detected in specific populations:
p.Gln163Ter in a Hispanic population [
p.Leu239Phe in central and eastern European populations [
Note: A number of
The
Selected
Variants listed in the table have been provided by the author.
• p.Gln163Ter in a Hispanic population [
• p.Leu239Phe in central and eastern European populations [
## Chapter Notes
Thomas D Bird, MD (2017-present)Jeffery M Vance, MD, PhD; University of Miami (2004-2017)Stephan Züchner, MD; University of Miami (2004-2017)
27 March 2025 (ma) Chapter retired: outdated; qualified authors not available for update
30 March 2017 (bp) Comprehensive update posted live
28 February 2013 (me) Comprehensive update posted live
3 June 2010 (me) Comprehensive update posted live
23 June 2006 (ca) Comprehensive update posted live
11 May 2004 (me) Review posted live
23 February 2004 (jv,sz) Original submission
• 27 March 2025 (ma) Chapter retired: outdated; qualified authors not available for update
• 30 March 2017 (bp) Comprehensive update posted live
• 28 February 2013 (me) Comprehensive update posted live
• 3 June 2010 (me) Comprehensive update posted live
• 23 June 2006 (ca) Comprehensive update posted live
• 11 May 2004 (me) Review posted live
• 23 February 2004 (jv,sz) Original submission
## Author History
Thomas D Bird, MD (2017-present)Jeffery M Vance, MD, PhD; University of Miami (2004-2017)Stephan Züchner, MD; University of Miami (2004-2017)
## Revision History
27 March 2025 (ma) Chapter retired: outdated; qualified authors not available for update
30 March 2017 (bp) Comprehensive update posted live
28 February 2013 (me) Comprehensive update posted live
3 June 2010 (me) Comprehensive update posted live
23 June 2006 (ca) Comprehensive update posted live
11 May 2004 (me) Review posted live
23 February 2004 (jv,sz) Original submission
• 27 March 2025 (ma) Chapter retired: outdated; qualified authors not available for update
• 30 March 2017 (bp) Comprehensive update posted live
• 28 February 2013 (me) Comprehensive update posted live
• 3 June 2010 (me) Comprehensive update posted live
• 23 June 2006 (ca) Comprehensive update posted live
• 11 May 2004 (me) Review posted live
• 23 February 2004 (jv,sz) Original submission
## References
## Literature Cited
|
[] |
11/5/2004
|
30/3/2017
|
6/3/2007
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
cmt-dib
|
cmt-dib
|
[
"Dominant Intermediate Charcot-Marie-Tooth Neuropathy Type B (DI-CMTB)",
"DI-CMTB",
"Dominant Intermediate Charcot-Marie-Tooth Neuropathy Type B",
"Dynamin-2",
"DNM2",
"DNM2-Related Intermediate Charcot-Marie-Tooth Neuropathy"
] |
Stephan Züchner, Feifei Tao
|
Summary The diagnosis is suspected in individuals with typical findings of CMT hereditary neuropathy and intermediate or axonal motor median nerve conduction velocities (NCV) ranging from 26 m/s to normal. Diagnosis requires identification of a heterozygous pathogenic variant in DI-CMTB is inherited in an autosomal dominant manner. Most individuals diagnosed with DI-CMTB have an affected parent. The proportion of cases caused by a heterozygous
|
## Diagnosis
Sensory and motor deficiencies involving the lower legs
Sensory loss
Depressed tendon reflexes
Distal muscle weakness and atrophy
Asymptomatic neutropenia
Early-onset cataracts (noted before age 15 years)
The diagnosis of DI-CMTB
Molecular testing approaches can include
In a person with a CMT phenotype and very slow NCV (<30 m/s), perform molecular genetic testing of
In a person with a CMT phenotype and intermediate to normal NCV, perform molecular genetic testing of the
In a person with a CMT phenotype and NCV between 30 and 45 m/s in whom testing for the above genes has not identified a pathogenic variant, molecular genetic testing of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications.
No deletions or duplications involving
• Sensory and motor deficiencies involving the lower legs
• Sensory loss
• Depressed tendon reflexes
• Distal muscle weakness and atrophy
• Sensory loss
• Depressed tendon reflexes
• Distal muscle weakness and atrophy
• Asymptomatic neutropenia
• Early-onset cataracts (noted before age 15 years)
• Sensory loss
• Depressed tendon reflexes
• Distal muscle weakness and atrophy
• In a person with a CMT phenotype and very slow NCV (<30 m/s), perform molecular genetic testing of
• In a person with a CMT phenotype and intermediate to normal NCV, perform molecular genetic testing of the
• In a person with a CMT phenotype and NCV between 30 and 45 m/s in whom testing for the above genes has not identified a pathogenic variant, molecular genetic testing of
## Suggestive Findings
Sensory and motor deficiencies involving the lower legs
Sensory loss
Depressed tendon reflexes
Distal muscle weakness and atrophy
Asymptomatic neutropenia
Early-onset cataracts (noted before age 15 years)
• Sensory and motor deficiencies involving the lower legs
• Sensory loss
• Depressed tendon reflexes
• Distal muscle weakness and atrophy
• Sensory loss
• Depressed tendon reflexes
• Distal muscle weakness and atrophy
• Asymptomatic neutropenia
• Early-onset cataracts (noted before age 15 years)
• Sensory loss
• Depressed tendon reflexes
• Distal muscle weakness and atrophy
## Establishing the Diagnosis
The diagnosis of DI-CMTB
Molecular testing approaches can include
In a person with a CMT phenotype and very slow NCV (<30 m/s), perform molecular genetic testing of
In a person with a CMT phenotype and intermediate to normal NCV, perform molecular genetic testing of the
In a person with a CMT phenotype and NCV between 30 and 45 m/s in whom testing for the above genes has not identified a pathogenic variant, molecular genetic testing of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications.
No deletions or duplications involving
• In a person with a CMT phenotype and very slow NCV (<30 m/s), perform molecular genetic testing of
• In a person with a CMT phenotype and intermediate to normal NCV, perform molecular genetic testing of the
• In a person with a CMT phenotype and NCV between 30 and 45 m/s in whom testing for the above genes has not identified a pathogenic variant, molecular genetic testing of
## Clinical Characteristics
Age of onset varies greatly among affected individuals and ranges from age two to 50 years. Some persons require AFO braces or other walking aids. Three percent of affected individuals become wheelchair bound; one person in the
Other findings include asymptomatic neutropenia and early-onset cataracts (often noted in childhood before age 15 years).
Electrophysiologic studies indicate intermediate or axonal motor median nerve conduction velocities (NCV) ranging from 26 m/s to normal values.
Strong genotype-phenotype correlations have not been reported.
The majority of
Anticipation is not observed.
DI-CMTB is a rare cause of CMT. Up to 3.4% of CMT (in which CMT1A, 1B, and 1X have already been excluded) is caused by a
## Clinical Description
Age of onset varies greatly among affected individuals and ranges from age two to 50 years. Some persons require AFO braces or other walking aids. Three percent of affected individuals become wheelchair bound; one person in the
Other findings include asymptomatic neutropenia and early-onset cataracts (often noted in childhood before age 15 years).
Electrophysiologic studies indicate intermediate or axonal motor median nerve conduction velocities (NCV) ranging from 26 m/s to normal values.
## Genotype-Phenotype Correlations
Strong genotype-phenotype correlations have not been reported.
The majority of
## Penetrance
## Anticipation
Anticipation is not observed.
## Prevalence
DI-CMTB is a rare cause of CMT. Up to 3.4% of CMT (in which CMT1A, 1B, and 1X have already been excluded) is caused by a
## Genetically Related (Allelic) Disorders
Some individuals with CNM have clinical findings that overlap with DI-CMTB [
## Differential Diagnosis
Other forms of intermediate CMT:
DI-CMTA, linked to the 10q24-q25.1 region
DI-CMTC, caused by heterozygous pathogenic variants in
DI-CMTD, caused by heterozygous pathogenic variants in
It is usually not possible to differentiate between DI-CMTB, other intermediate forms of CMT, and most CMT2 types based on clinical findings [
See
• DI-CMTA, linked to the 10q24-q25.1 region
• DI-CMTC, caused by heterozygous pathogenic variants in
• DI-CMTD, caused by heterozygous pathogenic variants in
## Management
To establish the extent of disease and needs in an individual diagnosed with
Neurologic examination
Electrophysiologic studies to establish a baseline for further monitoring of disease progression
Complete blood count (CBC) with absolute neutrophil count (ANC) to evaluate for neutropenia
Ophthalmologic examination for cataract
Consultation with a clinical geneticist and/or genetic counselor
Treatment of DI-CMTB is symptomatic and involves evaluation and management by a multidisciplinary team that includes neurologists, orthopedic surgeons, and physical and occupational therapists. Due to the great phenotypic variability, disease treatment should be tailored to the individual's needs.
Treatment may include:
Ankle/foot orthoses
Orthopedic surgery
Forearm crutches or canes; rarely, wheelchairs
Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory agents (NSAIDs)
Career and employment counseling
The most common secondary complications include foot contractures and acquired foot deformities, difficulty walking, and, in severe cases, inability to ambulate. Physical therapies such as stretching and exercise are recommended to prevent these secondary complications.
Surveillance includes regular evaluation by the multidisciplinary team to determine neurologic status and functional disability.
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
See
Although no systemic studies have been done concerning pregnancy in women with DI-CMTB, there are reports of an increased occurrence of abnormal fetal presentation and maternal postpartum bleeding in women with CMT in general [
Search
• Neurologic examination
• Electrophysiologic studies to establish a baseline for further monitoring of disease progression
• Complete blood count (CBC) with absolute neutrophil count (ANC) to evaluate for neutropenia
• Ophthalmologic examination for cataract
• Consultation with a clinical geneticist and/or genetic counselor
• Ankle/foot orthoses
• Orthopedic surgery
• Forearm crutches or canes; rarely, wheelchairs
• Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory agents (NSAIDs)
• Career and employment counseling
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Neurologic examination
Electrophysiologic studies to establish a baseline for further monitoring of disease progression
Complete blood count (CBC) with absolute neutrophil count (ANC) to evaluate for neutropenia
Ophthalmologic examination for cataract
Consultation with a clinical geneticist and/or genetic counselor
• Neurologic examination
• Electrophysiologic studies to establish a baseline for further monitoring of disease progression
• Complete blood count (CBC) with absolute neutrophil count (ANC) to evaluate for neutropenia
• Ophthalmologic examination for cataract
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Treatment of DI-CMTB is symptomatic and involves evaluation and management by a multidisciplinary team that includes neurologists, orthopedic surgeons, and physical and occupational therapists. Due to the great phenotypic variability, disease treatment should be tailored to the individual's needs.
Treatment may include:
Ankle/foot orthoses
Orthopedic surgery
Forearm crutches or canes; rarely, wheelchairs
Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory agents (NSAIDs)
Career and employment counseling
• Ankle/foot orthoses
• Orthopedic surgery
• Forearm crutches or canes; rarely, wheelchairs
• Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory agents (NSAIDs)
• Career and employment counseling
## Prevention of Secondary Complications
The most common secondary complications include foot contractures and acquired foot deformities, difficulty walking, and, in severe cases, inability to ambulate. Physical therapies such as stretching and exercise are recommended to prevent these secondary complications.
## Surveillance
Surveillance includes regular evaluation by the multidisciplinary team to determine neurologic status and functional disability.
## Agents/Circumstances to Avoid
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Although no systemic studies have been done concerning pregnancy in women with DI-CMTB, there are reports of an increased occurrence of abnormal fetal presentation and maternal postpartum bleeding in women with CMT in general [
## Therapies Under Investigation
Search
## Genetic Counseling
Most individuals diagnosed with DI-CMTB have an affected parent.
A proband with DI-CMTB may have the disorder as the result of
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or
Recommendations for the evaluation of parents of a proband with an apparent
Note: (1) Although most individuals diagnosed with DI-CMTB have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the pathogenic variant first occurred s/he may have somatic mosaicism for the variant and may be mildly/minimally affected.
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
If a parent of the proband is affected and/or has a pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
The sibs of a proband with clinically unaffected parents are still at increased risk for DI-CMTB because of the possibility of reduced penetrance in a parent.
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism.
The risk to other family members depends on the status of the proband's parents.
If a parent is affected and/or has a pathogenic variant, his or her family members may be at risk.
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
• Most individuals diagnosed with DI-CMTB have an affected parent.
• A proband with DI-CMTB may have the disorder as the result of
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or
• Recommendations for the evaluation of parents of a proband with an apparent
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected and/or has a pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• The sibs of a proband with clinically unaffected parents are still at increased risk for DI-CMTB because of the possibility of reduced penetrance in a parent.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism.
• The risk to other family members depends on the status of the proband's parents.
• If a parent is affected and/or has a pathogenic variant, his or her family members may be at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.
## Mode of Inheritance
## Risk to Family Members
Most individuals diagnosed with DI-CMTB have an affected parent.
A proband with DI-CMTB may have the disorder as the result of
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or
Recommendations for the evaluation of parents of a proband with an apparent
Note: (1) Although most individuals diagnosed with DI-CMTB have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the pathogenic variant first occurred s/he may have somatic mosaicism for the variant and may be mildly/minimally affected.
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
If a parent of the proband is affected and/or has a pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
The sibs of a proband with clinically unaffected parents are still at increased risk for DI-CMTB because of the possibility of reduced penetrance in a parent.
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism.
The risk to other family members depends on the status of the proband's parents.
If a parent is affected and/or has a pathogenic variant, his or her family members may be at risk.
• Most individuals diagnosed with DI-CMTB have an affected parent.
• A proband with DI-CMTB may have the disorder as the result of
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or
• Recommendations for the evaluation of parents of a proband with an apparent
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected and/or has a pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• The sibs of a proband with clinically unaffected parents are still at increased risk for DI-CMTB because of the possibility of reduced penetrance in a parent.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism.
• The risk to other family members depends on the status of the proband's parents.
• If a parent is affected and/or has a pathogenic variant, his or her family members may be at risk.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
## Resources
France
PO Box 105
Glenolden PA 19036
Department of Molecular Genetics
University of Antwerp
Antwerp Antwerpen B-2610
Belgium
432 Park Avenue South
4th Floor
New York NY 10016
Institute of Genetic Medicine
University of Newcastle upon Tyne
International Centre for Life
Newcastle upon Tyne NE1 3BZ
United Kingdom
1 Rue de l'International
BP59
Evry cedex 91002
France
Lt Gen van Heutszlaan 6
3743 JN Baarn
Netherlands
222 South Riverside Plaza
Suite 1500
Chicago IL 60606
61A Great Suffolk Street
London SE1 0BU
United Kingdom
•
• France
•
•
• PO Box 105
• Glenolden PA 19036
•
•
• Department of Molecular Genetics
• University of Antwerp
• Antwerp Antwerpen B-2610
• Belgium
•
• 432 Park Avenue South
• 4th Floor
• New York NY 10016
•
•
•
•
•
•
•
•
• Institute of Genetic Medicine
• University of Newcastle upon Tyne
• International Centre for Life
• Newcastle upon Tyne NE1 3BZ
• United Kingdom
•
•
• 1 Rue de l'International
• BP59
• Evry cedex 91002
• France
•
•
• Lt Gen van Heutszlaan 6
• 3743 JN Baarn
• Netherlands
•
•
• 222 South Riverside Plaza
• Suite 1500
• Chicago IL 60606
•
•
• 61A Great Suffolk Street
• London SE1 0BU
• United Kingdom
•
•
•
## Molecular Genetics
DNM2-Related Intermediate Charcot-Marie-Tooth Neuropathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for DNM2-Related Intermediate Charcot-Marie-Tooth Neuropathy (
## References
## Literature Cited
## Chapter Notes
19 September 2019 (ma) Chapter retired: Covered in
25 June 2015 (me) Comprehensive update posted live
8 July 2010 (me) Review posted live
26 March 2010 (sz) Original submission
• 19 September 2019 (ma) Chapter retired: Covered in
• 25 June 2015 (me) Comprehensive update posted live
• 8 July 2010 (me) Review posted live
• 26 March 2010 (sz) Original submission
## Revision History
19 September 2019 (ma) Chapter retired: Covered in
25 June 2015 (me) Comprehensive update posted live
8 July 2010 (me) Review posted live
26 March 2010 (sz) Original submission
• 19 September 2019 (ma) Chapter retired: Covered in
• 25 June 2015 (me) Comprehensive update posted live
• 8 July 2010 (me) Review posted live
• 26 March 2010 (sz) Original submission
|
[
"Z Argov, M de Visser. What we do not know about pregnancy in hereditary neuromuscular disorders.. Neuromuscul Disord. 2009;19:675-9",
"M Bitoun, T Stojkovic, B Prudhon, CA Maurage, P Latour, P Vermersch, P Guicheney. A novel mutation in the dynamin 2 gene in a Charcot-Marie-Tooth type 2 patient: clinical and pathological findings.. Neuromuscul Disord 2008;18:334-8",
"M Bitoun, S Maugenre, PY Jeannet, E Lacene, X Ferrer, P Laforet, JJ Martin, J Laporte, H Lochmuller, AH Beggs, M Fardeau, B Eymard, NB Romero, P Guicheney. Mutations in Dynamin 2 cause dominant centronuclear myopathy.. Nat Genet 2005;37:1207-9",
"KG Claeys, S Züchner, M Kennerson, J Berciano, A Garcia, K Verhoeven, E Storey, JR Merory, HM Bienfait, M Lammens, E Nelis, J Baets, E De Vriendt, ZN Berneman, I De Veuster, JM Vance, G Nicholson, V Timmerman, P De Jonghe. Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy.. Brain 2009;132:1741-52",
"CJ Davis, WG Bradley, R Madrid. The peroneal muscular atrophy syndrome: clinical, genetic, electrophysiological and nerve biopsy studies. I. Clinical, genetic and electrophysiological findings and classification.. J Genet Hum 1978;26:311-49",
"GM Fabrizi, M Ferrarini, T Cavallaro, I Cabrini, R Cerini, L Bertolasi, N Rizzuto. Two novel mutations in dynamin-2 cause axonal Charcot-Marie-Tooth disease.. Neurology 2007;69:291-5",
"D Fischer, M Herasse, M Bitoun, HM Barragán-Campos, J Chiras, P Laforêt, M Fardeau, B Eymard, P Guicheney, NB Romero. Characterization of the muscle involvement in dynamin 2-related centronuclear myopathy.. Brain 2006;129:1463-9",
"J Haberlová, R Mazanec, P Ridzoň, L Baránková, G Nürnberg, P Nürnberg, H Sticht, K Huehne, P Seeman, B Rautenstrauss. Phenotypic variability in a large Czech family with a dynamin 2-associated Charcot-Marie-Tooth neuropathy.. J Neurogenet. 2011;25:182-8",
"JM Hoff, NE Gilhus, AK Daltveit. Pregnancies and deliveries in patients with Charcot-Marie-Tooth disease.. Neurology. 2005;64:459-62",
"H Jungbluth, T Cullup, S Lillis, H Zhou, S Abbs, C Sewry, F Muntoni. Centronuclear myopathy with cataracts due to a novel dynamin 2 (DNM2) mutation.. Neuromuscul Disord 2010;20:49-52",
"ML Kennerson, D Zhu, RJ Gardner, E Storey, J Merory, SP Robertson, GA Nicholson. Dominant intermediate Charcot-Marie-Tooth neuropathy maps to chromosome 19p12-p13.2.. Am J Hum Genet 2001;69:883-8",
"A Melberg, C Kretz, H Kalimo, C Wallgren-Pettersson, A Toussaint, J Böhm, E Stålberg, J Laporte. Adult course in dynamin 2 dominant centronuclear myopathy with neonatal onset.. Neuromuscul Disord 2010;20:53-6",
"G Nicholson, S Myers. Intermediate forms of Charcot-Marie Tooth neuropathy: a review.. Neuromolecular Med 2006;8:123-30",
"RD Susman, S Quijano-Roy, N Yang, R Webster, NF Clarke, J Dowling, M Kennerson, G Nicholson, V Biancalana, B Ilkovski, KM Flanigan, S Arbuckle, C Malladi, P Robinson, S Vucic, M Mayer, NB Romero, JA Urtizberea, F García-Bragado, P Guicheney, M Bitoun, RY Carlier, KN North. Expanding the clinical, pathological and MRI phenotype of DNM2-related centronuclear myopathy.. Neuromuscul Disord 2010;20:229-37",
"S Züchner, M Noureddine, M Kennerson, K Verhoeven, K Claeys, P De Jonghe, J Merory, SA Oliveira, MC Speer, JE Stenger, G Walizada, D Zhu, MA Pericak-Vance, G Nicholson, V Timmerman, JM Vance. Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease.. Nat Genet 2005;37:289-94"
] |
8/7/2010
|
25/6/2015
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
cmt
|
cmt
|
[
"Distal Hereditary Motor Neuropathy (dHMN)",
"Hereditary Motor/Sensory Neuropathy (HMSN)",
"CMT",
"Distal Hereditary Motor Neuropathy (dHMN)",
"Hereditary Motor/Sensory Neuropathy (HMSN)",
"Charcot-Marie-Tooth Neuropathy Type 1",
"Charcot-Marie-Tooth Neuropathy Type 4",
"Charcot-Marie-Tooth Neuropathy Type 2",
"Charcot-Marie-Tooth Neuropathy X",
"[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 3, mitochondrial",
"Alanine--tRNA ligase, cytoplasmic",
"Apoptosis-inducing factor 1, mitochondrial",
"Bifunctional polynucleotide phosphatase/kinase",
"Cytoplasmic dynein 1 heavy chain 1",
"DNA-binding protein SMUBP-2",
"DnaJ homolog subfamily B member 2",
"Dynamin-2",
"E3 SUMO-protein ligase EGR2",
"E3 ubiquitin-protein ligase LRSAM1",
"FYVE, RhoGEF and PH domain-containing protein 4",
"Ganglioside-induced differentiation-associated protein 1",
"Gap junction beta-1 protein",
"Glycine--tRNA ligase",
"Guanine nucleotide-binding protein subunit beta-4",
"Heat shock protein beta-1",
"Heat shock protein beta-8",
"Kinesin-like protein KIF1B",
"Lipopolysaccharide-induced tumor necrosis factor-alpha factor",
"Methionine--tRNA ligase, cytoplasmic",
"Mitofusin-2",
"Myelin P2 protein",
"Myelin protein P0",
"Myotubularin-related protein 13",
"Neurofilament light polypeptide",
"Periaxin",
"Peripheral myelin protein 22",
"Phosphatidylinositol-3,5-bisphosphate 3-phosphatase MTMR2",
"Polyphosphoinositide phosphatase",
"Prelamin-A/C",
"Protein NDRG1",
"Ras-related protein Rab-7a",
"Ribose-phosphate pyrophosphokinase 1",
"SH3 domain and tetratricopeptide repeat-containing protein 2",
"Transient receptor potential cation channel subfamily V member 4",
"Tyrosine--tRNA ligase, cytoplasmic",
"AARS1",
"AIFM1",
"DNAJB2",
"DNM2",
"DYNC1H1",
"EGR2",
"FGD4",
"FIG4",
"GARS1",
"GDAP1",
"GJB1",
"GNB4",
"HSPB1",
"HSPB8",
"IGHMBP2",
"KIF1B",
"LITAF",
"LMNA",
"LRSAM1",
"MARS1",
"MFN2",
"MPZ",
"MTMR2",
"NDRG1",
"NEFL",
"PDK3",
"PMP2",
"PMP22",
"PNKP",
"PRPS1",
"PRX",
"RAB7A",
"SBF2",
"SH3TC2",
"TRPV4",
"YARS1",
"Charcot-Marie-Tooth Hereditary Neuropathy",
"Overview"
] |
Charcot-Marie-Tooth Hereditary Neuropathy Overview
|
Thomas D Bird
|
Summary The purpose of this overview is to: Describe the Review the Provide an Review Inform
|
## Clinical Characteristics of Charcot-Marie-Tooth (CMT) Hereditary Neuropathy
Charcot-Marie-Tooth (CMT) hereditary neuropathy refers to a group of disorders characterized by a chronic motor and sensory polyneuropathy, also known as hereditary motor and sensory neuropathy (HMSN).
Individuals with CMT manifest symmetric, slowly progressive distal motor neuropathy of the arms and legs usually beginning in the first to third decade and resulting in weakness and atrophy of the muscles in the feet and/or hands. The affected individual typically has distal muscle weakness and atrophy, weak ankle dorsiflexion, depressed tendon reflexes, and
Muscle weakness is often associated with mild to moderate distal sensory loss. Although usually described as "painless," the neuropathy can be painful [
Sensorineural hearing loss can occur.
The clinical diagnosis of CMT in a symptomatic person is based on characteristic findings of peripheral neuropathy on medical history and physical examination.
In general the three autosomal dominant neuropathy types based on NCV (normal >40-45 meters/second) were the following [
CMT – the subject of this overview – needs to be distinguished from the following entities: systemic disorders with neuropathy, other types of hereditary neuropathy (
Blindness, seizures, dementia, and intellectual disability are not part of the CMT hereditary neuropathy phenotype discussed in this overview and suggest a different diagnosis, including childhood-onset disorders with significant CNS involvement such as
Other Hereditary Neuropathies
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; mt = mitochondrial; XL = X-linked
Genes are listed in alphabetic order.
Some genetic myopathies that present with weakness in the distal lower and/or upper limbs can be confused with CMT (
Distal Myopathies
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Genes are listed in alphabetic order.
Hereditary sensory neuropathy (HSN) and hereditary sensory and autonomic neuropathy (HSAN) can produce mild, moderate, or severe sensory loss without muscle weakness or atrophy.
Hereditary Sensory Neuropathy (HSN) and Hereditary Sensory and Autonomic Neuropathy (HSAN)
HSAN = hereditary sensory and autonomic neuropathy; HSN = hereditary sensory neuropathy
Genes are listed in alphabetic order.
Acquired (non-genetic) neuropathies include alcoholism, vitamin B
## Clinical Findings
Individuals with CMT manifest symmetric, slowly progressive distal motor neuropathy of the arms and legs usually beginning in the first to third decade and resulting in weakness and atrophy of the muscles in the feet and/or hands. The affected individual typically has distal muscle weakness and atrophy, weak ankle dorsiflexion, depressed tendon reflexes, and
Muscle weakness is often associated with mild to moderate distal sensory loss. Although usually described as "painless," the neuropathy can be painful [
Sensorineural hearing loss can occur.
The clinical diagnosis of CMT in a symptomatic person is based on characteristic findings of peripheral neuropathy on medical history and physical examination.
## Classification of CMT Type
In general the three autosomal dominant neuropathy types based on NCV (normal >40-45 meters/second) were the following [
## Nomenclature
## Differential Diagnosis of CMT
CMT – the subject of this overview – needs to be distinguished from the following entities: systemic disorders with neuropathy, other types of hereditary neuropathy (
Blindness, seizures, dementia, and intellectual disability are not part of the CMT hereditary neuropathy phenotype discussed in this overview and suggest a different diagnosis, including childhood-onset disorders with significant CNS involvement such as
Other Hereditary Neuropathies
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; mt = mitochondrial; XL = X-linked
Genes are listed in alphabetic order.
Some genetic myopathies that present with weakness in the distal lower and/or upper limbs can be confused with CMT (
Distal Myopathies
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Genes are listed in alphabetic order.
Hereditary sensory neuropathy (HSN) and hereditary sensory and autonomic neuropathy (HSAN) can produce mild, moderate, or severe sensory loss without muscle weakness or atrophy.
Hereditary Sensory Neuropathy (HSN) and Hereditary Sensory and Autonomic Neuropathy (HSAN)
HSAN = hereditary sensory and autonomic neuropathy; HSN = hereditary sensory neuropathy
Genes are listed in alphabetic order.
Acquired (non-genetic) neuropathies include alcoholism, vitamin B
## Systemic Disorders with Neuropathy
Blindness, seizures, dementia, and intellectual disability are not part of the CMT hereditary neuropathy phenotype discussed in this overview and suggest a different diagnosis, including childhood-onset disorders with significant CNS involvement such as
## Other Hereditary Neuropathies
Other Hereditary Neuropathies
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; mt = mitochondrial; XL = X-linked
Genes are listed in alphabetic order.
## Distal Myopathies
Some genetic myopathies that present with weakness in the distal lower and/or upper limbs can be confused with CMT (
Distal Myopathies
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Genes are listed in alphabetic order.
## Hereditary Sensory Neuropathy and Hereditary Sensory and Autonomic Neuropathy
Hereditary sensory neuropathy (HSN) and hereditary sensory and autonomic neuropathy (HSAN) can produce mild, moderate, or severe sensory loss without muscle weakness or atrophy.
Hereditary Sensory Neuropathy (HSN) and Hereditary Sensory and Autonomic Neuropathy (HSAN)
HSAN = hereditary sensory and autonomic neuropathy; HSN = hereditary sensory neuropathy
Genes are listed in alphabetic order.
## Acquired Neuropathies
Acquired (non-genetic) neuropathies include alcoholism, vitamin B
## Causes of Charcot-Marie-Tooth (CMT) Hereditary Neuropathy
More than 80 different genes are associated with CMT [
CMT: Genes, Mode of Inheritance, Neuropathy Phenotype
AD = autosomal dominant; ALS = amyotrophic lateral sclerosis; AR = autosomal recessive; Ax = axonal; De = demyelinating; dHMN = distal hereditary motor neuropathy; DI-CMT = dominant intermediate CMT; DSMA = distal spinal muscular atrophy; HSAN = hereditary sensory and autonomic neuropathy; In = intermediate; UMN = upper motor neuron; XL = X-linked
Genes are listed in alphabetic order.
Designations used in other classification systems
Based on
Can be the first manifestation of CMT. Typically presents as hoarse voice and stridor associated with use of accessory inspiratory muscles [
A 78-kb interchromosomal insertion into the CMTX3 locus at Xq26.3-q27.3 requiring a custom-targeted assay [
## Evaluation Strategies to Identify the Genetic Cause of Charcot-Marie-Tooth (CMT) Hereditary Neuropathy in a Proband
Establishing a specific genetic cause of CMT hereditary neuropathy can aid in discussions of prognosis (which are beyond the scope of this
Establishing the specific cause of CMT hereditary neuropathy for a given individual involves obtaining a medical history and performing a physical examination to exclude
A three-generation family history with attention to other relatives with neurologic signs and symptoms should be obtained. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or review of their medical records, including the results of molecular genetic testing and EMG and NCV studies.
Individuals with CMT may have a negative family history for many reasons, including mild subclinical expression in other family members, autosomal recessive inheritance, or a
Health care providers ordering genetic testing should be familiar with the genetics of CMT. Given the complexity of interpreting genetic test results and their implications for genetic counseling, health care providers should consider referral to a neurogenetics center or a genetic counselor specializing in neurogenetics (see
Molecular genetic testing approaches can include gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not.
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
AD = autosomal dominant; AR = autosomal recessive; Ax = axonal; De = demyelinating; In = intermediate; MOI = mode of inheritance; NCV = nerve conduction velocity
## Family History
A three-generation family history with attention to other relatives with neurologic signs and symptoms should be obtained. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or review of their medical records, including the results of molecular genetic testing and EMG and NCV studies.
Individuals with CMT may have a negative family history for many reasons, including mild subclinical expression in other family members, autosomal recessive inheritance, or a
## Molecular Genetic Testing
Health care providers ordering genetic testing should be familiar with the genetics of CMT. Given the complexity of interpreting genetic test results and their implications for genetic counseling, health care providers should consider referral to a neurogenetics center or a genetic counselor specializing in neurogenetics (see
Molecular genetic testing approaches can include gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not.
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
AD = autosomal dominant; AR = autosomal recessive; Ax = axonal; De = demyelinating; In = intermediate; MOI = mode of inheritance; NCV = nerve conduction velocity
## Step 1
## Step 2
For an introduction to multigene panels click
## Step 3
For an introduction to comprehensive genomic testing click
AD = autosomal dominant; AR = autosomal recessive; Ax = axonal; De = demyelinating; In = intermediate; MOI = mode of inheritance; NCV = nerve conduction velocity
## Management of Charcot-Marie-Tooth (CMT) Hereditary Neuropathy
Reviews of treatment approaches to CMT [
Treatment is symptomatic. Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [
Quality of life and defining disability have been measured and compared among various groups of individuals with CMT [
Special shoes, including those with good ankle support, may be needed. Affected individuals often require ankle/foot orthoses (AFOs) to correct foot drop and aid walking. Night splints have not improved ankle range of motion [
Some individuals require forearm crutches or canes for gait stability; fewer than 5% of individuals need wheelchairs.
Daily heel cord stretching exercises to prevent Achilles tendon shortening are desirable, as well as gripping exercises for hand weakness [
Exercise is encouraged within the individual's capability and many individuals remain physically active [
Orthopedic surgery may be required to correct severe
The cause of any pain should be identified as accurately as possible [
Musculoskeletal pain may respond to acetaminophen or nonsteroidal anti-inflammatory agents [
Neuropathic pain may respond to tricyclic antidepressants or drugs such as carbamazepine or gabapentin.
Modafinil has been used to treat fatigue [
Those at increased risk for vocal cord paralysis (see
In a study of five individuals with CMT-associated sensorineural hearing loss and auditory neuropathy spectrum disorder,
Obesity is to be avoided because it makes walking more difficult.
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
Chemotherapy for cancer that includes vincristine may be especially damaging to peripheral nerves and severely worsen CMT [
CMT appears to be an independent risk factor for maternal complications during pregnancy and delivery [
In 9.3% of pregnancies, new manifestations of CMT can appear and existing manifestations (including reduced strength and sensitivity, cramps, and pain) can worsen, and may persist following pregnancy;
Placenta previa (1.6%) abnormal nonvertex presentation (8.4%), and preterm delivery (20.3%) occurred more frequently in the pregnancies of mothers with CMT.
• Musculoskeletal pain may respond to acetaminophen or nonsteroidal anti-inflammatory agents [
• Neuropathic pain may respond to tricyclic antidepressants or drugs such as carbamazepine or gabapentin.
• In 9.3% of pregnancies, new manifestations of CMT can appear and existing manifestations (including reduced strength and sensitivity, cramps, and pain) can worsen, and may persist following pregnancy;
• Placenta previa (1.6%) abnormal nonvertex presentation (8.4%), and preterm delivery (20.3%) occurred more frequently in the pregnancies of mothers with CMT.
## Treatment of Manifestations
Reviews of treatment approaches to CMT [
Treatment is symptomatic. Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [
Quality of life and defining disability have been measured and compared among various groups of individuals with CMT [
Special shoes, including those with good ankle support, may be needed. Affected individuals often require ankle/foot orthoses (AFOs) to correct foot drop and aid walking. Night splints have not improved ankle range of motion [
Some individuals require forearm crutches or canes for gait stability; fewer than 5% of individuals need wheelchairs.
Daily heel cord stretching exercises to prevent Achilles tendon shortening are desirable, as well as gripping exercises for hand weakness [
Exercise is encouraged within the individual's capability and many individuals remain physically active [
Orthopedic surgery may be required to correct severe
The cause of any pain should be identified as accurately as possible [
Musculoskeletal pain may respond to acetaminophen or nonsteroidal anti-inflammatory agents [
Neuropathic pain may respond to tricyclic antidepressants or drugs such as carbamazepine or gabapentin.
Modafinil has been used to treat fatigue [
Those at increased risk for vocal cord paralysis (see
In a study of five individuals with CMT-associated sensorineural hearing loss and auditory neuropathy spectrum disorder,
• Musculoskeletal pain may respond to acetaminophen or nonsteroidal anti-inflammatory agents [
• Neuropathic pain may respond to tricyclic antidepressants or drugs such as carbamazepine or gabapentin.
## Agents/Circumstances to Avoid
Obesity is to be avoided because it makes walking more difficult.
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
Chemotherapy for cancer that includes vincristine may be especially damaging to peripheral nerves and severely worsen CMT [
## Pregnancy Management
CMT appears to be an independent risk factor for maternal complications during pregnancy and delivery [
In 9.3% of pregnancies, new manifestations of CMT can appear and existing manifestations (including reduced strength and sensitivity, cramps, and pain) can worsen, and may persist following pregnancy;
Placenta previa (1.6%) abnormal nonvertex presentation (8.4%), and preterm delivery (20.3%) occurred more frequently in the pregnancies of mothers with CMT.
• In 9.3% of pregnancies, new manifestations of CMT can appear and existing manifestations (including reduced strength and sensitivity, cramps, and pain) can worsen, and may persist following pregnancy;
• Placenta previa (1.6%) abnormal nonvertex presentation (8.4%), and preterm delivery (20.3%) occurred more frequently in the pregnancies of mothers with CMT.
## Genetic Counseling of Family Members of an Individual with Charcot-Marie-Tooth (CMT) Hereditary Neuropathy
CMT hereditary neuropathy can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.
Genetic counseling regarding risk to family members depends on accurate diagnosis, determination of the mode of inheritance in each family, and results of molecular genetic testing. Given the complexity of the genetics of CMT, health care providers should consider referring at-risk relatives to a neurogenetics center or genetic counselor specializing in neurogenetics (see
Most individuals diagnosed with autosomal dominant CMT have an affected parent.
Some individuals diagnosed with autosomal dominant CMT have the disorder as the result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
The family history of some individuals diagnosed with autosomal dominant CMT may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known CMT-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism.
If the parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for CMT because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
The parents of an individual diagnosed with autosomal recessive CMT are obligate heterozygotes (i.e., carriers of one pathogenic variant).
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
The father of an affected male will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
If a male is the only affected family member (i.e., represents a simplex case), the mother may be a heterozygote or the affected male may have a
A female proband may have inherited the pathogenic variant from either her mother or her father, or the pathogenic variant may be
Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may or may not be affected.
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the recurrence risk to sibs is low but greater than that of the general population because of the theoretic possibility of germline mosaicism.
If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (carriers) and may or may not be affected.
If the father of the proband has a pathogenic variant, he will transmit it to all of his daughters and none of his sons.
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low but greater than that of the general population because of the theoretic possibility of germline mosaicism.
Affected males transmit the pathogenic variant to all of their daughters and none of their sons.
Heterozygous females have a 50% chance of transmitting the pathogenic variant to each child; sons who inherit the pathogenic variant will be affected; daughters may or may not be affected.
Note: Molecular genetic testing may be able to identify the family member in whom a
Predictive testing for at-risk relatives is possible once the CMT-related pathogenic variant has been identified in an affected family member.
Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
In a family with an established diagnosis of CMT it is appropriate to consider testing of symptomatic individuals regardless of age.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the CMT-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals diagnosed with autosomal dominant CMT have an affected parent.
• Some individuals diagnosed with autosomal dominant CMT have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• The family history of some individuals diagnosed with autosomal dominant CMT may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known CMT-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism.
• If the parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for CMT because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
• The parents of an individual diagnosed with autosomal recessive CMT are obligate heterozygotes (i.e., carriers of one pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The father of an affected male will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., represents a simplex case), the mother may be a heterozygote or the affected male may have a
• A female proband may have inherited the pathogenic variant from either her mother or her father, or the pathogenic variant may be
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
• If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may or may not be affected.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the recurrence risk to sibs is low but greater than that of the general population because of the theoretic possibility of germline mosaicism.
• If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (carriers) and may or may not be affected.
• If the father of the proband has a pathogenic variant, he will transmit it to all of his daughters and none of his sons.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low but greater than that of the general population because of the theoretic possibility of germline mosaicism.
• Affected males transmit the pathogenic variant to all of their daughters and none of their sons.
• Heterozygous females have a 50% chance of transmitting the pathogenic variant to each child; sons who inherit the pathogenic variant will be affected; daughters may or may not be affected.
• Predictive testing for at-risk relatives is possible once the CMT-related pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
CMT hereditary neuropathy can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.
Genetic counseling regarding risk to family members depends on accurate diagnosis, determination of the mode of inheritance in each family, and results of molecular genetic testing. Given the complexity of the genetics of CMT, health care providers should consider referring at-risk relatives to a neurogenetics center or genetic counselor specializing in neurogenetics (see
## Autosomal Dominant Inheritance – Risk to Family Members
Most individuals diagnosed with autosomal dominant CMT have an affected parent.
Some individuals diagnosed with autosomal dominant CMT have the disorder as the result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
The family history of some individuals diagnosed with autosomal dominant CMT may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known CMT-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism.
If the parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for CMT because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
• Most individuals diagnosed with autosomal dominant CMT have an affected parent.
• Some individuals diagnosed with autosomal dominant CMT have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• The family history of some individuals diagnosed with autosomal dominant CMT may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known CMT-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism.
• If the parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for CMT because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an individual diagnosed with autosomal recessive CMT are obligate heterozygotes (i.e., carriers of one pathogenic variant).
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an individual diagnosed with autosomal recessive CMT are obligate heterozygotes (i.e., carriers of one pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## X-Linked Inheritance – Risk to Family Members
The father of an affected male will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
If a male is the only affected family member (i.e., represents a simplex case), the mother may be a heterozygote or the affected male may have a
A female proband may have inherited the pathogenic variant from either her mother or her father, or the pathogenic variant may be
Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may or may not be affected.
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the recurrence risk to sibs is low but greater than that of the general population because of the theoretic possibility of germline mosaicism.
If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (carriers) and may or may not be affected.
If the father of the proband has a pathogenic variant, he will transmit it to all of his daughters and none of his sons.
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low but greater than that of the general population because of the theoretic possibility of germline mosaicism.
Affected males transmit the pathogenic variant to all of their daughters and none of their sons.
Heterozygous females have a 50% chance of transmitting the pathogenic variant to each child; sons who inherit the pathogenic variant will be affected; daughters may or may not be affected.
Note: Molecular genetic testing may be able to identify the family member in whom a
• The father of an affected male will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., represents a simplex case), the mother may be a heterozygote or the affected male may have a
• A female proband may have inherited the pathogenic variant from either her mother or her father, or the pathogenic variant may be
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
• If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may or may not be affected.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the recurrence risk to sibs is low but greater than that of the general population because of the theoretic possibility of germline mosaicism.
• If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (carriers) and may or may not be affected.
• If the father of the proband has a pathogenic variant, he will transmit it to all of his daughters and none of his sons.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low but greater than that of the general population because of the theoretic possibility of germline mosaicism.
• Affected males transmit the pathogenic variant to all of their daughters and none of their sons.
• Heterozygous females have a 50% chance of transmitting the pathogenic variant to each child; sons who inherit the pathogenic variant will be affected; daughters may or may not be affected.
## Related Genetic Counseling Issues
Predictive testing for at-risk relatives is possible once the CMT-related pathogenic variant has been identified in an affected family member.
Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
In a family with an established diagnosis of CMT it is appropriate to consider testing of symptomatic individuals regardless of age.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Predictive testing for at-risk relatives is possible once the CMT-related pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the CMT-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
France
Department of Molecular Genetics
University of Antwerp
Antwerp Antwerpen B-2610
Belgium
Institute of Translational and Clinical Research
University of Newcastle upon Tyne
International Centre for Life
Newcastle upon Tyne NE1 3BZ
United Kingdom
France
United Kingdom
•
• France
•
•
•
•
• Department of Molecular Genetics
• University of Antwerp
• Antwerp Antwerpen B-2610
• Belgium
•
•
•
•
•
•
•
• Institute of Translational and Clinical Research
• University of Newcastle upon Tyne
• International Centre for Life
• Newcastle upon Tyne NE1 3BZ
• United Kingdom
•
•
• France
•
•
•
•
•
•
•
•
• United Kingdom
•
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•
## Chapter Notes
23 January 2025 (tb) Revision:
11 July 2024 (tb) Revision:
25 April 2024 (tb) Revision:
14 March 2024 (tb) Revision: information regarding cochlear implants added to
23 February 2023 (tb) Revision:
29 September 2022 (tb) Revision:
24 February 2022 (tb) Revision: added
9 September 2021 (tb) Revision: added comment on
20 May 2021 (tb) Revision:
18 March 2021 (tb) Revision:
4 March 2021 (tb) Revision: Pregnancy Management section added [
14 May 2020 (tb) Revision:
2 January 2020 (tb) Revision: correction (
12 December 2019 (aa) Revision: information on
24 January 2019 (aa) Revision: gene (
28 June 2018 (bp) Comprehensive update posted live
31 May 2011 (me) Comprehensive update posted live
31 August 2007 (me) Comprehensive update posted live
27 April 2005 (me) Comprehensive update posted live
28 March 2003 (me) Comprehensive update posted live
20 June 2001 (me) Comprehensive update posted live
28 September 1998 (pb) Overview posted live
April 1996 (tb) Original submission
• 23 January 2025 (tb) Revision:
• 11 July 2024 (tb) Revision:
• 25 April 2024 (tb) Revision:
• 14 March 2024 (tb) Revision: information regarding cochlear implants added to
• 23 February 2023 (tb) Revision:
• 29 September 2022 (tb) Revision:
• 24 February 2022 (tb) Revision: added
• 9 September 2021 (tb) Revision: added comment on
• 20 May 2021 (tb) Revision:
• 18 March 2021 (tb) Revision:
• 4 March 2021 (tb) Revision: Pregnancy Management section added [
• 14 May 2020 (tb) Revision:
• 2 January 2020 (tb) Revision: correction (
• 12 December 2019 (aa) Revision: information on
• 24 January 2019 (aa) Revision: gene (
• 28 June 2018 (bp) Comprehensive update posted live
• 31 May 2011 (me) Comprehensive update posted live
• 31 August 2007 (me) Comprehensive update posted live
• 27 April 2005 (me) Comprehensive update posted live
• 28 March 2003 (me) Comprehensive update posted live
• 20 June 2001 (me) Comprehensive update posted live
• 28 September 1998 (pb) Overview posted live
• April 1996 (tb) Original submission
## Revision History
23 January 2025 (tb) Revision:
11 July 2024 (tb) Revision:
25 April 2024 (tb) Revision:
14 March 2024 (tb) Revision: information regarding cochlear implants added to
23 February 2023 (tb) Revision:
29 September 2022 (tb) Revision:
24 February 2022 (tb) Revision: added
9 September 2021 (tb) Revision: added comment on
20 May 2021 (tb) Revision:
18 March 2021 (tb) Revision:
4 March 2021 (tb) Revision: Pregnancy Management section added [
14 May 2020 (tb) Revision:
2 January 2020 (tb) Revision: correction (
12 December 2019 (aa) Revision: information on
24 January 2019 (aa) Revision: gene (
28 June 2018 (bp) Comprehensive update posted live
31 May 2011 (me) Comprehensive update posted live
31 August 2007 (me) Comprehensive update posted live
27 April 2005 (me) Comprehensive update posted live
28 March 2003 (me) Comprehensive update posted live
20 June 2001 (me) Comprehensive update posted live
28 September 1998 (pb) Overview posted live
April 1996 (tb) Original submission
• 23 January 2025 (tb) Revision:
• 11 July 2024 (tb) Revision:
• 25 April 2024 (tb) Revision:
• 14 March 2024 (tb) Revision: information regarding cochlear implants added to
• 23 February 2023 (tb) Revision:
• 29 September 2022 (tb) Revision:
• 24 February 2022 (tb) Revision: added
• 9 September 2021 (tb) Revision: added comment on
• 20 May 2021 (tb) Revision:
• 18 March 2021 (tb) Revision:
• 4 March 2021 (tb) Revision: Pregnancy Management section added [
• 14 May 2020 (tb) Revision:
• 2 January 2020 (tb) Revision: correction (
• 12 December 2019 (aa) Revision: information on
• 24 January 2019 (aa) Revision: gene (
• 28 June 2018 (bp) Comprehensive update posted live
• 31 May 2011 (me) Comprehensive update posted live
• 31 August 2007 (me) Comprehensive update posted live
• 27 April 2005 (me) Comprehensive update posted live
• 28 March 2003 (me) Comprehensive update posted live
• 20 June 2001 (me) Comprehensive update posted live
• 28 September 1998 (pb) Overview posted live
• April 1996 (tb) Original submission
## References
## Literature Cited
|
[] |
28/9/1998
|
28/6/2018
|
23/1/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cmt1
|
cmt1
|
[
"CMT1",
"HMSN1",
"Hereditary Motor and Sensory Neuropathy 1",
"CMT1",
"HMSN1",
"Hereditary Motor and Sensory Neuropathy 1",
"CMT1B",
"CMT1C",
"CMT1A",
"CMT1D",
"CMT1E",
"CMT1F/2E",
"E3 SUMO-protein ligase EGR2",
"Lipopolysaccharide-induced tumor necrosis factor-alpha factor",
"Myelin protein P0",
"Neurofilament light polypeptide",
"Peripheral myelin protein 22",
"EGR2",
"LITAF",
"MPZ",
"NEFL",
"PMP22",
"Charcot-Marie-Tooth Neuropathy Type 1"
] |
Charcot-Marie-Tooth Neuropathy Type 1 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Thomas D Bird
|
Summary Charcot-Marie-Tooth neuropathy type 1 (CMT1) is a demyelinating peripheral neuropathy characterized by distal muscle weakness and atrophy, sensory loss, and slow nerve conduction velocity. It is usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. Affected individuals usually become symptomatic between age five and 25 years. Fewer than 5% of individuals become wheelchair dependent. Life span is not shortened. CMT1A (70%-80% of all CMT1) involves duplication of CMT1 is inherited in an autosomal dominant manner. About two thirds of probands with CMT1A have inherited the
|
CMT1A
CMT1B
CMT1C
CMT1D
CMT1E
CMT2E/1F
For synonyms and outdated names see
• CMT1A
• CMT1B
• CMT1C
• CMT1D
• CMT1E
• CMT2E/1F
## Diagnosis
Charcot-Marie-Tooth neuropathy type (CMT1) is diagnosed in individuals with the following:
A progressive peripheral motor and sensory neuropathy
Slow nerve conduction velocity (NCV). NCVs are typically 10-30 meters per second, with a range of 5-38 m/s (normal: >40-45 m/s).
Palpably enlarged nerves, especially the ulnar nerve at the olecranon groove and the greater auricular nerve running along the lateral aspect of the neck
A family history consistent with autosomal dominant inheritance
Summary of Molecular Genetic Testing Used in Charcot-Marie-Tooth Neuropathy Type 1 (CMT1)
See
Detects a1.5-Mb duplication at 17p11.2 that includes
Each of these subtypes is identified based on detection of a pathogenic variant in the associated gene; hence, the variant detection rate is 100%.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
Because CMT1A (caused by the 1.5-Mb duplication at 17p11.2 including
If no
If no
Note: This testing strategy is different from that for axonal neuropathies and autosomal recessive neuropathies.
• A progressive peripheral motor and sensory neuropathy
• Slow nerve conduction velocity (NCV). NCVs are typically 10-30 meters per second, with a range of 5-38 m/s (normal: >40-45 m/s).
• Palpably enlarged nerves, especially the ulnar nerve at the olecranon groove and the greater auricular nerve running along the lateral aspect of the neck
• A family history consistent with autosomal dominant inheritance
• Because CMT1A (caused by the 1.5-Mb duplication at 17p11.2 including
• If no
• If no
## Clinical Diagnosis
Charcot-Marie-Tooth neuropathy type (CMT1) is diagnosed in individuals with the following:
A progressive peripheral motor and sensory neuropathy
Slow nerve conduction velocity (NCV). NCVs are typically 10-30 meters per second, with a range of 5-38 m/s (normal: >40-45 m/s).
Palpably enlarged nerves, especially the ulnar nerve at the olecranon groove and the greater auricular nerve running along the lateral aspect of the neck
A family history consistent with autosomal dominant inheritance
• A progressive peripheral motor and sensory neuropathy
• Slow nerve conduction velocity (NCV). NCVs are typically 10-30 meters per second, with a range of 5-38 m/s (normal: >40-45 m/s).
• Palpably enlarged nerves, especially the ulnar nerve at the olecranon groove and the greater auricular nerve running along the lateral aspect of the neck
• A family history consistent with autosomal dominant inheritance
## Molecular Genetic Testing
Summary of Molecular Genetic Testing Used in Charcot-Marie-Tooth Neuropathy Type 1 (CMT1)
See
Detects a1.5-Mb duplication at 17p11.2 that includes
Each of these subtypes is identified based on detection of a pathogenic variant in the associated gene; hence, the variant detection rate is 100%.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
## Testing Strategy
Because CMT1A (caused by the 1.5-Mb duplication at 17p11.2 including
If no
If no
Note: This testing strategy is different from that for axonal neuropathies and autosomal recessive neuropathies.
• Because CMT1A (caused by the 1.5-Mb duplication at 17p11.2 including
• If no
• If no
## Clinical Characteristics
Individuals with CMT1 usually become symptomatic between age five and 25 years [
The typical presenting symptom of CMT1 is weakness of the feet and ankles [
Onset in the first year of life often suggests an autosomal recessive cause of CMT but autosomal dominant types of CMT caused by duplication of
Proximal muscles usually remain strong.
Mild to moderate sensory deficits of position, vibration, and pain/temperature commonly occur in the feet, but many affected individuals are unaware of this finding. Pain, especially in the feet, is reported by 20%-30% of individuals [
In a study of 61 subjects with CMT1,
Episodic pressure palsies have been reported [
In CMT1A, prolonged distal motor latencies may already be present in the first months of life, and slow motor nerve conduction velocities (NCVs) have been found in some individuals by age two years [
Some individuals with CMT1B have onset in the first decade of life; others have a much later onset. The age of onset trend tends to run true in families [
CMT1 is slowly progressive over many years. Affected individuals experience long plateau periods without obvious deterioration [
In a study of persons with CMT1A over a five-year period,
In CMT1A,
The disease does not decrease life span.
Pes cavus foot deformity is common (>50%) and hip dysplasia may be under-recognized [
Pulmonary insufficiency and sleep apnea are sometimes seen [
Deafness has been occasionally reported in the CMT1 phenotype. Impaired auditory perception and processing has been reported as common (>60%) both in children with CMT1 and in those with CMT2 [
Vestibular abnormalities have been reported both in persons with CMT1A and in those with CMTX [
Lower-limb muscle atrophy and fatty infiltration can be demonstrated by MRI and followed longitudinally [
People with CMT1A can have symptoms that mimic those of HNPP [
Quality of life from the affected individual’s perspective has been studied by
The CMT1 subtypes, identified solely by molecular findings, are often clinically indistinguishable.
The amino acid substitution
The amino acid substitution
In addition to the above, the following findings in affected families demonstrate further heterogeneity in the CMT1 phenotype:
Pyramidal tract features
Optic atrophy [
Asymptomatic phrenic nerve involvement [
Other distinctive signs such as keratitis, skeletal dysplasia, or tonic pupils
One normal allele (as in
Two normal alleles represent the normal wild-type condition.
Three normal alleles (as in the common CMT1A 17p11.2 heterozygous duplication) cause a more severe phenotype.
Four normal alleles (as in homozygosity for the 17p11.2 duplication) result in the most severe phenotype.
Deletions or duplications of this same chromosomal region (17p11.2) can result in multiple congenital anomaly syndromes of
Severe neuropathy has been reported in persons with CMT1A and a second neuropathy-causing disease such as CMT1C [
The
Pupillary abnormalities have been reported in individuals with two
Mild late onset (>40 years) neuropathy was associated with four pathogenic variants (
The
Severe Dejerine-Sottas syndrome phenotype is associated with the
The
The
The
The
More severe neuropathy was seen in a girl with a
A novel dominant
Individuals with
Deafness [
The pathogenicity of
Penetrance of CMT1 is usually nearly 100%, but the wide range in age of onset and severity may result in under-recognition of individuals with mild or late-onset disease.
Heterozygosity for
Thirteen heterozygous missense variants in
Three missense variants at codon 72 of
Pathogenic variants in
Autosomal recessive forms of CMT may cause the DSS phenotype.
Persons with pathogenic variants in two different neuropathy-causing genes may have a DSS phenotype [
The overall prevalence of hereditary neuropathies is estimated at approximately 30:100,000 population. The prevalence of CMT1 is 15:100,000-20:100,000. The prevalence of CMT1A is approximately 10:100,000. These numbers hold true in a great variety of regions including China [
CMT1A represents about 70% of CMT1 [
In a large study of German individuals with a CMT1 phenotype (776),
In a Chinese population
• Pyramidal tract features
• Optic atrophy [
• Asymptomatic phrenic nerve involvement [
• Other distinctive signs such as keratitis, skeletal dysplasia, or tonic pupils
• One normal allele (as in
• Two normal alleles represent the normal wild-type condition.
• Three normal alleles (as in the common CMT1A 17p11.2 heterozygous duplication) cause a more severe phenotype.
• Four normal alleles (as in homozygosity for the 17p11.2 duplication) result in the most severe phenotype.
• Deletions or duplications of this same chromosomal region (17p11.2) can result in multiple congenital anomaly syndromes of
• The
• Pupillary abnormalities have been reported in individuals with two
• Mild late onset (>40 years) neuropathy was associated with four pathogenic variants (
• The
• Severe Dejerine-Sottas syndrome phenotype is associated with the
• The
• The
• The
• The
• More severe neuropathy was seen in a girl with a
• A novel dominant
• Individuals with
• Deafness [
• The pathogenicity of
• Heterozygosity for
• Thirteen heterozygous missense variants in
• Three missense variants at codon 72 of
• Pathogenic variants in
• Autosomal recessive forms of CMT may cause the DSS phenotype.
• Persons with pathogenic variants in two different neuropathy-causing genes may have a DSS phenotype [
## Clinical Description
Individuals with CMT1 usually become symptomatic between age five and 25 years [
The typical presenting symptom of CMT1 is weakness of the feet and ankles [
Onset in the first year of life often suggests an autosomal recessive cause of CMT but autosomal dominant types of CMT caused by duplication of
Proximal muscles usually remain strong.
Mild to moderate sensory deficits of position, vibration, and pain/temperature commonly occur in the feet, but many affected individuals are unaware of this finding. Pain, especially in the feet, is reported by 20%-30% of individuals [
In a study of 61 subjects with CMT1,
Episodic pressure palsies have been reported [
In CMT1A, prolonged distal motor latencies may already be present in the first months of life, and slow motor nerve conduction velocities (NCVs) have been found in some individuals by age two years [
Some individuals with CMT1B have onset in the first decade of life; others have a much later onset. The age of onset trend tends to run true in families [
CMT1 is slowly progressive over many years. Affected individuals experience long plateau periods without obvious deterioration [
In a study of persons with CMT1A over a five-year period,
In CMT1A,
The disease does not decrease life span.
Pes cavus foot deformity is common (>50%) and hip dysplasia may be under-recognized [
Pulmonary insufficiency and sleep apnea are sometimes seen [
Deafness has been occasionally reported in the CMT1 phenotype. Impaired auditory perception and processing has been reported as common (>60%) both in children with CMT1 and in those with CMT2 [
Vestibular abnormalities have been reported both in persons with CMT1A and in those with CMTX [
Lower-limb muscle atrophy and fatty infiltration can be demonstrated by MRI and followed longitudinally [
People with CMT1A can have symptoms that mimic those of HNPP [
Quality of life from the affected individual’s perspective has been studied by
The CMT1 subtypes, identified solely by molecular findings, are often clinically indistinguishable.
The amino acid substitution
The amino acid substitution
In addition to the above, the following findings in affected families demonstrate further heterogeneity in the CMT1 phenotype:
Pyramidal tract features
Optic atrophy [
Asymptomatic phrenic nerve involvement [
Other distinctive signs such as keratitis, skeletal dysplasia, or tonic pupils
• Pyramidal tract features
• Optic atrophy [
• Asymptomatic phrenic nerve involvement [
• Other distinctive signs such as keratitis, skeletal dysplasia, or tonic pupils
## Classic CMT1 Phenotype
Individuals with CMT1 usually become symptomatic between age five and 25 years [
The typical presenting symptom of CMT1 is weakness of the feet and ankles [
Onset in the first year of life often suggests an autosomal recessive cause of CMT but autosomal dominant types of CMT caused by duplication of
Proximal muscles usually remain strong.
Mild to moderate sensory deficits of position, vibration, and pain/temperature commonly occur in the feet, but many affected individuals are unaware of this finding. Pain, especially in the feet, is reported by 20%-30% of individuals [
In a study of 61 subjects with CMT1,
Episodic pressure palsies have been reported [
In CMT1A, prolonged distal motor latencies may already be present in the first months of life, and slow motor nerve conduction velocities (NCVs) have been found in some individuals by age two years [
Some individuals with CMT1B have onset in the first decade of life; others have a much later onset. The age of onset trend tends to run true in families [
CMT1 is slowly progressive over many years. Affected individuals experience long plateau periods without obvious deterioration [
In a study of persons with CMT1A over a five-year period,
In CMT1A,
The disease does not decrease life span.
Pes cavus foot deformity is common (>50%) and hip dysplasia may be under-recognized [
Pulmonary insufficiency and sleep apnea are sometimes seen [
Deafness has been occasionally reported in the CMT1 phenotype. Impaired auditory perception and processing has been reported as common (>60%) both in children with CMT1 and in those with CMT2 [
Vestibular abnormalities have been reported both in persons with CMT1A and in those with CMTX [
Lower-limb muscle atrophy and fatty infiltration can be demonstrated by MRI and followed longitudinally [
People with CMT1A can have symptoms that mimic those of HNPP [
Quality of life from the affected individual’s perspective has been studied by
## CMT1 Subtypes
The CMT1 subtypes, identified solely by molecular findings, are often clinically indistinguishable.
The amino acid substitution
The amino acid substitution
In addition to the above, the following findings in affected families demonstrate further heterogeneity in the CMT1 phenotype:
Pyramidal tract features
Optic atrophy [
Asymptomatic phrenic nerve involvement [
Other distinctive signs such as keratitis, skeletal dysplasia, or tonic pupils
• Pyramidal tract features
• Optic atrophy [
• Asymptomatic phrenic nerve involvement [
• Other distinctive signs such as keratitis, skeletal dysplasia, or tonic pupils
## Neuropathology
## Genotype-Phenotype Correlations
One normal allele (as in
Two normal alleles represent the normal wild-type condition.
Three normal alleles (as in the common CMT1A 17p11.2 heterozygous duplication) cause a more severe phenotype.
Four normal alleles (as in homozygosity for the 17p11.2 duplication) result in the most severe phenotype.
Deletions or duplications of this same chromosomal region (17p11.2) can result in multiple congenital anomaly syndromes of
Severe neuropathy has been reported in persons with CMT1A and a second neuropathy-causing disease such as CMT1C [
The
Pupillary abnormalities have been reported in individuals with two
Mild late onset (>40 years) neuropathy was associated with four pathogenic variants (
The
Severe Dejerine-Sottas syndrome phenotype is associated with the
The
The
The
The
More severe neuropathy was seen in a girl with a
A novel dominant
Individuals with
Deafness [
The pathogenicity of
• One normal allele (as in
• Two normal alleles represent the normal wild-type condition.
• Three normal alleles (as in the common CMT1A 17p11.2 heterozygous duplication) cause a more severe phenotype.
• Four normal alleles (as in homozygosity for the 17p11.2 duplication) result in the most severe phenotype.
• Deletions or duplications of this same chromosomal region (17p11.2) can result in multiple congenital anomaly syndromes of
• The
• Pupillary abnormalities have been reported in individuals with two
• Mild late onset (>40 years) neuropathy was associated with four pathogenic variants (
• The
• Severe Dejerine-Sottas syndrome phenotype is associated with the
• The
• The
• The
• The
• More severe neuropathy was seen in a girl with a
• A novel dominant
• Individuals with
• Deafness [
• The pathogenicity of
## Penetrance
Penetrance of CMT1 is usually nearly 100%, but the wide range in age of onset and severity may result in under-recognition of individuals with mild or late-onset disease.
## Nomenclature
Heterozygosity for
Thirteen heterozygous missense variants in
Three missense variants at codon 72 of
Pathogenic variants in
Autosomal recessive forms of CMT may cause the DSS phenotype.
Persons with pathogenic variants in two different neuropathy-causing genes may have a DSS phenotype [
• Heterozygosity for
• Thirteen heterozygous missense variants in
• Three missense variants at codon 72 of
• Pathogenic variants in
• Autosomal recessive forms of CMT may cause the DSS phenotype.
• Persons with pathogenic variants in two different neuropathy-causing genes may have a DSS phenotype [
## Prevalence
The overall prevalence of hereditary neuropathies is estimated at approximately 30:100,000 population. The prevalence of CMT1 is 15:100,000-20:100,000. The prevalence of CMT1A is approximately 10:100,000. These numbers hold true in a great variety of regions including China [
CMT1A represents about 70% of CMT1 [
In a large study of German individuals with a CMT1 phenotype (776),
In a Chinese population
## Genetically Related (Allelic) Disorders
The very rare autosomal recessive neuropathy CMT4 is caused by homozygosity for single-nucleotide variants in
Mutation of
The Roussy-Levy syndrome of CMT associated with ataxia or tremor has been shown to be caused by an
• The very rare autosomal recessive neuropathy CMT4 is caused by homozygosity for single-nucleotide variants in
• Mutation of
• The Roussy-Levy syndrome of CMT associated with ataxia or tremor has been shown to be caused by an
## Differential Diagnosis
Acquired causes of neuropathy and other inherited neuropathies need to be considered (see
In the autosomal dominant
DI-CMTA, linked to 10q24 [
DI-CMTB caused by pathogenic variants in
DI-CMTC caused by pathogenic variants in
DI-CMTD caused by pathogenic variants in
DI-CMTF caused by pathogenic variants in
It is usually not possible to differentiate between intermediate forms of CMT and most CMT2 subtypes based on clinical findings [
• DI-CMTA, linked to 10q24 [
• DI-CMTB caused by pathogenic variants in
• DI-CMTC caused by pathogenic variants in
• DI-CMTD caused by pathogenic variants in
• DI-CMTF caused by pathogenic variants in
## Management
To establish the extent of disease and needs in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 1 (CMT1), the following evaluations are recommended:
Physical examination to determine extent of weakness and atrophy,
NCV to help distinguish demyelinating, axonal, and mixed forms of neuropathy
Detailed family history
Consultation with a clinical geneticist and/or genetic counselor
Individuals with CMT1 are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [
Treatment is symptomatic and may include the following:
Special shoes, including those with good ankle support; affected individuals often require ankle/foot orthoses (AFOs) to correct foot drop and aid walking [
Orthopedic surgery to correct severe pes cavus deformity [
Forearm crutches or canes for gait stability for some individuals; fewer than 5% of individuals need wheelchairs.
Exercise within the individual's capability; many remain physically active. Exercise is
Serial night casting to help increase ankle flexibility [
Accurate identification, as far as possible, of the cause of pain:
Musculoskeletal pain may respond to acetaminophen or nonsteroidal anti-inflammatory agents [
Neuropathic pain may respond to tricyclic antidepressants or drugs such as carbamazepine or gabapentin.
Career and employment counseling to address persistent weakness of hands and/or feet
Interventions designed to improve leg cramps, tremor, agility, endurance, and ankle flexibility, thereby improving quality of life; see
No treatment reverses or slows the natural progression of CMT.
Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.
Individuals should be evaluated regularly by a team comprising physiatrists, neurologists, and physical and occupational therapists to determine neurologic status and functional disability.
Obesity is to be avoided because it makes walking more difficult.
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
See
Search
• Physical examination to determine extent of weakness and atrophy,
• NCV to help distinguish demyelinating, axonal, and mixed forms of neuropathy
• Detailed family history
• Consultation with a clinical geneticist and/or genetic counselor
• Special shoes, including those with good ankle support; affected individuals often require ankle/foot orthoses (AFOs) to correct foot drop and aid walking [
• Orthopedic surgery to correct severe pes cavus deformity [
• Forearm crutches or canes for gait stability for some individuals; fewer than 5% of individuals need wheelchairs.
• Exercise within the individual's capability; many remain physically active. Exercise is
• Serial night casting to help increase ankle flexibility [
• Accurate identification, as far as possible, of the cause of pain:
• Musculoskeletal pain may respond to acetaminophen or nonsteroidal anti-inflammatory agents [
• Neuropathic pain may respond to tricyclic antidepressants or drugs such as carbamazepine or gabapentin.
• Musculoskeletal pain may respond to acetaminophen or nonsteroidal anti-inflammatory agents [
• Neuropathic pain may respond to tricyclic antidepressants or drugs such as carbamazepine or gabapentin.
• Career and employment counseling to address persistent weakness of hands and/or feet
• Interventions designed to improve leg cramps, tremor, agility, endurance, and ankle flexibility, thereby improving quality of life; see
• Musculoskeletal pain may respond to acetaminophen or nonsteroidal anti-inflammatory agents [
• Neuropathic pain may respond to tricyclic antidepressants or drugs such as carbamazepine or gabapentin.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 1 (CMT1), the following evaluations are recommended:
Physical examination to determine extent of weakness and atrophy,
NCV to help distinguish demyelinating, axonal, and mixed forms of neuropathy
Detailed family history
Consultation with a clinical geneticist and/or genetic counselor
• Physical examination to determine extent of weakness and atrophy,
• NCV to help distinguish demyelinating, axonal, and mixed forms of neuropathy
• Detailed family history
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Individuals with CMT1 are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [
Treatment is symptomatic and may include the following:
Special shoes, including those with good ankle support; affected individuals often require ankle/foot orthoses (AFOs) to correct foot drop and aid walking [
Orthopedic surgery to correct severe pes cavus deformity [
Forearm crutches or canes for gait stability for some individuals; fewer than 5% of individuals need wheelchairs.
Exercise within the individual's capability; many remain physically active. Exercise is
Serial night casting to help increase ankle flexibility [
Accurate identification, as far as possible, of the cause of pain:
Musculoskeletal pain may respond to acetaminophen or nonsteroidal anti-inflammatory agents [
Neuropathic pain may respond to tricyclic antidepressants or drugs such as carbamazepine or gabapentin.
Career and employment counseling to address persistent weakness of hands and/or feet
Interventions designed to improve leg cramps, tremor, agility, endurance, and ankle flexibility, thereby improving quality of life; see
• Special shoes, including those with good ankle support; affected individuals often require ankle/foot orthoses (AFOs) to correct foot drop and aid walking [
• Orthopedic surgery to correct severe pes cavus deformity [
• Forearm crutches or canes for gait stability for some individuals; fewer than 5% of individuals need wheelchairs.
• Exercise within the individual's capability; many remain physically active. Exercise is
• Serial night casting to help increase ankle flexibility [
• Accurate identification, as far as possible, of the cause of pain:
• Musculoskeletal pain may respond to acetaminophen or nonsteroidal anti-inflammatory agents [
• Neuropathic pain may respond to tricyclic antidepressants or drugs such as carbamazepine or gabapentin.
• Musculoskeletal pain may respond to acetaminophen or nonsteroidal anti-inflammatory agents [
• Neuropathic pain may respond to tricyclic antidepressants or drugs such as carbamazepine or gabapentin.
• Career and employment counseling to address persistent weakness of hands and/or feet
• Interventions designed to improve leg cramps, tremor, agility, endurance, and ankle flexibility, thereby improving quality of life; see
• Musculoskeletal pain may respond to acetaminophen or nonsteroidal anti-inflammatory agents [
• Neuropathic pain may respond to tricyclic antidepressants or drugs such as carbamazepine or gabapentin.
## Prevention of Primary Manifestations
No treatment reverses or slows the natural progression of CMT.
## Prevention of Secondary Complications
Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.
## Surveillance
Individuals should be evaluated regularly by a team comprising physiatrists, neurologists, and physical and occupational therapists to determine neurologic status and functional disability.
## Agents/Circumstances to Avoid
Obesity is to be avoided because it makes walking more difficult.
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
## Evaluation of Relatives at Risk
See
## Pregnancy Management
## Therapies Under Investigation
Search
## Genetic Counseling
Charcot-Marie-Tooth neuropathy type 1 (CMT1) is inherited an autosomal dominant manner.
About 67%-80% of individuals with CMT1A have inherited the
Similar data are not available for the other subtypes of CMT1.
Recommendations for the evaluation of parents of a proband with an apparent
Note: Although most individuals diagnosed with CMT1 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.
The risk to the sibs depends on the genetic status of the proband's parents.
If a parent has the
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
If the pathogenic variant cannot be detected in leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism [
The risk to other family members depends on the status of the proband's parents.
If a parent has the pathogenic variant, his or her family members are at risk.
In a family with an established diagnosis of CMT1, testing is appropriate to consider in symptomatic individuals regardless of age.
See also the National Society of Genetic Counselors
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
If the
Requests for prenatal testing for typically adult-onset conditions which (like CMT1) do not affect intellect or life span are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
• About 67%-80% of individuals with CMT1A have inherited the
• Similar data are not available for the other subtypes of CMT1.
• Recommendations for the evaluation of parents of a proband with an apparent
• The risk to the sibs depends on the genetic status of the proband's parents.
• If a parent has the
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• If the pathogenic variant cannot be detected in leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism [
• The risk to other family members depends on the status of the proband's parents.
• If a parent has the pathogenic variant, his or her family members are at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Charcot-Marie-Tooth neuropathy type 1 (CMT1) is inherited an autosomal dominant manner.
## Risk to Family Members
About 67%-80% of individuals with CMT1A have inherited the
Similar data are not available for the other subtypes of CMT1.
Recommendations for the evaluation of parents of a proband with an apparent
Note: Although most individuals diagnosed with CMT1 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.
The risk to the sibs depends on the genetic status of the proband's parents.
If a parent has the
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
If the pathogenic variant cannot be detected in leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism [
The risk to other family members depends on the status of the proband's parents.
If a parent has the pathogenic variant, his or her family members are at risk.
• About 67%-80% of individuals with CMT1A have inherited the
• Similar data are not available for the other subtypes of CMT1.
• Recommendations for the evaluation of parents of a proband with an apparent
• The risk to the sibs depends on the genetic status of the proband's parents.
• If a parent has the
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• If the pathogenic variant cannot be detected in leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism [
• The risk to other family members depends on the status of the proband's parents.
• If a parent has the pathogenic variant, his or her family members are at risk.
## Related Genetic Counseling Issues
In a family with an established diagnosis of CMT1, testing is appropriate to consider in symptomatic individuals regardless of age.
See also the National Society of Genetic Counselors
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing
If the
Requests for prenatal testing for typically adult-onset conditions which (like CMT1) do not affect intellect or life span are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
## Resources
France
PO Box 105
Glenolden PA 19036
Department of Molecular Genetics
University of Antwerp
Antwerp Antwerpen B-2610
Belgium
432 Park Avenue South
4th Floor
New York NY 10016
Institute of Genetic Medicine
University of Newcastle upon Tyne
International Centre for Life
Newcastle upon Tyne NE1 3BZ
United Kingdom
1 Rue de l'International
BP59
Evry cedex 91002
France
Lt Gen van Heutszlaan 6
3743 JN Baarn
Netherlands
222 South Riverside Plaza
Suite 1500
Chicago IL 60606
61A Great Suffolk Street
London SE1 0BU
United Kingdom
•
• France
•
•
• PO Box 105
• Glenolden PA 19036
•
•
• Department of Molecular Genetics
• University of Antwerp
• Antwerp Antwerpen B-2610
• Belgium
•
• 432 Park Avenue South
• 4th Floor
• New York NY 10016
•
•
•
•
•
•
•
•
• Institute of Genetic Medicine
• University of Newcastle upon Tyne
• International Centre for Life
• Newcastle upon Tyne NE1 3BZ
• United Kingdom
•
•
• 1 Rue de l'International
• BP59
• Evry cedex 91002
• France
•
•
• Lt Gen van Heutszlaan 6
• 3743 JN Baarn
• Netherlands
•
•
• 222 South Riverside Plaza
• Suite 1500
• Chicago IL 60606
•
•
• 61A Great Suffolk Street
• London SE1 0BU
• United Kingdom
•
•
•
## Molecular Genetics
Charcot-Marie-Tooth Neuropathy Type 1: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Charcot-Marie-Tooth Neuropathy Type 1 (
Selected
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
See
See
Most pathogenic missense variants are localized in the transmembrane domains of peripheral myelin protein 22, indicating the functional importance of these domains. Individuals with
A mouse containing eight copies of human
Selected
Variants listed in the table have been provided by the author.
NA = not applicable
Variant designation that does not conform to current naming conventions
See
Nomenclature for variants in
See
See
See
Selected
Variants listed in the table have been provided by the author.
See
Selected
Variants listed in the table have been provided by the author.
See
Selected
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
See
## References
## Published Guidelines / Consensus Statements
## Literature Cited
## Suggested Reading
## Chapter Notes
5 July 2018 (ma) Chapter retired: covered in
26 March 2015 (ks) Revision:
18 December 2014 (me) Comprehensive update posted live
20 February 2014 (tb) Revision: Lee et al 2013 added to Preimplantation genetic diagnosis
7 November 2013 (tb) Revision: additions to Prevalence; figure added [
11 July 2013 (tb) Revision: additions to Prevalence and Natural History
18 October 2012 (me) Comprehensive update posted live
18 August 2011 (tb) Revision: Høyer et al 2011; see Testing, Genotype-Phenotype Correlations, Molecular Genetics
16 June 2011 (tb) Revision: additions to Differential Diagnosis –
1 March 2011 (cd) Revision: edits to Testing Strategy
14 September 2010 (me) Comprehensive update posted live
18 December 2007 (cd) Revision: prenatal diagnosis available for CMT1D
30 March 2007 (me) Comprehensive update posted to live Web site
20 October 2006 (cd) Revision: targeted mutation analysis, mutation scanning, and prenatal diagnosis for CMT1D no longer available
30 December 2005 (cd) Revision: prenatal diagnosis and mutation scanning clinically available for CMT1C
26 April 2005 (me) Comprehensive update posted live
9 September 2004 (tb,cd) Revision: addition of
10 May 2004 (tb) Author revisions
29 December 2003 (tb) Author revisions
22 April 2003 (tb) Author revisions
27 March 2003 (me) Comprehensive update posted live
10 May 2002 (tb) Author revisions
20 December 2001 (tb) Author revisions
12 September 2001 (tb) Author revisions
24 July 2001 (tb) Author revisions
27 June 2001 (tb) Author revisions
1 June 2001 (tb) Author revisions
16 January 2001 (tb) Author revisions
25 August 2000 (ca) Comprehensive update posted live
15 June 2000 (tb) Author revisions
15 May 2000 (tb) Author revisions
14 January 2000 (tb) Author revisions
31 August 1999 (tb) Author revisions
18 June 1999 (tb) Author revisions
8 April 1999 (tb) Author revisions
5 March 1999 (tb) Author revisions
12 October 1998 (tb) Author revisions
31 August 1998 (pb) Review posted live
April 1996 (tb) Original submission
• 5 July 2018 (ma) Chapter retired: covered in
• 26 March 2015 (ks) Revision:
• 18 December 2014 (me) Comprehensive update posted live
• 20 February 2014 (tb) Revision: Lee et al 2013 added to Preimplantation genetic diagnosis
• 7 November 2013 (tb) Revision: additions to Prevalence; figure added [
• 11 July 2013 (tb) Revision: additions to Prevalence and Natural History
• 18 October 2012 (me) Comprehensive update posted live
• 18 August 2011 (tb) Revision: Høyer et al 2011; see Testing, Genotype-Phenotype Correlations, Molecular Genetics
• 16 June 2011 (tb) Revision: additions to Differential Diagnosis –
• 1 March 2011 (cd) Revision: edits to Testing Strategy
• 14 September 2010 (me) Comprehensive update posted live
• 18 December 2007 (cd) Revision: prenatal diagnosis available for CMT1D
• 30 March 2007 (me) Comprehensive update posted to live Web site
• 20 October 2006 (cd) Revision: targeted mutation analysis, mutation scanning, and prenatal diagnosis for CMT1D no longer available
• 30 December 2005 (cd) Revision: prenatal diagnosis and mutation scanning clinically available for CMT1C
• 26 April 2005 (me) Comprehensive update posted live
• 9 September 2004 (tb,cd) Revision: addition of
• 10 May 2004 (tb) Author revisions
• 29 December 2003 (tb) Author revisions
• 22 April 2003 (tb) Author revisions
• 27 March 2003 (me) Comprehensive update posted live
• 10 May 2002 (tb) Author revisions
• 20 December 2001 (tb) Author revisions
• 12 September 2001 (tb) Author revisions
• 24 July 2001 (tb) Author revisions
• 27 June 2001 (tb) Author revisions
• 1 June 2001 (tb) Author revisions
• 16 January 2001 (tb) Author revisions
• 25 August 2000 (ca) Comprehensive update posted live
• 15 June 2000 (tb) Author revisions
• 15 May 2000 (tb) Author revisions
• 14 January 2000 (tb) Author revisions
• 31 August 1999 (tb) Author revisions
• 18 June 1999 (tb) Author revisions
• 8 April 1999 (tb) Author revisions
• 5 March 1999 (tb) Author revisions
• 12 October 1998 (tb) Author revisions
• 31 August 1998 (pb) Review posted live
• April 1996 (tb) Original submission
## Revision History
5 July 2018 (ma) Chapter retired: covered in
26 March 2015 (ks) Revision:
18 December 2014 (me) Comprehensive update posted live
20 February 2014 (tb) Revision: Lee et al 2013 added to Preimplantation genetic diagnosis
7 November 2013 (tb) Revision: additions to Prevalence; figure added [
11 July 2013 (tb) Revision: additions to Prevalence and Natural History
18 October 2012 (me) Comprehensive update posted live
18 August 2011 (tb) Revision: Høyer et al 2011; see Testing, Genotype-Phenotype Correlations, Molecular Genetics
16 June 2011 (tb) Revision: additions to Differential Diagnosis –
1 March 2011 (cd) Revision: edits to Testing Strategy
14 September 2010 (me) Comprehensive update posted live
18 December 2007 (cd) Revision: prenatal diagnosis available for CMT1D
30 March 2007 (me) Comprehensive update posted to live Web site
20 October 2006 (cd) Revision: targeted mutation analysis, mutation scanning, and prenatal diagnosis for CMT1D no longer available
30 December 2005 (cd) Revision: prenatal diagnosis and mutation scanning clinically available for CMT1C
26 April 2005 (me) Comprehensive update posted live
9 September 2004 (tb,cd) Revision: addition of
10 May 2004 (tb) Author revisions
29 December 2003 (tb) Author revisions
22 April 2003 (tb) Author revisions
27 March 2003 (me) Comprehensive update posted live
10 May 2002 (tb) Author revisions
20 December 2001 (tb) Author revisions
12 September 2001 (tb) Author revisions
24 July 2001 (tb) Author revisions
27 June 2001 (tb) Author revisions
1 June 2001 (tb) Author revisions
16 January 2001 (tb) Author revisions
25 August 2000 (ca) Comprehensive update posted live
15 June 2000 (tb) Author revisions
15 May 2000 (tb) Author revisions
14 January 2000 (tb) Author revisions
31 August 1999 (tb) Author revisions
18 June 1999 (tb) Author revisions
8 April 1999 (tb) Author revisions
5 March 1999 (tb) Author revisions
12 October 1998 (tb) Author revisions
31 August 1998 (pb) Review posted live
April 1996 (tb) Original submission
• 5 July 2018 (ma) Chapter retired: covered in
• 26 March 2015 (ks) Revision:
• 18 December 2014 (me) Comprehensive update posted live
• 20 February 2014 (tb) Revision: Lee et al 2013 added to Preimplantation genetic diagnosis
• 7 November 2013 (tb) Revision: additions to Prevalence; figure added [
• 11 July 2013 (tb) Revision: additions to Prevalence and Natural History
• 18 October 2012 (me) Comprehensive update posted live
• 18 August 2011 (tb) Revision: Høyer et al 2011; see Testing, Genotype-Phenotype Correlations, Molecular Genetics
• 16 June 2011 (tb) Revision: additions to Differential Diagnosis –
• 1 March 2011 (cd) Revision: edits to Testing Strategy
• 14 September 2010 (me) Comprehensive update posted live
• 18 December 2007 (cd) Revision: prenatal diagnosis available for CMT1D
• 30 March 2007 (me) Comprehensive update posted to live Web site
• 20 October 2006 (cd) Revision: targeted mutation analysis, mutation scanning, and prenatal diagnosis for CMT1D no longer available
• 30 December 2005 (cd) Revision: prenatal diagnosis and mutation scanning clinically available for CMT1C
• 26 April 2005 (me) Comprehensive update posted live
• 9 September 2004 (tb,cd) Revision: addition of
• 10 May 2004 (tb) Author revisions
• 29 December 2003 (tb) Author revisions
• 22 April 2003 (tb) Author revisions
• 27 March 2003 (me) Comprehensive update posted live
• 10 May 2002 (tb) Author revisions
• 20 December 2001 (tb) Author revisions
• 12 September 2001 (tb) Author revisions
• 24 July 2001 (tb) Author revisions
• 27 June 2001 (tb) Author revisions
• 1 June 2001 (tb) Author revisions
• 16 January 2001 (tb) Author revisions
• 25 August 2000 (ca) Comprehensive update posted live
• 15 June 2000 (tb) Author revisions
• 15 May 2000 (tb) Author revisions
• 14 January 2000 (tb) Author revisions
• 31 August 1999 (tb) Author revisions
• 18 June 1999 (tb) Author revisions
• 8 April 1999 (tb) Author revisions
• 5 March 1999 (tb) Author revisions
• 12 October 1998 (tb) Author revisions
• 31 August 1998 (pb) Review posted live
• April 1996 (tb) Original submission
Genetic diagnoses in CMT and related disorders
From
|
[] |
31/8/1998
|
18/12/2014
|
26/3/2015
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cmt2
|
cmt2
|
[
"Charcot-Marie-Tooth Disease, Axonal Type",
"CMT2",
"Hereditary Motor and Sensory Neuropathy 2",
"HMSN2",
"Charcot-Marie-Tooth Disease, Axonal Type",
"HMSN2",
"Hereditary Motor and Sensory Neuropathy 2",
"CMT2",
"CMT2B",
"CMT2B1",
"CMT2B2",
"CMT2C",
"GARS-Associated Axonal Neuropathy",
"CMT2E/1F",
"CMT2F",
"CMT2G",
"CMT2I/J",
"CMT2H/2K",
"CMT2L",
"CMT2N",
"CMT2O",
"CMT2P",
"CMT2A2",
"CMT2A1",
"CMT2U",
"CMT2S",
"CMT2T",
"Alanine--tRNA ligase, cytoplasmic",
"Alpha-N-acetylglucosaminidase",
"Cytoplasmic dynein 1 heavy chain 1",
"DNA-binding protein SMUBP-2",
"DnaJ homolog subfamily B member 2",
"E3 ubiquitin-protein ligase LRSAM1",
"Ganglioside-induced differentiation-associated protein 1",
"Glycine--tRNA ligase",
"Heat shock protein beta-1",
"Heat shock protein beta-8",
"Histidine--tRNA ligase, cytoplasmic",
"Kinesin-like protein KIF1B",
"Mediator of RNA polymerase II transcription subunit 25",
"Methionine--tRNA ligase, cytoplasmic",
"Mitofusin-2",
"Myelin protein P0",
"Neprilysin",
"Neurofilament light polypeptide",
"Prelamin-A/C",
"Probable 2-oxoglutarate dehydrogenase E1 component DHKTD1, mitochondrial",
"Ras-related protein Rab-7a",
"Transient receptor potential cation channel subfamily V member 4",
"Tripartite motif-containing protein 2",
"AARS",
"DHTKD1",
"DNAJB2",
"DYNC1H1",
"GARS",
"GDAP1",
"HARS",
"HSPB1",
"HSPB8",
"IGHMBP2",
"KIF1B",
"LMNA",
"LRSAM1",
"MARS",
"MED25",
"MFN2",
"MME",
"MPZ",
"NAGLU",
"NEFL",
"RAB7A",
"TRIM2",
"TRPV4",
"Charcot-Marie-Tooth Neuropathy Type 2"
] |
Charcot-Marie-Tooth Neuropathy Type 2 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Thomas D Bird
|
Summary Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) is an axonal (non-demyelinating) peripheral neuropathy characterized by distal muscle weakness and atrophy, mild sensory loss, and normal or near-normal nerve conduction velocities. CMT2 is clinically similar to CMT1, although typically less severe. Peripheral nerves are not enlarged or hypertrophic. The subtypes of CMT2 are similar clinically and distinguished only by molecular genetic findings. The diagnosis is based on clinical and EMG/NCV findings, and in many instances by identification of diagnostic changes in one of the genes that determine the CMT2 subtypes. Most subtypes of CMT2 are inherited in an autosomal dominant manner; however, some are inherited in an autosomal recessive manner. Most probands with an autosomal dominant CMT2 subtype have inherited the pathogenic variant from an affected parent. The offspring of an individual with autosomal dominant CMT2 are at a 50% risk of inheriting the pathogenic variant.
|
## Diagnosis
A progressive peripheral motor and sensory neuropathy
Nerve conduction velocities (NCVs) that are usually within the normal range (>40-45 m/s), although occasionally in a mildly abnormal range (30-40 m/s)
EMG testing that shows evidence of an axonal neuropathy with such findings as positive waves, polyphasic potentials, or fibrillations and reduced amplitudes of evoked motor and sensory responses
Greatly reduced compound motor action potentials (CMAP)
A family history that is typically (but not always) consistent with autosomal dominant inheritance. Note: Some subtypes are inherited in an autosomal recessive manner.
Note: Nerve biopsy is not required for diagnosis.
Molecular testing approaches can include
The order in which pathogenic variants most commonly occur (
Ethnicity, if founder variants are present (
Phenotypic findings that suggest specific CMT2 subtypes; for example:
Optic atrophy: CMT2A2 (
Vocal cord paresis: CMT2C (
For an introduction to multigene panels click
See
CMT2 Subtypes: Most Common Genetic Causes
CMT2 subtypes/genes/loci accounting for >2% of the disorder; listed in order of frequency
MOI = mode of inheritance
AD = autosomal dominant
AR = autosomal recessive
See
CMT2 Subtypes: Less Common Genetic Causes
CMT2 subtypes accounting for ≤2% of the disorder; listed alphabetically by subtype.
MOI = mode of inheritance
AD = autosomal dominant
AR = autosomal recessive
Click
• A progressive peripheral motor and sensory neuropathy
• Nerve conduction velocities (NCVs) that are usually within the normal range (>40-45 m/s), although occasionally in a mildly abnormal range (30-40 m/s)
• EMG testing that shows evidence of an axonal neuropathy with such findings as positive waves, polyphasic potentials, or fibrillations and reduced amplitudes of evoked motor and sensory responses
• Greatly reduced compound motor action potentials (CMAP)
• A family history that is typically (but not always) consistent with autosomal dominant inheritance. Note: Some subtypes are inherited in an autosomal recessive manner.
• The order in which pathogenic variants most commonly occur (
• Ethnicity, if founder variants are present (
• Phenotypic findings that suggest specific CMT2 subtypes; for example:
• Optic atrophy: CMT2A2 (
• Vocal cord paresis: CMT2C (
• Optic atrophy: CMT2A2 (
• Vocal cord paresis: CMT2C (
• Optic atrophy: CMT2A2 (
• Vocal cord paresis: CMT2C (
## Establishing the Diagnosis
A progressive peripheral motor and sensory neuropathy
Nerve conduction velocities (NCVs) that are usually within the normal range (>40-45 m/s), although occasionally in a mildly abnormal range (30-40 m/s)
EMG testing that shows evidence of an axonal neuropathy with such findings as positive waves, polyphasic potentials, or fibrillations and reduced amplitudes of evoked motor and sensory responses
Greatly reduced compound motor action potentials (CMAP)
A family history that is typically (but not always) consistent with autosomal dominant inheritance. Note: Some subtypes are inherited in an autosomal recessive manner.
Note: Nerve biopsy is not required for diagnosis.
Molecular testing approaches can include
The order in which pathogenic variants most commonly occur (
Ethnicity, if founder variants are present (
Phenotypic findings that suggest specific CMT2 subtypes; for example:
Optic atrophy: CMT2A2 (
Vocal cord paresis: CMT2C (
For an introduction to multigene panels click
See
CMT2 Subtypes: Most Common Genetic Causes
CMT2 subtypes/genes/loci accounting for >2% of the disorder; listed in order of frequency
MOI = mode of inheritance
AD = autosomal dominant
AR = autosomal recessive
See
CMT2 Subtypes: Less Common Genetic Causes
CMT2 subtypes accounting for ≤2% of the disorder; listed alphabetically by subtype.
MOI = mode of inheritance
AD = autosomal dominant
AR = autosomal recessive
Click
• A progressive peripheral motor and sensory neuropathy
• Nerve conduction velocities (NCVs) that are usually within the normal range (>40-45 m/s), although occasionally in a mildly abnormal range (30-40 m/s)
• EMG testing that shows evidence of an axonal neuropathy with such findings as positive waves, polyphasic potentials, or fibrillations and reduced amplitudes of evoked motor and sensory responses
• Greatly reduced compound motor action potentials (CMAP)
• A family history that is typically (but not always) consistent with autosomal dominant inheritance. Note: Some subtypes are inherited in an autosomal recessive manner.
• The order in which pathogenic variants most commonly occur (
• Ethnicity, if founder variants are present (
• Phenotypic findings that suggest specific CMT2 subtypes; for example:
• Optic atrophy: CMT2A2 (
• Vocal cord paresis: CMT2C (
• Optic atrophy: CMT2A2 (
• Vocal cord paresis: CMT2C (
• Optic atrophy: CMT2A2 (
• Vocal cord paresis: CMT2C (
## Clinical Characteristics
Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) is a disorder of peripheral nerves in which the motor system is more prominently involved than the sensory system, although both are involved [
Affected individuals usually become symptomatic between ages five and 25 years [
The adult with CMT2 typically has bilateral foot drop, symmetric atrophy of muscles below the knee (stork leg appearance) and absent tendon reflexes in the lower extremities. However, brisk tendon reflexes and extensor plantar responses have been reported as well as asymmetric muscle atrophy in up to 15% of affected individuals [
Atrophy of intrinsic hand muscles is less frequently present and tendon reflexes may be intact in the upper limbs.
Proximal muscles usually remain strong. Brisk tendon reflexes and extensor plantar responses have been reported [
Mild sensory deficits of position, vibration, and pain/temperature may occur in the feet or sensation may be intact. Pain, especially in the feet, is reported by about 20%-40% of affected individuals [
Vocal cord or phrenic nerve involvement resulting in difficulty with phonation or breathing has been observed [
Restless legs and sleep apnea have been observed [
CMT2 is progressive over many years, but affected individuals experience long plateau periods without obvious deterioration. In some, the disease can be so mild as to go unrecognized by the affected individual and physician. The disease does not decrease life span.
Nerve biopsy shows:
Loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments (not the hypertrophy or onion bulb formation seen in Charcot-Marie-Tooth hereditary neuropathy type 1 [CMT1]);
Large nodal gaps and shorter internodal lengths than controls, suggesting a developmental abnormality of internode formation [
CMT2A2 is characterized by early-onset, severe pure motor neuropathy [
CMT with pyramidal signs is also known as hereditary motor and sensory neuropathy V (HMSN V) [
CMT2I is a late-onset (>45 years) axonal neuropathy [
CMT2J is associated with deafness and/or pupillary abnormalities [
See also
No genotype-phenotype correlations are known for any of the genes known to cause CMT2.
Editor's note: In
Other experts in the field emphasize the physiology of the phenotypes such that all axonal varieties are classified as CMT2 regardless of mode of inheritance. Examples include:
The nomenclature for all types of CMT is undergoing revision. A new nomenclature for CMT is likely to name the subtypes by gene.
The overall prevalence of hereditary neuropathies is estimated at 3:10,000 population, varying by country from 10:100,000 to 80:100,000 [
In a study of 776 Germans with a CMT2 phenotype,
• Loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments (not the hypertrophy or onion bulb formation seen in Charcot-Marie-Tooth hereditary neuropathy type 1 [CMT1]);
• Large nodal gaps and shorter internodal lengths than controls, suggesting a developmental abnormality of internode formation [
• CMT2A2 is characterized by early-onset, severe pure motor neuropathy [
• CMT with pyramidal signs is also known as hereditary motor and sensory neuropathy V (HMSN V) [
• CMT2I is a late-onset (>45 years) axonal neuropathy [
• CMT2J is associated with deafness and/or pupillary abnormalities [
## Clinical Description
Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) is a disorder of peripheral nerves in which the motor system is more prominently involved than the sensory system, although both are involved [
Affected individuals usually become symptomatic between ages five and 25 years [
The adult with CMT2 typically has bilateral foot drop, symmetric atrophy of muscles below the knee (stork leg appearance) and absent tendon reflexes in the lower extremities. However, brisk tendon reflexes and extensor plantar responses have been reported as well as asymmetric muscle atrophy in up to 15% of affected individuals [
Atrophy of intrinsic hand muscles is less frequently present and tendon reflexes may be intact in the upper limbs.
Proximal muscles usually remain strong. Brisk tendon reflexes and extensor plantar responses have been reported [
Mild sensory deficits of position, vibration, and pain/temperature may occur in the feet or sensation may be intact. Pain, especially in the feet, is reported by about 20%-40% of affected individuals [
Vocal cord or phrenic nerve involvement resulting in difficulty with phonation or breathing has been observed [
Restless legs and sleep apnea have been observed [
CMT2 is progressive over many years, but affected individuals experience long plateau periods without obvious deterioration. In some, the disease can be so mild as to go unrecognized by the affected individual and physician. The disease does not decrease life span.
Nerve biopsy shows:
Loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments (not the hypertrophy or onion bulb formation seen in Charcot-Marie-Tooth hereditary neuropathy type 1 [CMT1]);
Large nodal gaps and shorter internodal lengths than controls, suggesting a developmental abnormality of internode formation [
CMT2A2 is characterized by early-onset, severe pure motor neuropathy [
CMT with pyramidal signs is also known as hereditary motor and sensory neuropathy V (HMSN V) [
CMT2I is a late-onset (>45 years) axonal neuropathy [
CMT2J is associated with deafness and/or pupillary abnormalities [
See also
• Loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments (not the hypertrophy or onion bulb formation seen in Charcot-Marie-Tooth hereditary neuropathy type 1 [CMT1]);
• Large nodal gaps and shorter internodal lengths than controls, suggesting a developmental abnormality of internode formation [
• CMT2A2 is characterized by early-onset, severe pure motor neuropathy [
• CMT with pyramidal signs is also known as hereditary motor and sensory neuropathy V (HMSN V) [
• CMT2I is a late-onset (>45 years) axonal neuropathy [
• CMT2J is associated with deafness and/or pupillary abnormalities [
## Phenotype Correlations with Genes Included in
CMT2A2 is characterized by early-onset, severe pure motor neuropathy [
CMT with pyramidal signs is also known as hereditary motor and sensory neuropathy V (HMSN V) [
CMT2I is a late-onset (>45 years) axonal neuropathy [
CMT2J is associated with deafness and/or pupillary abnormalities [
See also
• CMT2A2 is characterized by early-onset, severe pure motor neuropathy [
• CMT with pyramidal signs is also known as hereditary motor and sensory neuropathy V (HMSN V) [
• CMT2I is a late-onset (>45 years) axonal neuropathy [
• CMT2J is associated with deafness and/or pupillary abnormalities [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations are known for any of the genes known to cause CMT2.
## Nomenclature
Editor's note: In
Other experts in the field emphasize the physiology of the phenotypes such that all axonal varieties are classified as CMT2 regardless of mode of inheritance. Examples include:
The nomenclature for all types of CMT is undergoing revision. A new nomenclature for CMT is likely to name the subtypes by gene.
## Prevalence
The overall prevalence of hereditary neuropathies is estimated at 3:10,000 population, varying by country from 10:100,000 to 80:100,000 [
In a study of 776 Germans with a CMT2 phenotype,
## Genetically Related (Allelic) Disorders
Other phenotypes associated with mutation of the genes in
Allelic Disorders
See hyperlinked
## Differential Diagnosis
See
Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) can sometimes be difficult to distinguish from chronic idiopathic axonal neuropathy.
A median motor NCV of 38 m/s is often used as a threshold for differentiating CMT1 from CMT2; however, the CMT2 phenotype can result from mutation of genes primarily associated with CMT1 (caused by mutation of
CMT2B1 (
The "burning feet syndrome" [
Hereditary sensory neuropathy (including
Additional Disorders to Consider in the Differential Diagnosis of Charcot-Marie-Tooth Neuropathy Type 2
Giant axons infrequently seen on nerve biopsy
Mild cardiomyopathy
Likely associated w/neurofilament degradation
Mixed axonal & mild demyelinating disease
Early onset
Sensory ataxia
Tremor
Slow disease progression
Usually causes centronuclear myopathy
May be an overlap w/a predominantly CMT2 presentation
Sensory neuropathy associated w/hearing loss & later dementia
Spinal muscular atrophy w/calf predominance (but also including triceps & hand weakness)
Onset ranges from age 13 to 48 yrs
Severity ranges from mild to severe
Nerve conductions show reduced motor evoked amplitudes
May be referred to as distal hereditary motor neuronopathy 2D (HMN2D)
Moderate to severe motor & sensory neuropathy in males
Usually mild to no symptoms in females
Sensorineural deafness & central nervous system symptoms in some families
Sural nerve pathology shows demyelination compatible w/CMT1
Hearing impairment
Childhood-onset CMT syndrome later complicated by renal glomerulosclerosis
Nerve conductions vary from moderately slow to normal
Intellectual disability & hearing loss reported
Asymmetric weakness
Proximal weakness [
Prominent sensory loss
Pyramidal signs [
Severe incapacity in adulthood [
One family reported w/a CMT2 syndrome
One family reported presynaptic neuromuscular junction disorder resembling Lambert-Eaton myasthenic syndrome [
One family reported w/mixed NCV CMT
Mixed axonal & mild demyelinating phenotype [
Also classified as dominant intermediate CMT (DI-CMTC)
MOI = mode of inheritance
XL = X-linked
AD = autosomal dominant
AR = autosomal recessive
Other pathogenic variants in
The CMT2 phenotype may sometimes be associated with signs of spasticity (e.g., hyperactive tendon reflexes and/or Babinski signs), a phenotype sometimes referred to as HMSN V. Mutation of two genes has been identified:
Mutation of the nuclear gene
Mutation in the mitochondrial genome may also be associated with neuropathy (e.g., in
• The "burning feet syndrome" [
• Hereditary sensory neuropathy (including
• Giant axons infrequently seen on nerve biopsy
• Mild cardiomyopathy
• Likely associated w/neurofilament degradation
• Mixed axonal & mild demyelinating disease
• Early onset
• Sensory ataxia
• Tremor
• Slow disease progression
• Usually causes centronuclear myopathy
• May be an overlap w/a predominantly CMT2 presentation
• Sensory neuropathy associated w/hearing loss & later dementia
• Spinal muscular atrophy w/calf predominance (but also including triceps & hand weakness)
• Onset ranges from age 13 to 48 yrs
• Severity ranges from mild to severe
• Nerve conductions show reduced motor evoked amplitudes
• May be referred to as distal hereditary motor neuronopathy 2D (HMN2D)
• Moderate to severe motor & sensory neuropathy in males
• Usually mild to no symptoms in females
• Sensorineural deafness & central nervous system symptoms in some families
• Sural nerve pathology shows demyelination compatible w/CMT1
• Hearing impairment
• Childhood-onset CMT syndrome later complicated by renal glomerulosclerosis
• Nerve conductions vary from moderately slow to normal
• Intellectual disability & hearing loss reported
• Asymmetric weakness
• Proximal weakness [
• Prominent sensory loss
• Pyramidal signs [
• Severe incapacity in adulthood [
• One family reported w/a CMT2 syndrome
• One family reported presynaptic neuromuscular junction disorder resembling Lambert-Eaton myasthenic syndrome [
• One family reported w/mixed NCV CMT
• Mixed axonal & mild demyelinating phenotype [
• Also classified as dominant intermediate CMT (DI-CMTC)
• Mutation of the nuclear gene
• Mutation in the mitochondrial genome may also be associated with neuropathy (e.g., in
## Management
To establish the extent of disease and needs in an individual diagnosed with Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2), the following evaluations are recommended:
Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, and sensory loss
Nerve conduction velocity (NCV)
Complete family history
Consultation with a clinical geneticist and/or genetic counselor
Treatment is symptomatic. Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [
The following may be indicated:
Special shoes, including those with good ankle support
Ankle/foot orthoses (AFO) to correct foot drop and aid walking
Orthopedic surgery to correct severe pes cavus deformity [
Forearm crutches or canes for gait stability; fewer than 5% need wheelchairs.
Treatment of sleep apnea or restless legs [
Exercise within the individual's capability. In a systematic review of all reports of exercise for CMT,
Pain and depression should be treated symptomatically [
Daily heel cord-stretching exercises help prevent Achilles' tendon shortening.
Gait and condition of feet should be monitored to determine need for bracing, special shoes, or surgery.
Obesity is to be avoided because it makes walking more difficult.
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
See
A German study reviewed 63 pregnancies in 33 women with CMT and found no increase in the frequency of cesarean sections, forceps deliveries, premature births, or neonatal problems [
A Norway study found a higher than average rate of operative deliveries among women with CMT [
Search
• Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, and sensory loss
• Nerve conduction velocity (NCV)
• Complete family history
• Consultation with a clinical geneticist and/or genetic counselor
• Special shoes, including those with good ankle support
• Ankle/foot orthoses (AFO) to correct foot drop and aid walking
• Orthopedic surgery to correct severe pes cavus deformity [
• Forearm crutches or canes for gait stability; fewer than 5% need wheelchairs.
• Treatment of sleep apnea or restless legs [
• Exercise within the individual's capability. In a systematic review of all reports of exercise for CMT,
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2), the following evaluations are recommended:
Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, and sensory loss
Nerve conduction velocity (NCV)
Complete family history
Consultation with a clinical geneticist and/or genetic counselor
• Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, and sensory loss
• Nerve conduction velocity (NCV)
• Complete family history
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Treatment is symptomatic. Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [
The following may be indicated:
Special shoes, including those with good ankle support
Ankle/foot orthoses (AFO) to correct foot drop and aid walking
Orthopedic surgery to correct severe pes cavus deformity [
Forearm crutches or canes for gait stability; fewer than 5% need wheelchairs.
Treatment of sleep apnea or restless legs [
Exercise within the individual's capability. In a systematic review of all reports of exercise for CMT,
Pain and depression should be treated symptomatically [
• Special shoes, including those with good ankle support
• Ankle/foot orthoses (AFO) to correct foot drop and aid walking
• Orthopedic surgery to correct severe pes cavus deformity [
• Forearm crutches or canes for gait stability; fewer than 5% need wheelchairs.
• Treatment of sleep apnea or restless legs [
• Exercise within the individual's capability. In a systematic review of all reports of exercise for CMT,
## Prevention of Secondary Complications
Daily heel cord-stretching exercises help prevent Achilles' tendon shortening.
## Surveillance
Gait and condition of feet should be monitored to determine need for bracing, special shoes, or surgery.
## Agents/Circumstances to Avoid
Obesity is to be avoided because it makes walking more difficult.
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
## Evaluation of Relatives at Risk
See
## Pregnancy Management
A German study reviewed 63 pregnancies in 33 women with CMT and found no increase in the frequency of cesarean sections, forceps deliveries, premature births, or neonatal problems [
A Norway study found a higher than average rate of operative deliveries among women with CMT [
## Therapies Under Investigation
Search
## Genetic Counseling
Most CMT2 subtypes are inherited in an autosomal dominant manner. (Of note, CMT2 associated with pathogenic variants in
CMT2 associated with pathogenic variants in
Most individuals diagnosed with autosomal dominant CMT2 have an affected parent.
A proband with autosomal dominant CMT2 may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
Although most individuals diagnosed with autosomal dominant CMT2 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
The risk to sibs depends on the genetic status of the proband's parents.
If a parent of the proband is affected, the risk to the sibs is 50%.
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism. (Although no instances of germline mosaicism have been reported, it remains a possibility.)
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions regarding testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
It is appropriate to consider testing symptomatic individuals regardless of age in a family with an established diagnosis of CMT2.
For more information, see the National Society of Genetic Counselors
Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CMT2 are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
• Most individuals diagnosed with autosomal dominant CMT2 have an affected parent.
• A proband with autosomal dominant CMT2 may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• Although most individuals diagnosed with autosomal dominant CMT2 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
• The risk to sibs depends on the genetic status of the proband's parents.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism. (Although no instances of germline mosaicism have been reported, it remains a possibility.)
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions regarding testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Most CMT2 subtypes are inherited in an autosomal dominant manner. (Of note, CMT2 associated with pathogenic variants in
CMT2 associated with pathogenic variants in
## Risk to Family Members — Autosomal Dominant CMT2
Most individuals diagnosed with autosomal dominant CMT2 have an affected parent.
A proband with autosomal dominant CMT2 may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
Although most individuals diagnosed with autosomal dominant CMT2 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
The risk to sibs depends on the genetic status of the proband's parents.
If a parent of the proband is affected, the risk to the sibs is 50%.
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism. (Although no instances of germline mosaicism have been reported, it remains a possibility.)
• Most individuals diagnosed with autosomal dominant CMT2 have an affected parent.
• A proband with autosomal dominant CMT2 may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• Although most individuals diagnosed with autosomal dominant CMT2 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
• The risk to sibs depends on the genetic status of the proband's parents.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism. (Although no instances of germline mosaicism have been reported, it remains a possibility.)
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions regarding testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
It is appropriate to consider testing symptomatic individuals regardless of age in a family with an established diagnosis of CMT2.
For more information, see the National Society of Genetic Counselors
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions regarding testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CMT2 are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
## Resources
France
PO Box 105
Glenolden PA 19036
Department of Molecular Genetics
University of Antwerp
Antwerp Antwerpen B-2610
Belgium
432 Park Avenue South
4th Floor
New York NY 10016
Institute of Genetic Medicine
University of Newcastle upon Tyne
International Centre for Life
Newcastle upon Tyne NE1 3BZ
United Kingdom
1 Rue de l'International
BP59
Evry cedex 91002
France
Lt Gen van Heutszlaan 6
3743 JN Baarn
Netherlands
222 South Riverside Plaza
Suite 1500
Chicago IL 60606
61A Great Suffolk Street
London SE1 0BU
United Kingdom
•
• France
•
•
• PO Box 105
• Glenolden PA 19036
•
•
• Department of Molecular Genetics
• University of Antwerp
• Antwerp Antwerpen B-2610
• Belgium
•
• 432 Park Avenue South
• 4th Floor
• New York NY 10016
•
•
•
•
•
•
•
•
• Institute of Genetic Medicine
• University of Newcastle upon Tyne
• International Centre for Life
• Newcastle upon Tyne NE1 3BZ
• United Kingdom
•
•
• 1 Rue de l'International
• BP59
• Evry cedex 91002
• France
•
•
• Lt Gen van Heutszlaan 6
• 3743 JN Baarn
• Netherlands
•
•
• 222 South Riverside Plaza
• Suite 1500
• Chicago IL 60606
•
•
• 61A Great Suffolk Street
• London SE1 0BU
• United Kingdom
•
•
•
## Molecular Genetics
Charcot-Marie-Tooth Neuropathy Type 2: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Charcot-Marie-Tooth Neuropathy Type 2 (
The relationship of myelin and axon pathology to the pathogenesis of CMT is discussed in detail in several reviews [
Information on the three genes that account for more than 2% of CMT2 (
Click
Deletion of exons 7 and 8 in
Selected
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
## Molecular Pathogenesis
The relationship of myelin and axon pathology to the pathogenesis of CMT is discussed in detail in several reviews [
Information on the three genes that account for more than 2% of CMT2 (
Click
Deletion of exons 7 and 8 in
Selected
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
##
Deletion of exons 7 and 8 in
##
Selected
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
## References
## Published Guidelines / Consensus Statements
## Literature Cited
## Chapter Notes
5 July 2018 (ma) Chapter retired: covered in
14 April 2016 (tb) Revision:
24 March 2016 (bp) Comprehensive update posted live
30 April 2015 (tb) Revision: heterozygous mutation of
12 March 2015 (tb) Revision: discussion of CMT nomenclature; additions to Differential Diagnosis; references added [
2 October 2014 (tb) Revision: edits to Differential Diagnosis
31 July 2014 (tb) Revision: addition of
3 April 2014 (tb) Revision: addition of
20 February 2014 (tb) Revision: Lee et al 2013 added to Preimplantation genetic diagnosis
30 January 2014 (tb) Revision:
14 November 2013 (tb) Revision: figure added to Prevalence and Molecular Genetics [
11 July 2013 (tb) Revision: additions to Prevalence and Differential Diagnosis
3 January 2013 (cd) Revision: sequence analysis of select exons of
13 December 2012 (tb) Revision: mutations in
13 September 2012 (tb) Revision: addition of
30 August 2012 (cd) Revision: sequence analysis for
5 July 2012 (me) Comprehensive update posted live
9 February 2012 (tb) Revision: mutations in
22 December 2011 (tb) Revision: mutations in
15 September 2011 (tb) Revision: Differential Diagnosis — intermediate form of CMT
18 August 2011 (cd) Revision: targeted mutation analysis for p.Ala335Val in
1 March 2011 (cd) Revision: edits to Testing Strategy
27 January 2011 (cd) Revision: testing available clinically for CMT2C
27 May 2010 (cd) Revision: edits to Agents/Circumstances to Avoid
11 March 2010 (me) Comprehensive update posted live
7 January 2008 (cd) Revision: prenatal diagnosis for CMT2D available
16 August 2007 (me) Comprehensive update posted live
30 January 2007 (tb) Revision: sequence analysis clinically available on a limited basis for CMT2D
30 December 2005 (cd) Revision: testing and prenatal diagnosis for CMT2B clinically available; prenatal diagnosis for CMT2A clinically available
21 December 2005 (tb) Revision: Differential Diagnosis — HMSN-V
14 June 2005 (tb) Revision: CMT2K added
4 May 2005 (me) Comprehensive update posted live
6 December 2004 (tb) Revision: testing
9 September 2004 (tb,cd) Revision: MFN2 added; sequence analysis clinically available
9 August 2004 (tb,cd) Revision: CMT2B1
21 June 2004 (tb) Revision: CMT2F
10 May 2004 (tb) Author revisions
1 April 2004 (tb) Revision: prenatal diagnosis available for CMT2E
7 April 2003 (me) Comprehensive update posted live
12 September 2001 (tb) Author revisions
24 July 2001 (tb) Author revisions
27 June 2001 (tb) Author revisions
19 June 2001 (tb) Revision: CMT2A gene found
23 March 2001 (tb) Author revisions
16 January 2001 (tb) Author revisions
25 August 2000 (me) Comprehensive update posted live
15 June 2000 (tb) Author revisions
15 May 2000 (tb) Author revisions
3 February 2000 (tb) Author revisions
12 October 1998 (tb) Author revisions
24 September 1998 (pb) Review posted live
April 1996 (tb) Original submission
• 5 July 2018 (ma) Chapter retired: covered in
• 14 April 2016 (tb) Revision:
• 24 March 2016 (bp) Comprehensive update posted live
• 30 April 2015 (tb) Revision: heterozygous mutation of
• 12 March 2015 (tb) Revision: discussion of CMT nomenclature; additions to Differential Diagnosis; references added [
• 2 October 2014 (tb) Revision: edits to Differential Diagnosis
• 31 July 2014 (tb) Revision: addition of
• 3 April 2014 (tb) Revision: addition of
• 20 February 2014 (tb) Revision: Lee et al 2013 added to Preimplantation genetic diagnosis
• 30 January 2014 (tb) Revision:
• 14 November 2013 (tb) Revision: figure added to Prevalence and Molecular Genetics [
• 11 July 2013 (tb) Revision: additions to Prevalence and Differential Diagnosis
• 3 January 2013 (cd) Revision: sequence analysis of select exons of
• 13 December 2012 (tb) Revision: mutations in
• 13 September 2012 (tb) Revision: addition of
• 30 August 2012 (cd) Revision: sequence analysis for
• 5 July 2012 (me) Comprehensive update posted live
• 9 February 2012 (tb) Revision: mutations in
• 22 December 2011 (tb) Revision: mutations in
• 15 September 2011 (tb) Revision: Differential Diagnosis — intermediate form of CMT
• 18 August 2011 (cd) Revision: targeted mutation analysis for p.Ala335Val in
• 1 March 2011 (cd) Revision: edits to Testing Strategy
• 27 January 2011 (cd) Revision: testing available clinically for CMT2C
• 27 May 2010 (cd) Revision: edits to Agents/Circumstances to Avoid
• 11 March 2010 (me) Comprehensive update posted live
• 7 January 2008 (cd) Revision: prenatal diagnosis for CMT2D available
• 16 August 2007 (me) Comprehensive update posted live
• 30 January 2007 (tb) Revision: sequence analysis clinically available on a limited basis for CMT2D
• 30 December 2005 (cd) Revision: testing and prenatal diagnosis for CMT2B clinically available; prenatal diagnosis for CMT2A clinically available
• 21 December 2005 (tb) Revision: Differential Diagnosis — HMSN-V
• 14 June 2005 (tb) Revision: CMT2K added
• 4 May 2005 (me) Comprehensive update posted live
• 6 December 2004 (tb) Revision: testing
• 9 September 2004 (tb,cd) Revision: MFN2 added; sequence analysis clinically available
• 9 August 2004 (tb,cd) Revision: CMT2B1
• 21 June 2004 (tb) Revision: CMT2F
• 10 May 2004 (tb) Author revisions
• 1 April 2004 (tb) Revision: prenatal diagnosis available for CMT2E
• 7 April 2003 (me) Comprehensive update posted live
• 12 September 2001 (tb) Author revisions
• 24 July 2001 (tb) Author revisions
• 27 June 2001 (tb) Author revisions
• 19 June 2001 (tb) Revision: CMT2A gene found
• 23 March 2001 (tb) Author revisions
• 16 January 2001 (tb) Author revisions
• 25 August 2000 (me) Comprehensive update posted live
• 15 June 2000 (tb) Author revisions
• 15 May 2000 (tb) Author revisions
• 3 February 2000 (tb) Author revisions
• 12 October 1998 (tb) Author revisions
• 24 September 1998 (pb) Review posted live
• April 1996 (tb) Original submission
## Revision History
5 July 2018 (ma) Chapter retired: covered in
14 April 2016 (tb) Revision:
24 March 2016 (bp) Comprehensive update posted live
30 April 2015 (tb) Revision: heterozygous mutation of
12 March 2015 (tb) Revision: discussion of CMT nomenclature; additions to Differential Diagnosis; references added [
2 October 2014 (tb) Revision: edits to Differential Diagnosis
31 July 2014 (tb) Revision: addition of
3 April 2014 (tb) Revision: addition of
20 February 2014 (tb) Revision: Lee et al 2013 added to Preimplantation genetic diagnosis
30 January 2014 (tb) Revision:
14 November 2013 (tb) Revision: figure added to Prevalence and Molecular Genetics [
11 July 2013 (tb) Revision: additions to Prevalence and Differential Diagnosis
3 January 2013 (cd) Revision: sequence analysis of select exons of
13 December 2012 (tb) Revision: mutations in
13 September 2012 (tb) Revision: addition of
30 August 2012 (cd) Revision: sequence analysis for
5 July 2012 (me) Comprehensive update posted live
9 February 2012 (tb) Revision: mutations in
22 December 2011 (tb) Revision: mutations in
15 September 2011 (tb) Revision: Differential Diagnosis — intermediate form of CMT
18 August 2011 (cd) Revision: targeted mutation analysis for p.Ala335Val in
1 March 2011 (cd) Revision: edits to Testing Strategy
27 January 2011 (cd) Revision: testing available clinically for CMT2C
27 May 2010 (cd) Revision: edits to Agents/Circumstances to Avoid
11 March 2010 (me) Comprehensive update posted live
7 January 2008 (cd) Revision: prenatal diagnosis for CMT2D available
16 August 2007 (me) Comprehensive update posted live
30 January 2007 (tb) Revision: sequence analysis clinically available on a limited basis for CMT2D
30 December 2005 (cd) Revision: testing and prenatal diagnosis for CMT2B clinically available; prenatal diagnosis for CMT2A clinically available
21 December 2005 (tb) Revision: Differential Diagnosis — HMSN-V
14 June 2005 (tb) Revision: CMT2K added
4 May 2005 (me) Comprehensive update posted live
6 December 2004 (tb) Revision: testing
9 September 2004 (tb,cd) Revision: MFN2 added; sequence analysis clinically available
9 August 2004 (tb,cd) Revision: CMT2B1
21 June 2004 (tb) Revision: CMT2F
10 May 2004 (tb) Author revisions
1 April 2004 (tb) Revision: prenatal diagnosis available for CMT2E
7 April 2003 (me) Comprehensive update posted live
12 September 2001 (tb) Author revisions
24 July 2001 (tb) Author revisions
27 June 2001 (tb) Author revisions
19 June 2001 (tb) Revision: CMT2A gene found
23 March 2001 (tb) Author revisions
16 January 2001 (tb) Author revisions
25 August 2000 (me) Comprehensive update posted live
15 June 2000 (tb) Author revisions
15 May 2000 (tb) Author revisions
3 February 2000 (tb) Author revisions
12 October 1998 (tb) Author revisions
24 September 1998 (pb) Review posted live
April 1996 (tb) Original submission
• 5 July 2018 (ma) Chapter retired: covered in
• 14 April 2016 (tb) Revision:
• 24 March 2016 (bp) Comprehensive update posted live
• 30 April 2015 (tb) Revision: heterozygous mutation of
• 12 March 2015 (tb) Revision: discussion of CMT nomenclature; additions to Differential Diagnosis; references added [
• 2 October 2014 (tb) Revision: edits to Differential Diagnosis
• 31 July 2014 (tb) Revision: addition of
• 3 April 2014 (tb) Revision: addition of
• 20 February 2014 (tb) Revision: Lee et al 2013 added to Preimplantation genetic diagnosis
• 30 January 2014 (tb) Revision:
• 14 November 2013 (tb) Revision: figure added to Prevalence and Molecular Genetics [
• 11 July 2013 (tb) Revision: additions to Prevalence and Differential Diagnosis
• 3 January 2013 (cd) Revision: sequence analysis of select exons of
• 13 December 2012 (tb) Revision: mutations in
• 13 September 2012 (tb) Revision: addition of
• 30 August 2012 (cd) Revision: sequence analysis for
• 5 July 2012 (me) Comprehensive update posted live
• 9 February 2012 (tb) Revision: mutations in
• 22 December 2011 (tb) Revision: mutations in
• 15 September 2011 (tb) Revision: Differential Diagnosis — intermediate form of CMT
• 18 August 2011 (cd) Revision: targeted mutation analysis for p.Ala335Val in
• 1 March 2011 (cd) Revision: edits to Testing Strategy
• 27 January 2011 (cd) Revision: testing available clinically for CMT2C
• 27 May 2010 (cd) Revision: edits to Agents/Circumstances to Avoid
• 11 March 2010 (me) Comprehensive update posted live
• 7 January 2008 (cd) Revision: prenatal diagnosis for CMT2D available
• 16 August 2007 (me) Comprehensive update posted live
• 30 January 2007 (tb) Revision: sequence analysis clinically available on a limited basis for CMT2D
• 30 December 2005 (cd) Revision: testing and prenatal diagnosis for CMT2B clinically available; prenatal diagnosis for CMT2A clinically available
• 21 December 2005 (tb) Revision: Differential Diagnosis — HMSN-V
• 14 June 2005 (tb) Revision: CMT2K added
• 4 May 2005 (me) Comprehensive update posted live
• 6 December 2004 (tb) Revision: testing
• 9 September 2004 (tb,cd) Revision: MFN2 added; sequence analysis clinically available
• 9 August 2004 (tb,cd) Revision: CMT2B1
• 21 June 2004 (tb) Revision: CMT2F
• 10 May 2004 (tb) Author revisions
• 1 April 2004 (tb) Revision: prenatal diagnosis available for CMT2E
• 7 April 2003 (me) Comprehensive update posted live
• 12 September 2001 (tb) Author revisions
• 24 July 2001 (tb) Author revisions
• 27 June 2001 (tb) Author revisions
• 19 June 2001 (tb) Revision: CMT2A gene found
• 23 March 2001 (tb) Author revisions
• 16 January 2001 (tb) Author revisions
• 25 August 2000 (me) Comprehensive update posted live
• 15 June 2000 (tb) Author revisions
• 15 May 2000 (tb) Author revisions
• 3 February 2000 (tb) Author revisions
• 12 October 1998 (tb) Author revisions
• 24 September 1998 (pb) Review posted live
• April 1996 (tb) Original submission
|
[] |
24/9/1998
|
24/3/2016
|
14/4/2016
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cmt2a
|
cmt2a
|
[
"MFN2 Charcot-Marie-Tooth Neuropathy",
"MFN2-HMSN",
"MFN2-HMSN",
"MFN2 Charcot-Marie-Tooth Neuropathy",
"Mitofusin-2",
"MFN2",
"MFN2 Hereditary Motor and Sensory Neuropathy"
] |
Stephan Züchner
|
Summary Molecular genetic testing establishes the diagnosis of Approximately 90% of Once the
|
## Diagnosis
Formal diagnostic criteria for
Onset before age ten years (although a wide range has been reported)
Involvement of the lower extremities earlier and more severely than the upper extremities
Involvement of the distal upper extremities as the neuropathy progresses
Motor deficits more prominent than sensory deficits
Optic atrophy (~7% in the autosomal dominant form, and ~20% in the autosomal recessive form)
Nerve conduction velocities (NCVs) are normal (>42 m/s) or only slightly decreased [
Electromyogram (EMG) reveals signs of chronic denervation.
The diagnosis of
A heterozygous pathogenic variant involving
Biallelic
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
When the diagnosis of
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance –
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
<1%
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
One in 360 individuals with
• Onset before age ten years (although a wide range has been reported)
• Involvement of the lower extremities earlier and more severely than the upper extremities
• Involvement of the distal upper extremities as the neuropathy progresses
• Motor deficits more prominent than sensory deficits
• Optic atrophy (~7% in the autosomal dominant form, and ~20% in the autosomal recessive form)
• Nerve conduction velocities (NCVs) are normal (>42 m/s) or only slightly decreased [
• Electromyogram (EMG) reveals signs of chronic denervation.
• A heterozygous pathogenic variant involving
• Biallelic
## Suggestive Findings
Onset before age ten years (although a wide range has been reported)
Involvement of the lower extremities earlier and more severely than the upper extremities
Involvement of the distal upper extremities as the neuropathy progresses
Motor deficits more prominent than sensory deficits
Optic atrophy (~7% in the autosomal dominant form, and ~20% in the autosomal recessive form)
Nerve conduction velocities (NCVs) are normal (>42 m/s) or only slightly decreased [
Electromyogram (EMG) reveals signs of chronic denervation.
• Onset before age ten years (although a wide range has been reported)
• Involvement of the lower extremities earlier and more severely than the upper extremities
• Involvement of the distal upper extremities as the neuropathy progresses
• Motor deficits more prominent than sensory deficits
• Optic atrophy (~7% in the autosomal dominant form, and ~20% in the autosomal recessive form)
• Nerve conduction velocities (NCVs) are normal (>42 m/s) or only slightly decreased [
• Electromyogram (EMG) reveals signs of chronic denervation.
## Establishing the Diagnosis
The diagnosis of
A heterozygous pathogenic variant involving
Biallelic
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
When the diagnosis of
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance –
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
<1%
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
One in 360 individuals with
• A heterozygous pathogenic variant involving
• Biallelic
## Option 1
For an introduction to multigene panels click
## Option 2
When the diagnosis of
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance –
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
<1%
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
One in 360 individuals with
## Clinical Characteristics
The age at onset and disease progression of
Motor signs (weakness and atrophy) predominate, but mild sensory loss in the feet is common. Tendon reflexes are usually absent, but occasionally intact or increased. Mild pyramidal signs including extensor plantar responses, mild increase in tone, and preserved or increased reflexes but without spastic gait have been observed [
Some individuals with
Postural tremor is common [
Affected individuals with early onset (age <10 years) tend to have more severe disability than those with later onset [
Subacute onset of optic atrophy with subsequent slow recovery in 60% of individuals with early onset has been reported [
To date, a single individual with early-onset stroke has been reported [
Approximately 10% of families have biallelic compound heterozygous variants in
In contrast, variants in other amino acid residues are associated with variable expressivity (early vs later onset of disease) dependent on the amino acid substitution at the same residue.
The penetrance for AD
Hereditary motor and sensory neuropathy is most commonly referred to by the eponymous name "Charcot-Marie-Tooth (CMT) neuropathy" or "Charcot-Marie-Tooth disease."
Based on an older classification system in which subtypes were defined by clinical parameters such as mode of inheritance, clinical findings, neuropathy type (defined by electrophysiologic findings), and involved gene,
Clinical Designations Used to Refer to
AD = autosomal dominant; AR = autosomal recessive; HMSN = hereditary motor and sensory neuropathy; MOI = mode of inheritance
Older classification systems may further divide this designation into CMT2A2A (to refer to AD inheritance) and CMT2A2B (to refer to AR inheritance).
Classification using these clinically defined parameters becomes difficult when pathogenic variants in a single gene (e.g.,
To disambiguate, the general term
The proportion of CMT caused by pathogenic variants in
Subsequent publications confirm the frequencies in these early reports both in families/populations largely of Western European ancestry (i.e., in Italy [
• Subsequent publications confirm the frequencies in these early reports both in families/populations largely of Western European ancestry (i.e., in Italy [
## Clinical Description
The age at onset and disease progression of
Motor signs (weakness and atrophy) predominate, but mild sensory loss in the feet is common. Tendon reflexes are usually absent, but occasionally intact or increased. Mild pyramidal signs including extensor plantar responses, mild increase in tone, and preserved or increased reflexes but without spastic gait have been observed [
Some individuals with
Postural tremor is common [
Affected individuals with early onset (age <10 years) tend to have more severe disability than those with later onset [
Subacute onset of optic atrophy with subsequent slow recovery in 60% of individuals with early onset has been reported [
To date, a single individual with early-onset stroke has been reported [
Approximately 10% of families have biallelic compound heterozygous variants in
## Autosomal Dominant
The age at onset and disease progression of
Motor signs (weakness and atrophy) predominate, but mild sensory loss in the feet is common. Tendon reflexes are usually absent, but occasionally intact or increased. Mild pyramidal signs including extensor plantar responses, mild increase in tone, and preserved or increased reflexes but without spastic gait have been observed [
Some individuals with
Postural tremor is common [
Affected individuals with early onset (age <10 years) tend to have more severe disability than those with later onset [
Subacute onset of optic atrophy with subsequent slow recovery in 60% of individuals with early onset has been reported [
To date, a single individual with early-onset stroke has been reported [
## Semi-Dominant and Autosomal Recessive
Approximately 10% of families have biallelic compound heterozygous variants in
## All
## Genotype-Phenotype Correlations
In contrast, variants in other amino acid residues are associated with variable expressivity (early vs later onset of disease) dependent on the amino acid substitution at the same residue.
## Penetrance
The penetrance for AD
## Nomenclature
Hereditary motor and sensory neuropathy is most commonly referred to by the eponymous name "Charcot-Marie-Tooth (CMT) neuropathy" or "Charcot-Marie-Tooth disease."
Based on an older classification system in which subtypes were defined by clinical parameters such as mode of inheritance, clinical findings, neuropathy type (defined by electrophysiologic findings), and involved gene,
Clinical Designations Used to Refer to
AD = autosomal dominant; AR = autosomal recessive; HMSN = hereditary motor and sensory neuropathy; MOI = mode of inheritance
Older classification systems may further divide this designation into CMT2A2A (to refer to AD inheritance) and CMT2A2B (to refer to AR inheritance).
Classification using these clinically defined parameters becomes difficult when pathogenic variants in a single gene (e.g.,
To disambiguate, the general term
## Prevalence
The proportion of CMT caused by pathogenic variants in
Subsequent publications confirm the frequencies in these early reports both in families/populations largely of Western European ancestry (i.e., in Italy [
• Subsequent publications confirm the frequencies in these early reports both in families/populations largely of Western European ancestry (i.e., in Italy [
## Genetically Related (Allelic) Disorders
Biallelic pathogenic variants in
Leigh syndrome spectrum (LSS) was described in one individual with homozygous Arg104Trp pathogenic variants in
## Differential Diagnosis
All hereditary motor and sensory neuropathy (HMSN) forms in which axonal phenotypes have been reported, including
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Feet for evidence of
Mobility, ADL, & need for adaptive devices
Need for handicapped parking
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; AFOs = ankle/foot orthoses; EMG = electromyogram; MOI = mode of inheritance; NCV = nerve conduction velocity; OT = occupational therapy; PT = physical therapy; VEP = visual evoked potentials
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Exercise within the individual's capability
Daily heel cord stretching exercises to prevent Achilles tendon shortening
Special shoes including those with good ankle support
Ankle/foot orthoses to correct foot drop and aid walking [
Orthopedic surgery to correct severe
Forearm crutches or canes for gait stability
Wheelchairs for mobility because of gait instability
Exercising and developing coping strategies for fine motor deficits (e.g., buttoning shirts, sliding credit cards)
Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory agents [
Treatment of neuropathic pain with tricyclic antidepressants or drugs such as carbamazepine or gabapentin
Career and employment counseling because of persistent weakness of hands and/or feet
Individualized education plan (IEP) services that provides specially designed instruction and related services to children who qualify. Vision consultants should be a part of the child's IEP team to support access to academic material.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Recommended Surveillance for Individuals with
Neurologic exam
Electroneurography of peripheral nerves
EMG/ENG
PT assessment (gross motor skills incl gait & strength)
OT assessment (fine motor skills)
EMG = electromyogram; ENG = electronystagmography; OT = occupational therapy; PT = physical therapy
Obesity, which makes walking more difficult, should be avoided.
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
See
Search
• Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Feet for evidence of
• Mobility, ADL, & need for adaptive devices
• Need for handicapped parking
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Exercise within the individual's capability
• Daily heel cord stretching exercises to prevent Achilles tendon shortening
• Special shoes including those with good ankle support
• Ankle/foot orthoses to correct foot drop and aid walking [
• Orthopedic surgery to correct severe
• Forearm crutches or canes for gait stability
• Wheelchairs for mobility because of gait instability
• Exercising and developing coping strategies for fine motor deficits (e.g., buttoning shirts, sliding credit cards)
• Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory agents [
• Treatment of neuropathic pain with tricyclic antidepressants or drugs such as carbamazepine or gabapentin
• Career and employment counseling because of persistent weakness of hands and/or feet
•
• Individualized education plan (IEP) services that provides specially designed instruction and related services to children who qualify. Vision consultants should be a part of the child's IEP team to support access to academic material.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Individualized education plan (IEP) services that provides specially designed instruction and related services to children who qualify. Vision consultants should be a part of the child's IEP team to support access to academic material.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Individualized education plan (IEP) services that provides specially designed instruction and related services to children who qualify. Vision consultants should be a part of the child's IEP team to support access to academic material.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Neurologic exam
• Electroneurography of peripheral nerves
• EMG/ENG
• PT assessment (gross motor skills incl gait & strength)
• OT assessment (fine motor skills)
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Feet for evidence of
Mobility, ADL, & need for adaptive devices
Need for handicapped parking
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; AFOs = ankle/foot orthoses; EMG = electromyogram; MOI = mode of inheritance; NCV = nerve conduction velocity; OT = occupational therapy; PT = physical therapy; VEP = visual evoked potentials
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Feet for evidence of
• Mobility, ADL, & need for adaptive devices
• Need for handicapped parking
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Exercise within the individual's capability
Daily heel cord stretching exercises to prevent Achilles tendon shortening
Special shoes including those with good ankle support
Ankle/foot orthoses to correct foot drop and aid walking [
Orthopedic surgery to correct severe
Forearm crutches or canes for gait stability
Wheelchairs for mobility because of gait instability
Exercising and developing coping strategies for fine motor deficits (e.g., buttoning shirts, sliding credit cards)
Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory agents [
Treatment of neuropathic pain with tricyclic antidepressants or drugs such as carbamazepine or gabapentin
Career and employment counseling because of persistent weakness of hands and/or feet
Individualized education plan (IEP) services that provides specially designed instruction and related services to children who qualify. Vision consultants should be a part of the child's IEP team to support access to academic material.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Exercise within the individual's capability
• Daily heel cord stretching exercises to prevent Achilles tendon shortening
• Special shoes including those with good ankle support
• Ankle/foot orthoses to correct foot drop and aid walking [
• Orthopedic surgery to correct severe
• Forearm crutches or canes for gait stability
• Wheelchairs for mobility because of gait instability
• Exercising and developing coping strategies for fine motor deficits (e.g., buttoning shirts, sliding credit cards)
• Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory agents [
• Treatment of neuropathic pain with tricyclic antidepressants or drugs such as carbamazepine or gabapentin
• Career and employment counseling because of persistent weakness of hands and/or feet
•
• Individualized education plan (IEP) services that provides specially designed instruction and related services to children who qualify. Vision consultants should be a part of the child's IEP team to support access to academic material.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Individualized education plan (IEP) services that provides specially designed instruction and related services to children who qualify. Vision consultants should be a part of the child's IEP team to support access to academic material.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Individualized education plan (IEP) services that provides specially designed instruction and related services to children who qualify. Vision consultants should be a part of the child's IEP team to support access to academic material.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
## Surveillance
Recommended Surveillance for Individuals with
Neurologic exam
Electroneurography of peripheral nerves
EMG/ENG
PT assessment (gross motor skills incl gait & strength)
OT assessment (fine motor skills)
EMG = electromyogram; ENG = electronystagmography; OT = occupational therapy; PT = physical therapy
• Neurologic exam
• Electroneurography of peripheral nerves
• EMG/ENG
• PT assessment (gross motor skills incl gait & strength)
• OT assessment (fine motor skills)
## Agents/Circumstances to Avoid
Obesity, which makes walking more difficult, should be avoided.
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Semi-dominant inheritance (i.e., a pathogenic variant is associated with mild disease in the heterozygous state and more severe disease in the homozygous or compound heterozygous state) of
Most individuals diagnosed with autosomal dominant
A proband with
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
The family history of some individuals diagnosed with
Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected [
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Intrafamilial clinical variability has been observed in
If the proband has a known
When the parents are clinically unaffected, the risk to sibs of the proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
Individuals who are heterozygous for one autosomal recessive
If both parents are known to be heterozygous for an
Individuals who are heterozygous for one autosomal recessive
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, at risk of being affected, or at risk of being a carrier of autosomal recessive
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals diagnosed with autosomal dominant
• A proband with
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• The family history of some individuals diagnosed with
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected [
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Intrafamilial clinical variability has been observed in
• If the proband has a known
• When the parents are clinically unaffected, the risk to sibs of the proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• Individuals who are heterozygous for one autosomal recessive
• If both parents are known to be heterozygous for an
• Individuals who are heterozygous for one autosomal recessive
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, at risk of being affected, or at risk of being a carrier of autosomal recessive
## Mode of Inheritance
Semi-dominant inheritance (i.e., a pathogenic variant is associated with mild disease in the heterozygous state and more severe disease in the homozygous or compound heterozygous state) of
## Autosomal Dominant Inheritance – Risk to Family Members
Most individuals diagnosed with autosomal dominant
A proband with
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
The family history of some individuals diagnosed with
Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected [
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Intrafamilial clinical variability has been observed in
If the proband has a known
When the parents are clinically unaffected, the risk to sibs of the proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for
• Most individuals diagnosed with autosomal dominant
• A proband with
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• The family history of some individuals diagnosed with
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected [
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Intrafamilial clinical variability has been observed in
• If the proband has a known
• When the parents are clinically unaffected, the risk to sibs of the proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for
## Autosomal Recessive Inheritance
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
Individuals who are heterozygous for one autosomal recessive
If both parents are known to be heterozygous for an
Individuals who are heterozygous for one autosomal recessive
Carrier testing for at-risk relatives requires prior identification of the
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• Individuals who are heterozygous for one autosomal recessive
• If both parents are known to be heterozygous for an
• Individuals who are heterozygous for one autosomal recessive
## Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
Individuals who are heterozygous for one autosomal recessive
If both parents are known to be heterozygous for an
Individuals who are heterozygous for one autosomal recessive
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• Individuals who are heterozygous for one autosomal recessive
• If both parents are known to be heterozygous for an
• Individuals who are heterozygous for one autosomal recessive
## Carrier (Heterozygote) Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, at risk of being affected, or at risk of being a carrier of autosomal recessive
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, at risk of being affected, or at risk of being a carrier of autosomal recessive
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
France
Department of Molecular Genetics
University of Antwerp
Antwerp Antwerpen B-2610
Belgium
Institute of Translational and Clinical Research
University of Newcastle upon Tyne
International Centre for Life
Newcastle upon Tyne NE1 3BZ
United Kingdom
France
United Kingdom
•
• France
•
•
•
•
• Department of Molecular Genetics
• University of Antwerp
• Antwerp Antwerpen B-2610
• Belgium
•
•
•
•
•
•
•
• Institute of Translational and Clinical Research
• University of Newcastle upon Tyne
• International Centre for Life
• Newcastle upon Tyne NE1 3BZ
• United Kingdom
•
•
• France
•
•
•
•
•
•
• United Kingdom
•
•
•
## Molecular Genetics
MFN2 Hereditary Motor and Sensory Neuropathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for MFN2 Hereditary Motor and Sensory Neuropathy (
MFN2 is a key protein in mitochondrial fusion. It has been suggested that pathogenic variants in
## Molecular Pathogenesis
MFN2 is a key protein in mitochondrial fusion. It has been suggested that pathogenic variants in
## Chapter Notes
27 March 2025 (aa) Revision: Leigh syndrome spectrum added to
14 May 2020 (bp) Comprehensive update posted live
1 August 2013 (me) Comprehensive update posted live
12 September 2007 (me) Comprehensive update posted live
18 February 2005 (me) Review posted live
13 September 2004 (sz) Original submission
• 27 March 2025 (aa) Revision: Leigh syndrome spectrum added to
• 14 May 2020 (bp) Comprehensive update posted live
• 1 August 2013 (me) Comprehensive update posted live
• 12 September 2007 (me) Comprehensive update posted live
• 18 February 2005 (me) Review posted live
• 13 September 2004 (sz) Original submission
## Revision History
27 March 2025 (aa) Revision: Leigh syndrome spectrum added to
14 May 2020 (bp) Comprehensive update posted live
1 August 2013 (me) Comprehensive update posted live
12 September 2007 (me) Comprehensive update posted live
18 February 2005 (me) Review posted live
13 September 2004 (sz) Original submission
• 27 March 2025 (aa) Revision: Leigh syndrome spectrum added to
• 14 May 2020 (bp) Comprehensive update posted live
• 1 August 2013 (me) Comprehensive update posted live
• 12 September 2007 (me) Comprehensive update posted live
• 18 February 2005 (me) Review posted live
• 13 September 2004 (sz) Original submission
## References
## Literature Cited
|
[] |
18/2/2005
|
14/5/2020
|
27/3/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
cmt2c
|
cmt2c
|
[
"Charcot-Marie-Tooth Neuropathy Type 2C (CMT2C)",
"Scapuloperoneal Spinal Muscular Atrophy (SPSMA)",
"Congenital Distal Spinal Muscular Atrophy (CDSMA)",
"Familial Digital Arthropathy-Brachydactyly",
"Autosomal Dominant Brachyolmia",
"Spondylometaphyseal Dysplasia, Kozlowski Type",
"Spondyloepiphyseal Dysplasia, Maroteaux Type",
"Parastremmatic Dysplasia",
"Metatropic Dysplasia",
"Transient receptor potential cation channel subfamily V member 4",
"TRPV4",
"Autosomal Dominant TRPV4 Disorders"
] |
Autosomal Dominant
|
Brett A McCray, Alice Schindler, Julie E Hoover-Fong, Charlotte J Sumner
|
Summary The autosomal dominant The three autosomal dominant neuromuscular disorders (mildest to most severe) are: Charcot-Marie-Tooth disease type 2C Scapuloperoneal spinal muscular atrophy Congenital distal spinal muscular atrophy The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: Familial digital arthropathy-brachydactyly Autosomal dominant brachyolmia Spondylometaphyseal dysplasia, Kozlowski type Spondyloepiphyseal dysplasia, Maroteaux type Parastremmatic dysplasia Metatropic dysplasia The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias. The diagnosis of an autosomal dominant For neuromuscular disorders, neuropathy and respiratory dysfunction are managed in a routine manner; individuals with laryngeal dysfunction require ENT evaluation that should include speech therapy, laryngoscopy, and, in some instances, surgery. For skeletal dysplasias, physical therapy/exercise and heel-cord stretching to maintain function; surgical intervention when kyphoscoliosis compromises pulmonary function and/or causes pain and/or when upper cervical spine instability and/or cervical myelopathy are present.
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Charcot-Marie-Tooth neuropathy type 2C (CMT2C)
Scapuloperoneal spinal muscular atrophy (SPSMA)
Congenital distal spinal muscular atrophy (CDSMA)
Familial digital arthropathy-brachydactyly
Autosomal dominant brachyolmia
Spondylometaphyseal dysplasia, Kozlowski type
Spondyloepiphyseal dysplasia, Maroteaux type
Parastremmatic dysplasia
Metatropic dysplasia
For synonyms and outdated names see
The phenotypes comprising the two groups of autosomal dominant
• Charcot-Marie-Tooth neuropathy type 2C (CMT2C)
• Scapuloperoneal spinal muscular atrophy (SPSMA)
• Congenital distal spinal muscular atrophy (CDSMA)
• Familial digital arthropathy-brachydactyly
• Autosomal dominant brachyolmia
• Spondylometaphyseal dysplasia, Kozlowski type
• Spondyloepiphyseal dysplasia, Maroteaux type
• Parastremmatic dysplasia
• Metatropic dysplasia
## Diagnosis
An
A progressive peripheral neuronopathy/neuropathy (primarily motor, rather than sensory) associated with pes cavus, distal amyotrophy, and foot drop
Nerve conduction studies [
Electromyography shows predominantly chronic neurogenic changes.
Nerve biopsy is infrequently employed, as the findings (loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments) do not differentiate between various causes of axonal neuropathy.
Laryngeal dysfunction (i.e., vocal fold paresis) that may be bilateral and severe (resulting in inspiratory stridor and/or a raspy [hoarse] voice) or asymmetric (often more severe on the left than the right). Mild paresis may be inferred by presence of flaccid dysphonia [
Sensorineural hearing loss (SNHL), which is bilateral and progressive and ranges from mild to moderate. Onset is from childhood to adulthood [
Respiratory dysfunction in some cases including intercostal and diaphragm muscle weakness, which may lead to respiratory insufficiency and/or sleep apnea [
Joint contractures (appearing similar to arthrogryposis multiplex congenita [AMC]) and short stature in some cases
A family history consistent with autosomal dominant inheritance
Slowly progressive lower motor neuron loss associated with muscle weakness and atrophy proximally in the shoulder girdle region (with characteristic scapular winging) and distally in the peroneal (lower leg) muscles. In severe cases, absence of muscle and weakness are evident at birth [
Muscle biopsy (infrequently performed) shows evidence of denervation and renervation [
Laryngeal dysfunction (laryngomalacia and vocal fold anomalies as in
SNHL (as in
Sensory deficits (rare)
Kyphoscoliosis
Congenital-onset, non-progressive or slowly progressive lower motor neuron loss associated with muscle weakness and atrophy, predominantly affecting the lower extremities (distal greater than proximal)
Flexion contractures of the knees and hips often present at birth (i.e., AMC). Severe bilateral clubfoot is also seen.
MRI of calf and thigh muscles shows a distinct pattern of fatty atrophy with preservation of the biceps femoris in the lateral thighs and of the medial gastrocnemius in the posteromedial calves [
Neurologic Findings by
AMC = arthrogryposis multiplex congenita; CMT2C = Charcot-Marie-Tooth disease type 2C; CDSMA = congenital distal spinal muscular atrophy; SNHL= sensorineural hearing loss; SPSMA = scapuloperoneal spinal muscular atrophy
More mild manifestation: congenital weakness of the distal part of the lower limbs only. More severe manifestation: weakness of the pelvic girdle and trunk muscles, resulting in scoliosis.
Secondary to diaphragmatic and intercostal muscle involvement
Cold sensitivity (i.e., worsening of hand weakness in the cold)
Rounded shoulders, laterally displaced scapulae
Proximal muscle weakness (shoulder girdle, pelvic girdle) later in the disease course
An
Familial digital arthropathy-brachydactyly characterized by the following:
Normal hands and feet at birth, then relative shortening of the middle and distal phalanges with swelling and decreased range of motion of the interphalangeal joints in early childhood
Progressive arthropathy of the other joints of the hands and feet with pain and deformity
No clinical overlap with other
The other autosomal dominant
Short stature
Progressive spinal deformity with scoliosis with or without kyphosis, and radiographic features of platyspondyly and overfaced pedicles
At least one additional distinctive feature (See
Radiographic and Clinical Features of Autosomal Dominant
NA = not applicable
Rarest
Overfaced pedicles = lateral border of the vertebrae appears outside the lateral edge of the pedicles, a characteristic feature of
Additional findings: hyperplastic femoral trochanters, severe genu valgum, bowing of long bones, legs twisted along the long axis
Histologic findings: thin seal of bone at the chondroosseous junction, absent primary metaphyseal spongiosa, abnormal metaphyseal vascular invasion, arrest of endochondral ring structures with persistence of circumferential growth
The term "Halberd-shaped pelvis" is derived from the shape of a Swedish battle ax.
Progressive kyphoscoliosis and platyspondyly subsequently alter proportions from short-limb to short-trunk dwarfism.
The diagnosis of an
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
For an introduction to multigene panels click
Molecular Genetic Testing Used in Autosomal Dominant
See
See
Sequence analysis can detect variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The authors are unaware of a whole-gene or contiguous gene deletion of
• A progressive peripheral neuronopathy/neuropathy (primarily motor, rather than sensory) associated with pes cavus, distal amyotrophy, and foot drop
• Nerve conduction studies [
• Electromyography shows predominantly chronic neurogenic changes.
• Nerve biopsy is infrequently employed, as the findings (loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments) do not differentiate between various causes of axonal neuropathy.
• Nerve conduction studies [
• Electromyography shows predominantly chronic neurogenic changes.
• Nerve biopsy is infrequently employed, as the findings (loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments) do not differentiate between various causes of axonal neuropathy.
• Laryngeal dysfunction (i.e., vocal fold paresis) that may be bilateral and severe (resulting in inspiratory stridor and/or a raspy [hoarse] voice) or asymmetric (often more severe on the left than the right). Mild paresis may be inferred by presence of flaccid dysphonia [
• Sensorineural hearing loss (SNHL), which is bilateral and progressive and ranges from mild to moderate. Onset is from childhood to adulthood [
• Respiratory dysfunction in some cases including intercostal and diaphragm muscle weakness, which may lead to respiratory insufficiency and/or sleep apnea [
• Joint contractures (appearing similar to arthrogryposis multiplex congenita [AMC]) and short stature in some cases
• A family history consistent with autosomal dominant inheritance
• Nerve conduction studies [
• Electromyography shows predominantly chronic neurogenic changes.
• Nerve biopsy is infrequently employed, as the findings (loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments) do not differentiate between various causes of axonal neuropathy.
• Slowly progressive lower motor neuron loss associated with muscle weakness and atrophy proximally in the shoulder girdle region (with characteristic scapular winging) and distally in the peroneal (lower leg) muscles. In severe cases, absence of muscle and weakness are evident at birth [
• Muscle biopsy (infrequently performed) shows evidence of denervation and renervation [
• Laryngeal dysfunction (laryngomalacia and vocal fold anomalies as in
• SNHL (as in
• Sensory deficits (rare)
• Kyphoscoliosis
• Congenital-onset, non-progressive or slowly progressive lower motor neuron loss associated with muscle weakness and atrophy, predominantly affecting the lower extremities (distal greater than proximal)
• Flexion contractures of the knees and hips often present at birth (i.e., AMC). Severe bilateral clubfoot is also seen.
• MRI of calf and thigh muscles shows a distinct pattern of fatty atrophy with preservation of the biceps femoris in the lateral thighs and of the medial gastrocnemius in the posteromedial calves [
• Familial digital arthropathy-brachydactyly characterized by the following:
• Normal hands and feet at birth, then relative shortening of the middle and distal phalanges with swelling and decreased range of motion of the interphalangeal joints in early childhood
• Progressive arthropathy of the other joints of the hands and feet with pain and deformity
• No clinical overlap with other
• Normal hands and feet at birth, then relative shortening of the middle and distal phalanges with swelling and decreased range of motion of the interphalangeal joints in early childhood
• Progressive arthropathy of the other joints of the hands and feet with pain and deformity
• No clinical overlap with other
• The other autosomal dominant
• Short stature
• Progressive spinal deformity with scoliosis with or without kyphosis, and radiographic features of platyspondyly and overfaced pedicles
• At least one additional distinctive feature (See
• Short stature
• Progressive spinal deformity with scoliosis with or without kyphosis, and radiographic features of platyspondyly and overfaced pedicles
• At least one additional distinctive feature (See
• Normal hands and feet at birth, then relative shortening of the middle and distal phalanges with swelling and decreased range of motion of the interphalangeal joints in early childhood
• Progressive arthropathy of the other joints of the hands and feet with pain and deformity
• No clinical overlap with other
• Short stature
• Progressive spinal deformity with scoliosis with or without kyphosis, and radiographic features of platyspondyly and overfaced pedicles
• At least one additional distinctive feature (See
## Suggestive Findings
An
A progressive peripheral neuronopathy/neuropathy (primarily motor, rather than sensory) associated with pes cavus, distal amyotrophy, and foot drop
Nerve conduction studies [
Electromyography shows predominantly chronic neurogenic changes.
Nerve biopsy is infrequently employed, as the findings (loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments) do not differentiate between various causes of axonal neuropathy.
Laryngeal dysfunction (i.e., vocal fold paresis) that may be bilateral and severe (resulting in inspiratory stridor and/or a raspy [hoarse] voice) or asymmetric (often more severe on the left than the right). Mild paresis may be inferred by presence of flaccid dysphonia [
Sensorineural hearing loss (SNHL), which is bilateral and progressive and ranges from mild to moderate. Onset is from childhood to adulthood [
Respiratory dysfunction in some cases including intercostal and diaphragm muscle weakness, which may lead to respiratory insufficiency and/or sleep apnea [
Joint contractures (appearing similar to arthrogryposis multiplex congenita [AMC]) and short stature in some cases
A family history consistent with autosomal dominant inheritance
Slowly progressive lower motor neuron loss associated with muscle weakness and atrophy proximally in the shoulder girdle region (with characteristic scapular winging) and distally in the peroneal (lower leg) muscles. In severe cases, absence of muscle and weakness are evident at birth [
Muscle biopsy (infrequently performed) shows evidence of denervation and renervation [
Laryngeal dysfunction (laryngomalacia and vocal fold anomalies as in
SNHL (as in
Sensory deficits (rare)
Kyphoscoliosis
Congenital-onset, non-progressive or slowly progressive lower motor neuron loss associated with muscle weakness and atrophy, predominantly affecting the lower extremities (distal greater than proximal)
Flexion contractures of the knees and hips often present at birth (i.e., AMC). Severe bilateral clubfoot is also seen.
MRI of calf and thigh muscles shows a distinct pattern of fatty atrophy with preservation of the biceps femoris in the lateral thighs and of the medial gastrocnemius in the posteromedial calves [
Neurologic Findings by
AMC = arthrogryposis multiplex congenita; CMT2C = Charcot-Marie-Tooth disease type 2C; CDSMA = congenital distal spinal muscular atrophy; SNHL= sensorineural hearing loss; SPSMA = scapuloperoneal spinal muscular atrophy
More mild manifestation: congenital weakness of the distal part of the lower limbs only. More severe manifestation: weakness of the pelvic girdle and trunk muscles, resulting in scoliosis.
Secondary to diaphragmatic and intercostal muscle involvement
Cold sensitivity (i.e., worsening of hand weakness in the cold)
Rounded shoulders, laterally displaced scapulae
Proximal muscle weakness (shoulder girdle, pelvic girdle) later in the disease course
An
Familial digital arthropathy-brachydactyly characterized by the following:
Normal hands and feet at birth, then relative shortening of the middle and distal phalanges with swelling and decreased range of motion of the interphalangeal joints in early childhood
Progressive arthropathy of the other joints of the hands and feet with pain and deformity
No clinical overlap with other
The other autosomal dominant
Short stature
Progressive spinal deformity with scoliosis with or without kyphosis, and radiographic features of platyspondyly and overfaced pedicles
At least one additional distinctive feature (See
Radiographic and Clinical Features of Autosomal Dominant
NA = not applicable
Rarest
Overfaced pedicles = lateral border of the vertebrae appears outside the lateral edge of the pedicles, a characteristic feature of
Additional findings: hyperplastic femoral trochanters, severe genu valgum, bowing of long bones, legs twisted along the long axis
Histologic findings: thin seal of bone at the chondroosseous junction, absent primary metaphyseal spongiosa, abnormal metaphyseal vascular invasion, arrest of endochondral ring structures with persistence of circumferential growth
The term "Halberd-shaped pelvis" is derived from the shape of a Swedish battle ax.
Progressive kyphoscoliosis and platyspondyly subsequently alter proportions from short-limb to short-trunk dwarfism.
• A progressive peripheral neuronopathy/neuropathy (primarily motor, rather than sensory) associated with pes cavus, distal amyotrophy, and foot drop
• Nerve conduction studies [
• Electromyography shows predominantly chronic neurogenic changes.
• Nerve biopsy is infrequently employed, as the findings (loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments) do not differentiate between various causes of axonal neuropathy.
• Nerve conduction studies [
• Electromyography shows predominantly chronic neurogenic changes.
• Nerve biopsy is infrequently employed, as the findings (loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments) do not differentiate between various causes of axonal neuropathy.
• Laryngeal dysfunction (i.e., vocal fold paresis) that may be bilateral and severe (resulting in inspiratory stridor and/or a raspy [hoarse] voice) or asymmetric (often more severe on the left than the right). Mild paresis may be inferred by presence of flaccid dysphonia [
• Sensorineural hearing loss (SNHL), which is bilateral and progressive and ranges from mild to moderate. Onset is from childhood to adulthood [
• Respiratory dysfunction in some cases including intercostal and diaphragm muscle weakness, which may lead to respiratory insufficiency and/or sleep apnea [
• Joint contractures (appearing similar to arthrogryposis multiplex congenita [AMC]) and short stature in some cases
• A family history consistent with autosomal dominant inheritance
• Nerve conduction studies [
• Electromyography shows predominantly chronic neurogenic changes.
• Nerve biopsy is infrequently employed, as the findings (loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments) do not differentiate between various causes of axonal neuropathy.
• Slowly progressive lower motor neuron loss associated with muscle weakness and atrophy proximally in the shoulder girdle region (with characteristic scapular winging) and distally in the peroneal (lower leg) muscles. In severe cases, absence of muscle and weakness are evident at birth [
• Muscle biopsy (infrequently performed) shows evidence of denervation and renervation [
• Laryngeal dysfunction (laryngomalacia and vocal fold anomalies as in
• SNHL (as in
• Sensory deficits (rare)
• Kyphoscoliosis
• Congenital-onset, non-progressive or slowly progressive lower motor neuron loss associated with muscle weakness and atrophy, predominantly affecting the lower extremities (distal greater than proximal)
• Flexion contractures of the knees and hips often present at birth (i.e., AMC). Severe bilateral clubfoot is also seen.
• MRI of calf and thigh muscles shows a distinct pattern of fatty atrophy with preservation of the biceps femoris in the lateral thighs and of the medial gastrocnemius in the posteromedial calves [
• Familial digital arthropathy-brachydactyly characterized by the following:
• Normal hands and feet at birth, then relative shortening of the middle and distal phalanges with swelling and decreased range of motion of the interphalangeal joints in early childhood
• Progressive arthropathy of the other joints of the hands and feet with pain and deformity
• No clinical overlap with other
• Normal hands and feet at birth, then relative shortening of the middle and distal phalanges with swelling and decreased range of motion of the interphalangeal joints in early childhood
• Progressive arthropathy of the other joints of the hands and feet with pain and deformity
• No clinical overlap with other
• The other autosomal dominant
• Short stature
• Progressive spinal deformity with scoliosis with or without kyphosis, and radiographic features of platyspondyly and overfaced pedicles
• At least one additional distinctive feature (See
• Short stature
• Progressive spinal deformity with scoliosis with or without kyphosis, and radiographic features of platyspondyly and overfaced pedicles
• At least one additional distinctive feature (See
• Normal hands and feet at birth, then relative shortening of the middle and distal phalanges with swelling and decreased range of motion of the interphalangeal joints in early childhood
• Progressive arthropathy of the other joints of the hands and feet with pain and deformity
• No clinical overlap with other
• Short stature
• Progressive spinal deformity with scoliosis with or without kyphosis, and radiographic features of platyspondyly and overfaced pedicles
• At least one additional distinctive feature (See
## Neuromuscular Disorders
An
A progressive peripheral neuronopathy/neuropathy (primarily motor, rather than sensory) associated with pes cavus, distal amyotrophy, and foot drop
Nerve conduction studies [
Electromyography shows predominantly chronic neurogenic changes.
Nerve biopsy is infrequently employed, as the findings (loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments) do not differentiate between various causes of axonal neuropathy.
Laryngeal dysfunction (i.e., vocal fold paresis) that may be bilateral and severe (resulting in inspiratory stridor and/or a raspy [hoarse] voice) or asymmetric (often more severe on the left than the right). Mild paresis may be inferred by presence of flaccid dysphonia [
Sensorineural hearing loss (SNHL), which is bilateral and progressive and ranges from mild to moderate. Onset is from childhood to adulthood [
Respiratory dysfunction in some cases including intercostal and diaphragm muscle weakness, which may lead to respiratory insufficiency and/or sleep apnea [
Joint contractures (appearing similar to arthrogryposis multiplex congenita [AMC]) and short stature in some cases
A family history consistent with autosomal dominant inheritance
Slowly progressive lower motor neuron loss associated with muscle weakness and atrophy proximally in the shoulder girdle region (with characteristic scapular winging) and distally in the peroneal (lower leg) muscles. In severe cases, absence of muscle and weakness are evident at birth [
Muscle biopsy (infrequently performed) shows evidence of denervation and renervation [
Laryngeal dysfunction (laryngomalacia and vocal fold anomalies as in
SNHL (as in
Sensory deficits (rare)
Kyphoscoliosis
Congenital-onset, non-progressive or slowly progressive lower motor neuron loss associated with muscle weakness and atrophy, predominantly affecting the lower extremities (distal greater than proximal)
Flexion contractures of the knees and hips often present at birth (i.e., AMC). Severe bilateral clubfoot is also seen.
MRI of calf and thigh muscles shows a distinct pattern of fatty atrophy with preservation of the biceps femoris in the lateral thighs and of the medial gastrocnemius in the posteromedial calves [
Neurologic Findings by
AMC = arthrogryposis multiplex congenita; CMT2C = Charcot-Marie-Tooth disease type 2C; CDSMA = congenital distal spinal muscular atrophy; SNHL= sensorineural hearing loss; SPSMA = scapuloperoneal spinal muscular atrophy
More mild manifestation: congenital weakness of the distal part of the lower limbs only. More severe manifestation: weakness of the pelvic girdle and trunk muscles, resulting in scoliosis.
Secondary to diaphragmatic and intercostal muscle involvement
Cold sensitivity (i.e., worsening of hand weakness in the cold)
Rounded shoulders, laterally displaced scapulae
Proximal muscle weakness (shoulder girdle, pelvic girdle) later in the disease course
• A progressive peripheral neuronopathy/neuropathy (primarily motor, rather than sensory) associated with pes cavus, distal amyotrophy, and foot drop
• Nerve conduction studies [
• Electromyography shows predominantly chronic neurogenic changes.
• Nerve biopsy is infrequently employed, as the findings (loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments) do not differentiate between various causes of axonal neuropathy.
• Nerve conduction studies [
• Electromyography shows predominantly chronic neurogenic changes.
• Nerve biopsy is infrequently employed, as the findings (loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments) do not differentiate between various causes of axonal neuropathy.
• Laryngeal dysfunction (i.e., vocal fold paresis) that may be bilateral and severe (resulting in inspiratory stridor and/or a raspy [hoarse] voice) or asymmetric (often more severe on the left than the right). Mild paresis may be inferred by presence of flaccid dysphonia [
• Sensorineural hearing loss (SNHL), which is bilateral and progressive and ranges from mild to moderate. Onset is from childhood to adulthood [
• Respiratory dysfunction in some cases including intercostal and diaphragm muscle weakness, which may lead to respiratory insufficiency and/or sleep apnea [
• Joint contractures (appearing similar to arthrogryposis multiplex congenita [AMC]) and short stature in some cases
• A family history consistent with autosomal dominant inheritance
• Nerve conduction studies [
• Electromyography shows predominantly chronic neurogenic changes.
• Nerve biopsy is infrequently employed, as the findings (loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments) do not differentiate between various causes of axonal neuropathy.
• Slowly progressive lower motor neuron loss associated with muscle weakness and atrophy proximally in the shoulder girdle region (with characteristic scapular winging) and distally in the peroneal (lower leg) muscles. In severe cases, absence of muscle and weakness are evident at birth [
• Muscle biopsy (infrequently performed) shows evidence of denervation and renervation [
• Laryngeal dysfunction (laryngomalacia and vocal fold anomalies as in
• SNHL (as in
• Sensory deficits (rare)
• Kyphoscoliosis
• Congenital-onset, non-progressive or slowly progressive lower motor neuron loss associated with muscle weakness and atrophy, predominantly affecting the lower extremities (distal greater than proximal)
• Flexion contractures of the knees and hips often present at birth (i.e., AMC). Severe bilateral clubfoot is also seen.
• MRI of calf and thigh muscles shows a distinct pattern of fatty atrophy with preservation of the biceps femoris in the lateral thighs and of the medial gastrocnemius in the posteromedial calves [
## Skeletal Dysplasias
An
Familial digital arthropathy-brachydactyly characterized by the following:
Normal hands and feet at birth, then relative shortening of the middle and distal phalanges with swelling and decreased range of motion of the interphalangeal joints in early childhood
Progressive arthropathy of the other joints of the hands and feet with pain and deformity
No clinical overlap with other
The other autosomal dominant
Short stature
Progressive spinal deformity with scoliosis with or without kyphosis, and radiographic features of platyspondyly and overfaced pedicles
At least one additional distinctive feature (See
Radiographic and Clinical Features of Autosomal Dominant
NA = not applicable
Rarest
Overfaced pedicles = lateral border of the vertebrae appears outside the lateral edge of the pedicles, a characteristic feature of
Additional findings: hyperplastic femoral trochanters, severe genu valgum, bowing of long bones, legs twisted along the long axis
Histologic findings: thin seal of bone at the chondroosseous junction, absent primary metaphyseal spongiosa, abnormal metaphyseal vascular invasion, arrest of endochondral ring structures with persistence of circumferential growth
The term "Halberd-shaped pelvis" is derived from the shape of a Swedish battle ax.
Progressive kyphoscoliosis and platyspondyly subsequently alter proportions from short-limb to short-trunk dwarfism.
• Familial digital arthropathy-brachydactyly characterized by the following:
• Normal hands and feet at birth, then relative shortening of the middle and distal phalanges with swelling and decreased range of motion of the interphalangeal joints in early childhood
• Progressive arthropathy of the other joints of the hands and feet with pain and deformity
• No clinical overlap with other
• Normal hands and feet at birth, then relative shortening of the middle and distal phalanges with swelling and decreased range of motion of the interphalangeal joints in early childhood
• Progressive arthropathy of the other joints of the hands and feet with pain and deformity
• No clinical overlap with other
• The other autosomal dominant
• Short stature
• Progressive spinal deformity with scoliosis with or without kyphosis, and radiographic features of platyspondyly and overfaced pedicles
• At least one additional distinctive feature (See
• Short stature
• Progressive spinal deformity with scoliosis with or without kyphosis, and radiographic features of platyspondyly and overfaced pedicles
• At least one additional distinctive feature (See
• Normal hands and feet at birth, then relative shortening of the middle and distal phalanges with swelling and decreased range of motion of the interphalangeal joints in early childhood
• Progressive arthropathy of the other joints of the hands and feet with pain and deformity
• No clinical overlap with other
• Short stature
• Progressive spinal deformity with scoliosis with or without kyphosis, and radiographic features of platyspondyly and overfaced pedicles
• At least one additional distinctive feature (See
## Establishing the Diagnosis
The diagnosis of an
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
For an introduction to multigene panels click
Molecular Genetic Testing Used in Autosomal Dominant
See
See
Sequence analysis can detect variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The authors are unaware of a whole-gene or contiguous gene deletion of
## Clinical Characteristics
The two groups of disorders and the phenotypes comprising autosomal dominant
Neuromuscular disorders (see
Charcot-Marie-Tooth disease type 2C
Scapuloperoneal spinal muscular atrophy
Congenital distal spinal muscular atrophy
Skeletal dysplasias (see
Familial digital arthropathy-brachydactyly
Autosomal dominant brachyolmia
Spondylometaphyseal dysplasia, Kozlowski type
Spondyloepiphyseal dysplasia, Maroteaux type
Parastremmatic dysplasia
Metatropic dysplasia
The phenotypic spectra within both neuromuscular and skeletal groups are broad and overlapping, and the phenotypes of both groups can in rare cases overlap as well [
Of note, sensorineural hearing loss (SNHL), which is bilateral and progressive and ranges from mild to moderate, can occur in both phenotypes. Onset is from childhood to adulthood [
The autosomal dominant
Clinical findings and age of onset can be extremely variable in
Affected individuals typically demonstrate progressive weakness and atrophy of distal muscles in the feet and/or hands, usually associated with depressed tendon reflexes and mild or no sensory loss. However, the congenital phenotypes, scapuloperoneal spinal muscular atrophy (SPSMA) and congenital distal spinal muscular atrophy (CDSMA), are characterized by long plateau periods without obvious deterioration [
Laryngeal dysfunction is a hallmark of Charcot-Marie-Tooth disease type 2C (CMT2C) and is often observed in individuals with SPSMA and CDSMA [
Individuals with severe features may have a decreased life span secondary to respiratory complications [
The remaining autosomal dominant
Metatropic dysplasia may be lethal in the prenatal or perinatal period, largely due to an extremely narrow chest and hypoplastic lung parenchyma. Infants who survive the perinatal period typically develop severe kyphoscoliosis that eventually compromises pulmonary function. Other skeletal findings in some individuals with severe metatropic dysplasia are poor joint range of motion, joint contractures, and torticollis; these arthrogryposis multiplex congenita-like contractures represent an overlap between the neuromuscular and skeletal phenotypes of autosomal dominant
In general, specific sets of
Functional studies suggest that
The familial digital arthropathy-brachydactyly-causing pathogenic variants are restricted to finger 3 of the ankyrin repeats domain (pathogenic variants
Charcot-Marie-Tooth neuropathy type 2C is also referred to as hereditary motor and sensory neuropathy type 2C.
Spondyloepiphyseal dysplasia, Maroteaux type is also referred to as pseudo-Morquio syndrome type 2.
The prevalence of the autosomal dominant
• Neuromuscular disorders (see
• Charcot-Marie-Tooth disease type 2C
• Scapuloperoneal spinal muscular atrophy
• Congenital distal spinal muscular atrophy
• Charcot-Marie-Tooth disease type 2C
• Scapuloperoneal spinal muscular atrophy
• Congenital distal spinal muscular atrophy
• Skeletal dysplasias (see
• Familial digital arthropathy-brachydactyly
• Autosomal dominant brachyolmia
• Spondylometaphyseal dysplasia, Kozlowski type
• Spondyloepiphyseal dysplasia, Maroteaux type
• Parastremmatic dysplasia
• Metatropic dysplasia
• Familial digital arthropathy-brachydactyly
• Autosomal dominant brachyolmia
• Spondylometaphyseal dysplasia, Kozlowski type
• Spondyloepiphyseal dysplasia, Maroteaux type
• Parastremmatic dysplasia
• Metatropic dysplasia
• Charcot-Marie-Tooth disease type 2C
• Scapuloperoneal spinal muscular atrophy
• Congenital distal spinal muscular atrophy
• Familial digital arthropathy-brachydactyly
• Autosomal dominant brachyolmia
• Spondylometaphyseal dysplasia, Kozlowski type
• Spondyloepiphyseal dysplasia, Maroteaux type
• Parastremmatic dysplasia
• Metatropic dysplasia
## Clinical Description
The two groups of disorders and the phenotypes comprising autosomal dominant
Neuromuscular disorders (see
Charcot-Marie-Tooth disease type 2C
Scapuloperoneal spinal muscular atrophy
Congenital distal spinal muscular atrophy
Skeletal dysplasias (see
Familial digital arthropathy-brachydactyly
Autosomal dominant brachyolmia
Spondylometaphyseal dysplasia, Kozlowski type
Spondyloepiphyseal dysplasia, Maroteaux type
Parastremmatic dysplasia
Metatropic dysplasia
The phenotypic spectra within both neuromuscular and skeletal groups are broad and overlapping, and the phenotypes of both groups can in rare cases overlap as well [
Of note, sensorineural hearing loss (SNHL), which is bilateral and progressive and ranges from mild to moderate, can occur in both phenotypes. Onset is from childhood to adulthood [
The autosomal dominant
Clinical findings and age of onset can be extremely variable in
Affected individuals typically demonstrate progressive weakness and atrophy of distal muscles in the feet and/or hands, usually associated with depressed tendon reflexes and mild or no sensory loss. However, the congenital phenotypes, scapuloperoneal spinal muscular atrophy (SPSMA) and congenital distal spinal muscular atrophy (CDSMA), are characterized by long plateau periods without obvious deterioration [
Laryngeal dysfunction is a hallmark of Charcot-Marie-Tooth disease type 2C (CMT2C) and is often observed in individuals with SPSMA and CDSMA [
Individuals with severe features may have a decreased life span secondary to respiratory complications [
The remaining autosomal dominant
Metatropic dysplasia may be lethal in the prenatal or perinatal period, largely due to an extremely narrow chest and hypoplastic lung parenchyma. Infants who survive the perinatal period typically develop severe kyphoscoliosis that eventually compromises pulmonary function. Other skeletal findings in some individuals with severe metatropic dysplasia are poor joint range of motion, joint contractures, and torticollis; these arthrogryposis multiplex congenita-like contractures represent an overlap between the neuromuscular and skeletal phenotypes of autosomal dominant
• Neuromuscular disorders (see
• Charcot-Marie-Tooth disease type 2C
• Scapuloperoneal spinal muscular atrophy
• Congenital distal spinal muscular atrophy
• Charcot-Marie-Tooth disease type 2C
• Scapuloperoneal spinal muscular atrophy
• Congenital distal spinal muscular atrophy
• Skeletal dysplasias (see
• Familial digital arthropathy-brachydactyly
• Autosomal dominant brachyolmia
• Spondylometaphyseal dysplasia, Kozlowski type
• Spondyloepiphyseal dysplasia, Maroteaux type
• Parastremmatic dysplasia
• Metatropic dysplasia
• Familial digital arthropathy-brachydactyly
• Autosomal dominant brachyolmia
• Spondylometaphyseal dysplasia, Kozlowski type
• Spondyloepiphyseal dysplasia, Maroteaux type
• Parastremmatic dysplasia
• Metatropic dysplasia
• Charcot-Marie-Tooth disease type 2C
• Scapuloperoneal spinal muscular atrophy
• Congenital distal spinal muscular atrophy
• Familial digital arthropathy-brachydactyly
• Autosomal dominant brachyolmia
• Spondylometaphyseal dysplasia, Kozlowski type
• Spondyloepiphyseal dysplasia, Maroteaux type
• Parastremmatic dysplasia
• Metatropic dysplasia
## Neuromuscular Disorders
The autosomal dominant
Clinical findings and age of onset can be extremely variable in
Affected individuals typically demonstrate progressive weakness and atrophy of distal muscles in the feet and/or hands, usually associated with depressed tendon reflexes and mild or no sensory loss. However, the congenital phenotypes, scapuloperoneal spinal muscular atrophy (SPSMA) and congenital distal spinal muscular atrophy (CDSMA), are characterized by long plateau periods without obvious deterioration [
Laryngeal dysfunction is a hallmark of Charcot-Marie-Tooth disease type 2C (CMT2C) and is often observed in individuals with SPSMA and CDSMA [
Individuals with severe features may have a decreased life span secondary to respiratory complications [
## Skeletal Dysplasias
The remaining autosomal dominant
Metatropic dysplasia may be lethal in the prenatal or perinatal period, largely due to an extremely narrow chest and hypoplastic lung parenchyma. Infants who survive the perinatal period typically develop severe kyphoscoliosis that eventually compromises pulmonary function. Other skeletal findings in some individuals with severe metatropic dysplasia are poor joint range of motion, joint contractures, and torticollis; these arthrogryposis multiplex congenita-like contractures represent an overlap between the neuromuscular and skeletal phenotypes of autosomal dominant
## Genotype-Phenotype Correlations
In general, specific sets of
Functional studies suggest that
The familial digital arthropathy-brachydactyly-causing pathogenic variants are restricted to finger 3 of the ankyrin repeats domain (pathogenic variants
## Penetrance
## Nomenclature
Charcot-Marie-Tooth neuropathy type 2C is also referred to as hereditary motor and sensory neuropathy type 2C.
Spondyloepiphyseal dysplasia, Maroteaux type is also referred to as pseudo-Morquio syndrome type 2.
## Prevalence
The prevalence of the autosomal dominant
## Genetically Related (Allelic) Disorders
Biallelic
A single individual with homozygous p.Ser94Leu pathogenic variants and a combined phenotype of axonal neuropathy, vocal cord paresis, and arthrogryposis multiplex congenita (in vitro analysis of the p.Ser94Leu variant demonstrated gain of abnormal function) [
Two sibs with compound partial loss-of-function
No phenotypes other than those discussed in this
• A single individual with homozygous p.Ser94Leu pathogenic variants and a combined phenotype of axonal neuropathy, vocal cord paresis, and arthrogryposis multiplex congenita (in vitro analysis of the p.Ser94Leu variant demonstrated gain of abnormal function) [
• Two sibs with compound partial loss-of-function
## Differential Diagnosis
Autosomal dominant
Note: See
Genes of Interest in the Differential Diagnosis of Autosomal Dominant
AD
Genes are listed in alphabetic order.
AD = autosomal dominant; ALS = amyotrophic lateral sclerosis; AR = autosomal recessive; CMT = Charcot-Marie-Tooth neuropathy; dHMN = distal hereditary motor neuropathy; dSMA = distal spinal muscular atrophy; MOI = mode of inheritance; SMA = spinal muscular atrophy; XL = X-linked
Autosomal dominant
Genes of Interest in the Differential Diagnosis of Intermediate and Severe Autosomal Dominant
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; MPS = mucopolysaccharidosis; XL = X-linked
Autosomal recessive otospondylomegaepiphyseal dysplasia may also be referred to as Weissenbacher Zweymuller syndrome.
## Autosomal Dominant
Autosomal dominant
Note: See
Genes of Interest in the Differential Diagnosis of Autosomal Dominant
AD
Genes are listed in alphabetic order.
AD = autosomal dominant; ALS = amyotrophic lateral sclerosis; AR = autosomal recessive; CMT = Charcot-Marie-Tooth neuropathy; dHMN = distal hereditary motor neuropathy; dSMA = distal spinal muscular atrophy; MOI = mode of inheritance; SMA = spinal muscular atrophy; XL = X-linked
## Autosomal Dominant
Autosomal dominant
Genes of Interest in the Differential Diagnosis of Intermediate and Severe Autosomal Dominant
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; MPS = mucopolysaccharidosis; XL = X-linked
Autosomal recessive otospondylomegaepiphyseal dysplasia may also be referred to as Weissenbacher Zweymuller syndrome.
## Management
To establish the extent of disease and needs in an individual diagnosed with an
Recommended Evaluations Following Initial Diagnosis in Individuals with an Autosomal Dominant
Community or
Social work involvement for parental support;
Home nursing referral;
Referral to physiatry, PT, OT, & speech therapy.
EMG = electromyography; NCV = nerve conduction velocity; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
To establish the extent of disease and needs in an individual diagnosed with an
Recommended Evaluations Following Initial Diagnosis in Individuals with an Autosomal Dominant
Community or
Social work involvement for parental support;
Home nursing referral;
Referral to physiatry, PT, & OT.
MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment is focused on symptom management. Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, ENT specialists, and physical and occupational therapists.
Treatment of Manifestations in Individuals with an Autosomal Dominant
Special shoes, incl those w/good ankle support
AFO to correct foot drop & aid walking
Orthopedic surgery to correct severe pes cavus deformity as needed
Forearm crutches, canes/walkers for gait stability, & wheelchairs
Exercise w/in person's capability (Many remain physically active.)
Laryngeal surgery for vocal fold paresis (arytenoidectomy & tracheostomy)
Speech therapy
AFO = ankle-foot orthosis; BiPAP = bilevel positive airway pressure; SNHL = sensorineural hearing loss
Treatment of Manifestations in Individuals with an Autosomal Dominant
Obtain cervical spine radiographs & MRI;
Refer for eval by pediatric orthopedic surgeon or neurosurgeon at tertiary care facility.
PT = physical therapy; SNHL = sensorineural hearing loss
Recommended Surveillance for Individuals with an Autosomal Dominant
PT = physical therapy; SNHL = sensorineural hearing loss
Recommended Surveillance for Individuals with an Autosomal Dominant
A child reaches school age;
Surgical procedures involving general anesthesia.
SNHL = sensorineural hearing loss
In general, obesity is to be avoided because it makes walking more difficult for individuals with neuropathy, skeletal dysplasia, or both
In individuals with odontoid hypoplasia, avoid extreme neck flexion and extension.
Avoid activities and occupations that place undue stress on the spine and weight-bearing joints.
See
There is no registry or data regarding the frequency or outcome of pregnancies in women with a
See
Search
Career and employment choices may be influenced by persistent weakness of hands and/or feet and orthopedic involvement.
• Community or
• Social work involvement for parental support;
• Home nursing referral;
• Referral to physiatry, PT, OT, & speech therapy.
• Community or
• Social work involvement for parental support;
• Home nursing referral;
• Referral to physiatry, PT, & OT.
• Special shoes, incl those w/good ankle support
• AFO to correct foot drop & aid walking
• Orthopedic surgery to correct severe pes cavus deformity as needed
• Forearm crutches, canes/walkers for gait stability, & wheelchairs
• Exercise w/in person's capability (Many remain physically active.)
• Laryngeal surgery for vocal fold paresis (arytenoidectomy & tracheostomy)
• Speech therapy
• Obtain cervical spine radiographs & MRI;
• Refer for eval by pediatric orthopedic surgeon or neurosurgeon at tertiary care facility.
• A child reaches school age;
• Surgical procedures involving general anesthesia.
• In individuals with odontoid hypoplasia, avoid extreme neck flexion and extension.
• Avoid activities and occupations that place undue stress on the spine and weight-bearing joints.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with an
Recommended Evaluations Following Initial Diagnosis in Individuals with an Autosomal Dominant
Community or
Social work involvement for parental support;
Home nursing referral;
Referral to physiatry, PT, OT, & speech therapy.
EMG = electromyography; NCV = nerve conduction velocity; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
To establish the extent of disease and needs in an individual diagnosed with an
Recommended Evaluations Following Initial Diagnosis in Individuals with an Autosomal Dominant
Community or
Social work involvement for parental support;
Home nursing referral;
Referral to physiatry, PT, & OT.
MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Community or
• Social work involvement for parental support;
• Home nursing referral;
• Referral to physiatry, PT, OT, & speech therapy.
• Community or
• Social work involvement for parental support;
• Home nursing referral;
• Referral to physiatry, PT, & OT.
## Treatment of Manifestations
Treatment is focused on symptom management. Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, ENT specialists, and physical and occupational therapists.
Treatment of Manifestations in Individuals with an Autosomal Dominant
Special shoes, incl those w/good ankle support
AFO to correct foot drop & aid walking
Orthopedic surgery to correct severe pes cavus deformity as needed
Forearm crutches, canes/walkers for gait stability, & wheelchairs
Exercise w/in person's capability (Many remain physically active.)
Laryngeal surgery for vocal fold paresis (arytenoidectomy & tracheostomy)
Speech therapy
AFO = ankle-foot orthosis; BiPAP = bilevel positive airway pressure; SNHL = sensorineural hearing loss
Treatment of Manifestations in Individuals with an Autosomal Dominant
Obtain cervical spine radiographs & MRI;
Refer for eval by pediatric orthopedic surgeon or neurosurgeon at tertiary care facility.
PT = physical therapy; SNHL = sensorineural hearing loss
• Special shoes, incl those w/good ankle support
• AFO to correct foot drop & aid walking
• Orthopedic surgery to correct severe pes cavus deformity as needed
• Forearm crutches, canes/walkers for gait stability, & wheelchairs
• Exercise w/in person's capability (Many remain physically active.)
• Laryngeal surgery for vocal fold paresis (arytenoidectomy & tracheostomy)
• Speech therapy
• Obtain cervical spine radiographs & MRI;
• Refer for eval by pediatric orthopedic surgeon or neurosurgeon at tertiary care facility.
## Surveillance
Recommended Surveillance for Individuals with an Autosomal Dominant
PT = physical therapy; SNHL = sensorineural hearing loss
Recommended Surveillance for Individuals with an Autosomal Dominant
A child reaches school age;
Surgical procedures involving general anesthesia.
SNHL = sensorineural hearing loss
• A child reaches school age;
• Surgical procedures involving general anesthesia.
## Agents/Circumstances to Avoid
In general, obesity is to be avoided because it makes walking more difficult for individuals with neuropathy, skeletal dysplasia, or both
In individuals with odontoid hypoplasia, avoid extreme neck flexion and extension.
Avoid activities and occupations that place undue stress on the spine and weight-bearing joints.
• In individuals with odontoid hypoplasia, avoid extreme neck flexion and extension.
• Avoid activities and occupations that place undue stress on the spine and weight-bearing joints.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
There is no registry or data regarding the frequency or outcome of pregnancies in women with a
See
## Therapies Under Investigation
Search
## Other
Career and employment choices may be influenced by persistent weakness of hands and/or feet and orthopedic involvement.
## Genetic Counseling
Because the most severe
Individuals with less severe skeletal phenotypes or neuromuscular phenotypes often have the disorder as the result of a
Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotype or reduced penetrance in the parent with the pathogenic variant. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing indicates that neither parent has the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the
The specific phenotype, age of onset, and disease severity cannot be predicted accurately in a sib who inherits a familial pathogenic variant because of reduced penetrance and variable expressivity. A heterozygous sib may have the same phenotype as the proband or have less severe or more severe clinical manifestations (see
If the
If the parents have not been tested for the
Each child of an individual with a
Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with a
If the proband and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, each child has a 25% likelihood of having average stature, a 25% likelihood of having the same skeletal dysplasia as the father, a 25% likelihood of having the same skeletal dysplasia as the mother, and a 25% likelihood of inheriting a pathogenic variant from both parents and being at risk for a potentially poor outcome.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Genetic counseling is recommended when both parents have a skeletal dysplasia.
Predictive testing for at-risk relatives is possible once the
Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of a
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Because the most severe
• Individuals with less severe skeletal phenotypes or neuromuscular phenotypes often have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotype or reduced penetrance in the parent with the pathogenic variant. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing indicates that neither parent has the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• If a parent of the proband is affected and/or is known to have the
• The specific phenotype, age of onset, and disease severity cannot be predicted accurately in a sib who inherits a familial pathogenic variant because of reduced penetrance and variable expressivity. A heterozygous sib may have the same phenotype as the proband or have less severe or more severe clinical manifestations (see
• If the
• If the parents have not been tested for the
• Each child of an individual with a
• Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with a
• If the proband and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, each child has a 25% likelihood of having average stature, a 25% likelihood of having the same skeletal dysplasia as the father, a 25% likelihood of having the same skeletal dysplasia as the mother, and a 25% likelihood of inheriting a pathogenic variant from both parents and being at risk for a potentially poor outcome.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Genetic counseling is recommended when both parents have a skeletal dysplasia.
• Predictive testing for at-risk relatives is possible once the
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
## Mode of Inheritance
## Risk to Family Members
Because the most severe
Individuals with less severe skeletal phenotypes or neuromuscular phenotypes often have the disorder as the result of a
Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotype or reduced penetrance in the parent with the pathogenic variant. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing indicates that neither parent has the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the
The specific phenotype, age of onset, and disease severity cannot be predicted accurately in a sib who inherits a familial pathogenic variant because of reduced penetrance and variable expressivity. A heterozygous sib may have the same phenotype as the proband or have less severe or more severe clinical manifestations (see
If the
If the parents have not been tested for the
Each child of an individual with a
Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with a
If the proband and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, each child has a 25% likelihood of having average stature, a 25% likelihood of having the same skeletal dysplasia as the father, a 25% likelihood of having the same skeletal dysplasia as the mother, and a 25% likelihood of inheriting a pathogenic variant from both parents and being at risk for a potentially poor outcome.
• Because the most severe
• Individuals with less severe skeletal phenotypes or neuromuscular phenotypes often have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotype or reduced penetrance in the parent with the pathogenic variant. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing indicates that neither parent has the pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• If a parent of the proband is affected and/or is known to have the
• The specific phenotype, age of onset, and disease severity cannot be predicted accurately in a sib who inherits a familial pathogenic variant because of reduced penetrance and variable expressivity. A heterozygous sib may have the same phenotype as the proband or have less severe or more severe clinical manifestations (see
• If the
• If the parents have not been tested for the
• Each child of an individual with a
• Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with a
• If the proband and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, each child has a 25% likelihood of having average stature, a 25% likelihood of having the same skeletal dysplasia as the father, a 25% likelihood of having the same skeletal dysplasia as the mother, and a 25% likelihood of inheriting a pathogenic variant from both parents and being at risk for a potentially poor outcome.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Genetic counseling is recommended when both parents have a skeletal dysplasia.
Predictive testing for at-risk relatives is possible once the
Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of a
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Genetic counseling is recommended when both parents have a skeletal dysplasia.
• Predictive testing for at-risk relatives is possible once the
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
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## Molecular Genetics
Autosomal Dominant TRPV4 Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Autosomal Dominant TRPV4 Disorders (
Osmosensation and flow sensing in the kidney [
Endothelial barrier function in the vascular system [
Mechanosensation and nociception in the sensory nervous system [
Stretch sensation in the bladder [
Skin barrier function [
Chondrogenesis [
Bone homeostasis [
Regulation of adipose oxidative metabolism [
While the precise mechanisms of pathogenesis in
The p.Arg186Gln, p.Arg237Leu, p.Arg269His, p.Arg269Cys, p.Arg316Cys, p.Arg316His, and p.Arg232Cys pathogenic variants showed increased ion channel activity resulting in intracellular calcium levels in vitro, and p.Arg269Cys led to increased intracellular calcium in vivo [
Notable
Variants listed in the table have been provided by the authors.
Denotes a combined neuromuscular and skeletal phenotype
• Osmosensation and flow sensing in the kidney [
• Endothelial barrier function in the vascular system [
• Mechanosensation and nociception in the sensory nervous system [
• Stretch sensation in the bladder [
• Skin barrier function [
• Chondrogenesis [
• Bone homeostasis [
• Regulation of adipose oxidative metabolism [
• The p.Arg186Gln, p.Arg237Leu, p.Arg269His, p.Arg269Cys, p.Arg316Cys, p.Arg316His, and p.Arg232Cys pathogenic variants showed increased ion channel activity resulting in intracellular calcium levels in vitro, and p.Arg269Cys led to increased intracellular calcium in vivo [
## Molecular Pathogenesis
Osmosensation and flow sensing in the kidney [
Endothelial barrier function in the vascular system [
Mechanosensation and nociception in the sensory nervous system [
Stretch sensation in the bladder [
Skin barrier function [
Chondrogenesis [
Bone homeostasis [
Regulation of adipose oxidative metabolism [
While the precise mechanisms of pathogenesis in
The p.Arg186Gln, p.Arg237Leu, p.Arg269His, p.Arg269Cys, p.Arg316Cys, p.Arg316His, and p.Arg232Cys pathogenic variants showed increased ion channel activity resulting in intracellular calcium levels in vitro, and p.Arg269Cys led to increased intracellular calcium in vivo [
Notable
Variants listed in the table have been provided by the authors.
Denotes a combined neuromuscular and skeletal phenotype
• Osmosensation and flow sensing in the kidney [
• Endothelial barrier function in the vascular system [
• Mechanosensation and nociception in the sensory nervous system [
• Stretch sensation in the bladder [
• Skin barrier function [
• Chondrogenesis [
• Bone homeostasis [
• Regulation of adipose oxidative metabolism [
• The p.Arg186Gln, p.Arg237Leu, p.Arg269His, p.Arg269Cys, p.Arg316Cys, p.Arg316His, and p.Arg232Cys pathogenic variants showed increased ion channel activity resulting in intracellular calcium levels in vitro, and p.Arg269Cys led to increased intracellular calcium in vivo [
## Chapter Notes
17 September 2020 (sw) Comprehensive update posted live
15 May 2014 (me) Review posted live
30 July 2013 (as) Original submission
• 17 September 2020 (sw) Comprehensive update posted live
• 15 May 2014 (me) Review posted live
• 30 July 2013 (as) Original submission
## Revision History
17 September 2020 (sw) Comprehensive update posted live
15 May 2014 (me) Review posted live
30 July 2013 (as) Original submission
• 17 September 2020 (sw) Comprehensive update posted live
• 15 May 2014 (me) Review posted live
• 30 July 2013 (as) Original submission
## References
Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
## Published Guidelines / Consensus Statements
Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
## Literature Cited
|
[] |
15/5/2014
|
17/9/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
cmt2d
|
cmt2d
|
[
"GARS1 Adolescent- or Early Adult-Onset Hereditary Motor/Sensory Neuropathy (GARS1-HMSN)",
"Distal Spinal Muscular Atrophy V (dSMA-V)",
"GARS1 Infantile-Onset Spinal Muscular Atrophy (GARS1-iSMA)",
"Glycine--tRNA ligase",
"GARS1",
"GARS1-Associated Axonal Neuropathy"
] |
Rebecca Markovitz, Rajarshi Ghosh, Timothy Lotze, Lorraine Potocki
|
Summary The phenotypic spectrum of The diagnosis of Once the
|
For synonyms and outdated names see
For other genetic causes of these phenotypes see
## Diagnosis
No consensus clinical diagnostic criteria for
Typically, infantile onset of respiratory distress, poor feeding, and muscle weakness, with distal weakness greater than proximal; however, some children may present with features similar to toddlers.
Absence of molecular genetic findings of
Bilateral weakness and atrophy of thenar and first dorsal interosseous muscles with progression to involve hypothenar, foot, and peroneal muscles in many individuals and mild-to-moderate impairment of vibration sense developing in advanced illness in some individuals (see
Sensory deficits including reduction of pinprick, temperature, touch, and vibration perception in a stocking and (less often) glove pattern
EMG shows denervation predominantly in the distal muscle groups at normal motor distal latencies and conduction velocities (see
Absent or markedly reduced (frequently <1 mV) compound muscle action potentials (CMAPs) are recorded from the abductor pollicis brevis (APB) by median nerve stimulation [
Preserved CMAPs are recorded from the abductor digiti minimi (ADM) by ulnar nerve stimulation.
CMAP amplitude recorded by stimulation of the peroneal nerve is <2 mV in most individuals and <1 mV in individuals having clinically evident leg atrophy.
Normal median SNAP amplitudes and conduction velocities are seen in most individuals, even those with mildly prolonged distal motor latency.
In individuals with advanced disease, needle EMG shows no voluntary motor activity in the abductor pollicis and first dorsal interossei because of marked atrophy. Spontaneous activity is often seen in these muscles.
The elicited sural SNAPs are preserved but with a reduced amplitude, despite sensory axonal loss identified histopathologically on examination of a sensory nerve from an individual with the CMT2D subtype; similar but milder changes were seen in individuals with dSMA-V.
Note: EMG is more widely available than nerve biopsy, which can be used in a single individual in a family or in diagnostically difficult cases.
The diagnosis of
Note: Identification of a heterozygous
The molecular genetic testing approach will likely depend on the age of onset of disease manifestations.
For an introduction to comprehensive genomic testing click
Note that commercial multigene panels for early-onset neuropathies may often not include
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Typically, infantile onset of respiratory distress, poor feeding, and muscle weakness, with distal weakness greater than proximal; however, some children may present with features similar to toddlers.
• Absence of molecular genetic findings of
• Bilateral weakness and atrophy of thenar and first dorsal interosseous muscles with progression to involve hypothenar, foot, and peroneal muscles in many individuals and mild-to-moderate impairment of vibration sense developing in advanced illness in some individuals (see
• Sensory deficits including reduction of pinprick, temperature, touch, and vibration perception in a stocking and (less often) glove pattern
• Absent or markedly reduced (frequently <1 mV) compound muscle action potentials (CMAPs) are recorded from the abductor pollicis brevis (APB) by median nerve stimulation [
• Preserved CMAPs are recorded from the abductor digiti minimi (ADM) by ulnar nerve stimulation.
• CMAP amplitude recorded by stimulation of the peroneal nerve is <2 mV in most individuals and <1 mV in individuals having clinically evident leg atrophy.
• Normal median SNAP amplitudes and conduction velocities are seen in most individuals, even those with mildly prolonged distal motor latency.
• In individuals with advanced disease, needle EMG shows no voluntary motor activity in the abductor pollicis and first dorsal interossei because of marked atrophy. Spontaneous activity is often seen in these muscles.
• The elicited sural SNAPs are preserved but with a reduced amplitude, despite sensory axonal loss identified histopathologically on examination of a sensory nerve from an individual with the CMT2D subtype; similar but milder changes were seen in individuals with dSMA-V.
## Suggestive Findings
Typically, infantile onset of respiratory distress, poor feeding, and muscle weakness, with distal weakness greater than proximal; however, some children may present with features similar to toddlers.
Absence of molecular genetic findings of
Bilateral weakness and atrophy of thenar and first dorsal interosseous muscles with progression to involve hypothenar, foot, and peroneal muscles in many individuals and mild-to-moderate impairment of vibration sense developing in advanced illness in some individuals (see
Sensory deficits including reduction of pinprick, temperature, touch, and vibration perception in a stocking and (less often) glove pattern
EMG shows denervation predominantly in the distal muscle groups at normal motor distal latencies and conduction velocities (see
Absent or markedly reduced (frequently <1 mV) compound muscle action potentials (CMAPs) are recorded from the abductor pollicis brevis (APB) by median nerve stimulation [
Preserved CMAPs are recorded from the abductor digiti minimi (ADM) by ulnar nerve stimulation.
CMAP amplitude recorded by stimulation of the peroneal nerve is <2 mV in most individuals and <1 mV in individuals having clinically evident leg atrophy.
Normal median SNAP amplitudes and conduction velocities are seen in most individuals, even those with mildly prolonged distal motor latency.
In individuals with advanced disease, needle EMG shows no voluntary motor activity in the abductor pollicis and first dorsal interossei because of marked atrophy. Spontaneous activity is often seen in these muscles.
The elicited sural SNAPs are preserved but with a reduced amplitude, despite sensory axonal loss identified histopathologically on examination of a sensory nerve from an individual with the CMT2D subtype; similar but milder changes were seen in individuals with dSMA-V.
Note: EMG is more widely available than nerve biopsy, which can be used in a single individual in a family or in diagnostically difficult cases.
• Typically, infantile onset of respiratory distress, poor feeding, and muscle weakness, with distal weakness greater than proximal; however, some children may present with features similar to toddlers.
• Absence of molecular genetic findings of
• Bilateral weakness and atrophy of thenar and first dorsal interosseous muscles with progression to involve hypothenar, foot, and peroneal muscles in many individuals and mild-to-moderate impairment of vibration sense developing in advanced illness in some individuals (see
• Sensory deficits including reduction of pinprick, temperature, touch, and vibration perception in a stocking and (less often) glove pattern
• Absent or markedly reduced (frequently <1 mV) compound muscle action potentials (CMAPs) are recorded from the abductor pollicis brevis (APB) by median nerve stimulation [
• Preserved CMAPs are recorded from the abductor digiti minimi (ADM) by ulnar nerve stimulation.
• CMAP amplitude recorded by stimulation of the peroneal nerve is <2 mV in most individuals and <1 mV in individuals having clinically evident leg atrophy.
• Normal median SNAP amplitudes and conduction velocities are seen in most individuals, even those with mildly prolonged distal motor latency.
• In individuals with advanced disease, needle EMG shows no voluntary motor activity in the abductor pollicis and first dorsal interossei because of marked atrophy. Spontaneous activity is often seen in these muscles.
• The elicited sural SNAPs are preserved but with a reduced amplitude, despite sensory axonal loss identified histopathologically on examination of a sensory nerve from an individual with the CMT2D subtype; similar but milder changes were seen in individuals with dSMA-V.
## Clinical Findings
Typically, infantile onset of respiratory distress, poor feeding, and muscle weakness, with distal weakness greater than proximal; however, some children may present with features similar to toddlers.
Absence of molecular genetic findings of
Bilateral weakness and atrophy of thenar and first dorsal interosseous muscles with progression to involve hypothenar, foot, and peroneal muscles in many individuals and mild-to-moderate impairment of vibration sense developing in advanced illness in some individuals (see
Sensory deficits including reduction of pinprick, temperature, touch, and vibration perception in a stocking and (less often) glove pattern
• Typically, infantile onset of respiratory distress, poor feeding, and muscle weakness, with distal weakness greater than proximal; however, some children may present with features similar to toddlers.
• Absence of molecular genetic findings of
• Bilateral weakness and atrophy of thenar and first dorsal interosseous muscles with progression to involve hypothenar, foot, and peroneal muscles in many individuals and mild-to-moderate impairment of vibration sense developing in advanced illness in some individuals (see
• Sensory deficits including reduction of pinprick, temperature, touch, and vibration perception in a stocking and (less often) glove pattern
## Electrophysiologic Studies
EMG shows denervation predominantly in the distal muscle groups at normal motor distal latencies and conduction velocities (see
Absent or markedly reduced (frequently <1 mV) compound muscle action potentials (CMAPs) are recorded from the abductor pollicis brevis (APB) by median nerve stimulation [
Preserved CMAPs are recorded from the abductor digiti minimi (ADM) by ulnar nerve stimulation.
CMAP amplitude recorded by stimulation of the peroneal nerve is <2 mV in most individuals and <1 mV in individuals having clinically evident leg atrophy.
Normal median SNAP amplitudes and conduction velocities are seen in most individuals, even those with mildly prolonged distal motor latency.
In individuals with advanced disease, needle EMG shows no voluntary motor activity in the abductor pollicis and first dorsal interossei because of marked atrophy. Spontaneous activity is often seen in these muscles.
The elicited sural SNAPs are preserved but with a reduced amplitude, despite sensory axonal loss identified histopathologically on examination of a sensory nerve from an individual with the CMT2D subtype; similar but milder changes were seen in individuals with dSMA-V.
Note: EMG is more widely available than nerve biopsy, which can be used in a single individual in a family or in diagnostically difficult cases.
• Absent or markedly reduced (frequently <1 mV) compound muscle action potentials (CMAPs) are recorded from the abductor pollicis brevis (APB) by median nerve stimulation [
• Preserved CMAPs are recorded from the abductor digiti minimi (ADM) by ulnar nerve stimulation.
• CMAP amplitude recorded by stimulation of the peroneal nerve is <2 mV in most individuals and <1 mV in individuals having clinically evident leg atrophy.
• Normal median SNAP amplitudes and conduction velocities are seen in most individuals, even those with mildly prolonged distal motor latency.
• In individuals with advanced disease, needle EMG shows no voluntary motor activity in the abductor pollicis and first dorsal interossei because of marked atrophy. Spontaneous activity is often seen in these muscles.
• The elicited sural SNAPs are preserved but with a reduced amplitude, despite sensory axonal loss identified histopathologically on examination of a sensory nerve from an individual with the CMT2D subtype; similar but milder changes were seen in individuals with dSMA-V.
## Establishing the Diagnosis
The diagnosis of
Note: Identification of a heterozygous
The molecular genetic testing approach will likely depend on the age of onset of disease manifestations.
For an introduction to comprehensive genomic testing click
Note that commercial multigene panels for early-onset neuropathies may often not include
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
Individuals with
Age of onset ranges from the neonatal period to the toddler years. The presenting manifestations are typically respiratory distress, poor feeding, and muscle weakness (distal weakness greater than proximal).
Neonates present emergently with respiratory distress (stridor, weak cry, and respiratory insufficiency), poor feeding, and severe hypotonia, ultimately requiring mechanical ventilation and early placement of a gastrostomy tube. In neonates, the neurologic examination is notable for hypotonia, hyporeflexia, and tongue fasciculations in some.
Infants typically have delayed motor milestones with subsequent motor milestone regression. They do not achieve independent walking [
Age of onset ranges from eight to 36 years, with most individuals (75%) developing manifestations during the second decade of life [
The presenting manifestation is typically muscle weakness, often initially evident as transient cramping and pain in the hands on exposure to cold and cramping in calf muscles on exertion. Progressive weakness and atrophy of the thenar and first dorsal interosseus muscles are the major complaints (
The lower limbs are involved in about 50% of affected individuals. Lower-extremity involvement ranges from weakness and atrophy of the extensor digitorum brevis and weakness of toe dorsiflexors to classic peroneal muscular atrophy with foot drop and a high steppage gait. Peroneal muscles are affected earlier and more severely than the calf muscles. Peroneal muscular atrophy is associated with
Proximal limb muscle weakness is not observed in the upper or lower extremities.
Sensory examination is either normal or shows mild-to-moderate impairment of vibration sense in the hands and feet and reduction of pinprick, temperature, touch, and vibration perception in a stocking and (less often) glove pattern.
A minority of individuals show upper motor neuron signs (mild pyramidal signs and spasticity) [
While progression of manifestations is often slow, extending over decades, some individuals may have a more rapid evolution of lower extremity involvement, which may more often be seen in the setting of both motor and sensory changes [
To the authors' knowledge, reduced penetrance has not been described for
For adolescent- or adult-onset
Disease prevalence is unknown;
## Clinical Description
Individuals with
Age of onset ranges from the neonatal period to the toddler years. The presenting manifestations are typically respiratory distress, poor feeding, and muscle weakness (distal weakness greater than proximal).
Neonates present emergently with respiratory distress (stridor, weak cry, and respiratory insufficiency), poor feeding, and severe hypotonia, ultimately requiring mechanical ventilation and early placement of a gastrostomy tube. In neonates, the neurologic examination is notable for hypotonia, hyporeflexia, and tongue fasciculations in some.
Infants typically have delayed motor milestones with subsequent motor milestone regression. They do not achieve independent walking [
Age of onset ranges from eight to 36 years, with most individuals (75%) developing manifestations during the second decade of life [
The presenting manifestation is typically muscle weakness, often initially evident as transient cramping and pain in the hands on exposure to cold and cramping in calf muscles on exertion. Progressive weakness and atrophy of the thenar and first dorsal interosseus muscles are the major complaints (
The lower limbs are involved in about 50% of affected individuals. Lower-extremity involvement ranges from weakness and atrophy of the extensor digitorum brevis and weakness of toe dorsiflexors to classic peroneal muscular atrophy with foot drop and a high steppage gait. Peroneal muscles are affected earlier and more severely than the calf muscles. Peroneal muscular atrophy is associated with
Proximal limb muscle weakness is not observed in the upper or lower extremities.
Sensory examination is either normal or shows mild-to-moderate impairment of vibration sense in the hands and feet and reduction of pinprick, temperature, touch, and vibration perception in a stocking and (less often) glove pattern.
A minority of individuals show upper motor neuron signs (mild pyramidal signs and spasticity) [
While progression of manifestations is often slow, extending over decades, some individuals may have a more rapid evolution of lower extremity involvement, which may more often be seen in the setting of both motor and sensory changes [
Age of onset ranges from the neonatal period to the toddler years. The presenting manifestations are typically respiratory distress, poor feeding, and muscle weakness (distal weakness greater than proximal).
Neonates present emergently with respiratory distress (stridor, weak cry, and respiratory insufficiency), poor feeding, and severe hypotonia, ultimately requiring mechanical ventilation and early placement of a gastrostomy tube. In neonates, the neurologic examination is notable for hypotonia, hyporeflexia, and tongue fasciculations in some.
Infants typically have delayed motor milestones with subsequent motor milestone regression. They do not achieve independent walking [
Age of onset ranges from eight to 36 years, with most individuals (75%) developing manifestations during the second decade of life [
The presenting manifestation is typically muscle weakness, often initially evident as transient cramping and pain in the hands on exposure to cold and cramping in calf muscles on exertion. Progressive weakness and atrophy of the thenar and first dorsal interosseus muscles are the major complaints (
The lower limbs are involved in about 50% of affected individuals. Lower-extremity involvement ranges from weakness and atrophy of the extensor digitorum brevis and weakness of toe dorsiflexors to classic peroneal muscular atrophy with foot drop and a high steppage gait. Peroneal muscles are affected earlier and more severely than the calf muscles. Peroneal muscular atrophy is associated with
Proximal limb muscle weakness is not observed in the upper or lower extremities.
Sensory examination is either normal or shows mild-to-moderate impairment of vibration sense in the hands and feet and reduction of pinprick, temperature, touch, and vibration perception in a stocking and (less often) glove pattern.
A minority of individuals show upper motor neuron signs (mild pyramidal signs and spasticity) [
While progression of manifestations is often slow, extending over decades, some individuals may have a more rapid evolution of lower extremity involvement, which may more often be seen in the setting of both motor and sensory changes [
## Genotype-Phenotype Correlations
## Penetrance
To the authors' knowledge, reduced penetrance has not been described for
For adolescent- or adult-onset
## Nomenclature
## Prevalence
Disease prevalence is unknown;
## Genetically Related (Allelic) Disorders
Biallelic germline pathogenic variants in
## Differential Diagnosis
Hereditary Disorders with Hypotonia in the Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; CK = creatine kinase; DiffDx = differential diagnosis; dSMA = distal spinal muscular atrophy; iSMA = infantile spinal muscular atrophy; MOI = mode of inheritance; SMARD = spinal muscular atrophy with respiratory distress; XL = X-linked
Prader-Willi syndrome (PWS) is caused by an absence of expression of imprinted genes in the paternally derived PWS / Angelman syndrome region (15q11.2-q13) of chromosome 15 by one of several genetic mechanisms (paternal deletion, maternal uniparental disomy 15, and rarely an imprinting defect). The risk to the sibs of an affected child of having PWS depends on the genetic mechanism that resulted in the absence of expression of the paternally contributed 15q11.2-q13 region.
Pathogenic variants in one of multiple genes encoding proteins expressed at the neuromuscular junction are currently known to be associated with subtypes of CMS. The most commonly associated genes include those listed in the table (see
Multiple genes are associated with congenital muscular dystrophy (CMD). The frequency of CMD subtypes vary by population [
SMARD spans a phenotypic spectrum [
Zellweger spectrum disorder (ZSD) is typically inherited in an autosomal recessive manner (one
Other inherited disorders to consider in the differential diagnosis of
Infantile botulism may also resemble
## Infantile-Onset Spinal Muscular Atrophy
Hereditary Disorders with Hypotonia in the Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; CK = creatine kinase; DiffDx = differential diagnosis; dSMA = distal spinal muscular atrophy; iSMA = infantile spinal muscular atrophy; MOI = mode of inheritance; SMARD = spinal muscular atrophy with respiratory distress; XL = X-linked
Prader-Willi syndrome (PWS) is caused by an absence of expression of imprinted genes in the paternally derived PWS / Angelman syndrome region (15q11.2-q13) of chromosome 15 by one of several genetic mechanisms (paternal deletion, maternal uniparental disomy 15, and rarely an imprinting defect). The risk to the sibs of an affected child of having PWS depends on the genetic mechanism that resulted in the absence of expression of the paternally contributed 15q11.2-q13 region.
Pathogenic variants in one of multiple genes encoding proteins expressed at the neuromuscular junction are currently known to be associated with subtypes of CMS. The most commonly associated genes include those listed in the table (see
Multiple genes are associated with congenital muscular dystrophy (CMD). The frequency of CMD subtypes vary by population [
SMARD spans a phenotypic spectrum [
Zellweger spectrum disorder (ZSD) is typically inherited in an autosomal recessive manner (one
Other inherited disorders to consider in the differential diagnosis of
Infantile botulism may also resemble
## Adolescent- or Early Adult-Onset Hereditary Motor/Sensory Neuropathy (Charcot-Marie-Tooth Hereditary Neuropathy)
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Incl eval of aspiration risk w/formal swallow study, nutritional status, & time required to complete a feed.
Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
Incl assessment of gross motor & fine motor skills.
Assess equipment needed for safety (car seat / car bed) & independence, such as power chair & other equipment in the home to improve quality of life for patient & caregiver.
Use of community or
Need for social work involvement for caretaker support.
OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis in Individuals with
To determine extent of weakness & atrophy,
To evaluate for pain
To evaluate for less common fixed manifestations (e.g., spasticity, hyperreflexia, ataxia)
Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Feet for evidence of
Mobility, ADL, & need for adaptive devices
Need for handicapped parking
Use of community or
Need for social work involvement for caretaker support.
ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapist/therapy; PT = physical therapist/therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Supportive treatment of children with
Supportive Treatment of Manifestations in Individuals with
Clinical feeding eval & radiographic swallowing study
Nutritional supplementation
Placement of gastrostomy tube for aspiration concerns
Noninvasive ventilation as indicated by pulmonary function testing, blood gas, & sleep study
Airway clearance techniques to incl cough assist devices & secretion mgmt
For patients w/severe respiratory involvement, discussions surrounding goals of immediate care vs long-term care & prognosis are imperative.
Bracing w/orthotics; range of motion exercises
Assistive devices to incl adaptive strollers, car seats, & wheelchairs
Surgical intervention for scoliosis & hip dislocation based on age, assoc pain, & functional benefit
Ongoing assessment of need for palliative care involvement &/or home nursing
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Assistance w/coordinating multiple subspecialty appointments
OT = occupational therapist; PM&R = physical medicine and rehabilitation; PT = physical therapist
Treatment is symptomatic. Affected individuals are often managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists.
All individuals require assessment of their mobility needs and type of adaptations and devices that can be implemented to enhance their mobility. Devices include orthotics, which are often needed to correct foot drop and aid in walking.
Daily heel cord stretching helps prevent Achilles tendon shortening, foot deformities, and contractures.
Orthopedic surgery may be required for ankle fusion or to correct severe
Some individuals require devices to assist with stability and mobility.
Numerous devices are available to facilitate various activities of daily living.
Recommended Surveillance for Individuals with
OT = occupational therapist; PT = physical therapist
Recommended Surveillance for Individuals with
Screening neurologic exam w/focus on progression of limb weakness
Eval for pain
PT
OT
PM&R assessment for adaptive & mobility devices
Primary care/neurologist/patient: comprehensive dermatologic assessment to assess for pressure ulcers or sores & skin breakdown; particular attention to feet, hips, & other pressure points
OT = occupational therapist; PM&R = physical medicine and rehabilitation; PT = physical therapist
Medications that are toxic or potentially toxic to persons with HMSN comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
Chemotherapy for cancer that includes vincristine may be especially damaging to peripheral nerves and may severely worsen HMSN [
Given the relatively few individuals reported with
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an individual with
See
Search
• Incl eval of aspiration risk w/formal swallow study, nutritional status, & time required to complete a feed.
• Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
• Incl assessment of gross motor & fine motor skills.
• Assess equipment needed for safety (car seat / car bed) & independence, such as power chair & other equipment in the home to improve quality of life for patient & caregiver.
• Use of community or
• Need for social work involvement for caretaker support.
• To determine extent of weakness & atrophy,
• To evaluate for pain
• To evaluate for less common fixed manifestations (e.g., spasticity, hyperreflexia, ataxia)
• Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Feet for evidence of
• Mobility, ADL, & need for adaptive devices
• Need for handicapped parking
• Use of community or
• Need for social work involvement for caretaker support.
• Clinical feeding eval & radiographic swallowing study
• Nutritional supplementation
• Placement of gastrostomy tube for aspiration concerns
• Noninvasive ventilation as indicated by pulmonary function testing, blood gas, & sleep study
• Airway clearance techniques to incl cough assist devices & secretion mgmt
• For patients w/severe respiratory involvement, discussions surrounding goals of immediate care vs long-term care & prognosis are imperative.
• Bracing w/orthotics; range of motion exercises
• Assistive devices to incl adaptive strollers, car seats, & wheelchairs
• Surgical intervention for scoliosis & hip dislocation based on age, assoc pain, & functional benefit
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Assistance w/coordinating multiple subspecialty appointments
• Screening neurologic exam w/focus on progression of limb weakness
• Eval for pain
• PT
• OT
• PM&R assessment for adaptive & mobility devices
• Primary care/neurologist/patient: comprehensive dermatologic assessment to assess for pressure ulcers or sores & skin breakdown; particular attention to feet, hips, & other pressure points
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Incl eval of aspiration risk w/formal swallow study, nutritional status, & time required to complete a feed.
Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
Incl assessment of gross motor & fine motor skills.
Assess equipment needed for safety (car seat / car bed) & independence, such as power chair & other equipment in the home to improve quality of life for patient & caregiver.
Use of community or
Need for social work involvement for caretaker support.
OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis in Individuals with
To determine extent of weakness & atrophy,
To evaluate for pain
To evaluate for less common fixed manifestations (e.g., spasticity, hyperreflexia, ataxia)
Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Feet for evidence of
Mobility, ADL, & need for adaptive devices
Need for handicapped parking
Use of community or
Need for social work involvement for caretaker support.
ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapist/therapy; PT = physical therapist/therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Incl eval of aspiration risk w/formal swallow study, nutritional status, & time required to complete a feed.
• Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
• Incl assessment of gross motor & fine motor skills.
• Assess equipment needed for safety (car seat / car bed) & independence, such as power chair & other equipment in the home to improve quality of life for patient & caregiver.
• Use of community or
• Need for social work involvement for caretaker support.
• To determine extent of weakness & atrophy,
• To evaluate for pain
• To evaluate for less common fixed manifestations (e.g., spasticity, hyperreflexia, ataxia)
• Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Feet for evidence of
• Mobility, ADL, & need for adaptive devices
• Need for handicapped parking
• Use of community or
• Need for social work involvement for caretaker support.
## Treatment of Manifestations
Supportive treatment of children with
Supportive Treatment of Manifestations in Individuals with
Clinical feeding eval & radiographic swallowing study
Nutritional supplementation
Placement of gastrostomy tube for aspiration concerns
Noninvasive ventilation as indicated by pulmonary function testing, blood gas, & sleep study
Airway clearance techniques to incl cough assist devices & secretion mgmt
For patients w/severe respiratory involvement, discussions surrounding goals of immediate care vs long-term care & prognosis are imperative.
Bracing w/orthotics; range of motion exercises
Assistive devices to incl adaptive strollers, car seats, & wheelchairs
Surgical intervention for scoliosis & hip dislocation based on age, assoc pain, & functional benefit
Ongoing assessment of need for palliative care involvement &/or home nursing
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Assistance w/coordinating multiple subspecialty appointments
OT = occupational therapist; PM&R = physical medicine and rehabilitation; PT = physical therapist
Treatment is symptomatic. Affected individuals are often managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists.
All individuals require assessment of their mobility needs and type of adaptations and devices that can be implemented to enhance their mobility. Devices include orthotics, which are often needed to correct foot drop and aid in walking.
Daily heel cord stretching helps prevent Achilles tendon shortening, foot deformities, and contractures.
Orthopedic surgery may be required for ankle fusion or to correct severe
Some individuals require devices to assist with stability and mobility.
Numerous devices are available to facilitate various activities of daily living.
• Clinical feeding eval & radiographic swallowing study
• Nutritional supplementation
• Placement of gastrostomy tube for aspiration concerns
• Noninvasive ventilation as indicated by pulmonary function testing, blood gas, & sleep study
• Airway clearance techniques to incl cough assist devices & secretion mgmt
• For patients w/severe respiratory involvement, discussions surrounding goals of immediate care vs long-term care & prognosis are imperative.
• Bracing w/orthotics; range of motion exercises
• Assistive devices to incl adaptive strollers, car seats, & wheelchairs
• Surgical intervention for scoliosis & hip dislocation based on age, assoc pain, & functional benefit
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Assistance w/coordinating multiple subspecialty appointments
Supportive treatment of children with
Supportive Treatment of Manifestations in Individuals with
Clinical feeding eval & radiographic swallowing study
Nutritional supplementation
Placement of gastrostomy tube for aspiration concerns
Noninvasive ventilation as indicated by pulmonary function testing, blood gas, & sleep study
Airway clearance techniques to incl cough assist devices & secretion mgmt
For patients w/severe respiratory involvement, discussions surrounding goals of immediate care vs long-term care & prognosis are imperative.
Bracing w/orthotics; range of motion exercises
Assistive devices to incl adaptive strollers, car seats, & wheelchairs
Surgical intervention for scoliosis & hip dislocation based on age, assoc pain, & functional benefit
Ongoing assessment of need for palliative care involvement &/or home nursing
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Assistance w/coordinating multiple subspecialty appointments
OT = occupational therapist; PM&R = physical medicine and rehabilitation; PT = physical therapist
• Clinical feeding eval & radiographic swallowing study
• Nutritional supplementation
• Placement of gastrostomy tube for aspiration concerns
• Noninvasive ventilation as indicated by pulmonary function testing, blood gas, & sleep study
• Airway clearance techniques to incl cough assist devices & secretion mgmt
• For patients w/severe respiratory involvement, discussions surrounding goals of immediate care vs long-term care & prognosis are imperative.
• Bracing w/orthotics; range of motion exercises
• Assistive devices to incl adaptive strollers, car seats, & wheelchairs
• Surgical intervention for scoliosis & hip dislocation based on age, assoc pain, & functional benefit
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Assistance w/coordinating multiple subspecialty appointments
Treatment is symptomatic. Affected individuals are often managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists.
All individuals require assessment of their mobility needs and type of adaptations and devices that can be implemented to enhance their mobility. Devices include orthotics, which are often needed to correct foot drop and aid in walking.
Daily heel cord stretching helps prevent Achilles tendon shortening, foot deformities, and contractures.
Orthopedic surgery may be required for ankle fusion or to correct severe
Some individuals require devices to assist with stability and mobility.
Numerous devices are available to facilitate various activities of daily living.
## Surveillance
Recommended Surveillance for Individuals with
OT = occupational therapist; PT = physical therapist
Recommended Surveillance for Individuals with
Screening neurologic exam w/focus on progression of limb weakness
Eval for pain
PT
OT
PM&R assessment for adaptive & mobility devices
Primary care/neurologist/patient: comprehensive dermatologic assessment to assess for pressure ulcers or sores & skin breakdown; particular attention to feet, hips, & other pressure points
OT = occupational therapist; PM&R = physical medicine and rehabilitation; PT = physical therapist
• Screening neurologic exam w/focus on progression of limb weakness
• Eval for pain
• PT
• OT
• PM&R assessment for adaptive & mobility devices
• Primary care/neurologist/patient: comprehensive dermatologic assessment to assess for pressure ulcers or sores & skin breakdown; particular attention to feet, hips, & other pressure points
## Agents/Circumstances to Avoid
Medications that are toxic or potentially toxic to persons with HMSN comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
Chemotherapy for cancer that includes vincristine may be especially damaging to peripheral nerves and may severely worsen HMSN [
Given the relatively few individuals reported with
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an individual with
See
## Therapies Under Investigation
Search
## Genetic Counseling
All probands reported to date with
Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If a parent of the proband is known to have the
If the
Most individuals diagnosed with
A proband with
Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
Intrafamilial clinical variability and reduced penetrance have been observed in
If the
If the parents have not been tested for the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• All probands reported to date with
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is known to have the
• If the
• Most individuals diagnosed with
• A proband with
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• Intrafamilial clinical variability and reduced penetrance have been observed in
• If the
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
## Risk to Family Members
All probands reported to date with
Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If a parent of the proband is known to have the
If the
Most individuals diagnosed with
A proband with
Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
Intrafamilial clinical variability and reduced penetrance have been observed in
If the
If the parents have not been tested for the
• All probands reported to date with
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is known to have the
• If the
• Most individuals diagnosed with
• A proband with
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• Intrafamilial clinical variability and reduced penetrance have been observed in
• If the
• If the parents have not been tested for the
All probands reported to date with
Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If a parent of the proband is known to have the
If the
• All probands reported to date with
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is known to have the
• If the
Most individuals diagnosed with
A proband with
Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
Intrafamilial clinical variability and reduced penetrance have been observed in
If the
If the parents have not been tested for the
• Most individuals diagnosed with
• A proband with
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• Intrafamilial clinical variability and reduced penetrance have been observed in
• If the
• If the parents have not been tested for the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Department of Molecular Genetics
University of Antwerp
Antwerp Antwerpen B-2610
Belgium
•
•
•
• Department of Molecular Genetics
• University of Antwerp
• Antwerp Antwerpen B-2610
• Belgium
•
•
•
•
•
•
## Molecular Genetics
GARS-Associated Axonal Neuropathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GARS-Associated Axonal Neuropathy (
The molecular pathology that underlies the spectrum of neuromuscular and sensory phenotypes observed in
The protein GARS, which functions as a homodimer, is a member of the ubiquitously expressed aminoacyl-tRNA synthetase family whose key function is charging tRNA with glycine. GARS comprises an N-terminal appended WHEP-TRS domain, a catalytic core, and a C-terminal anticodon binding domain. Variants in
While absence of phenotypes in heterozygous null variants in mice provides evidence against haploinsufficiency [
An overview of the gene-disease association can be found
Notable
CMT2D = Charcot-Marie-Tooth neuropathy type 2D (distal motor and sensory involvement); dSMA-V = distal spinal muscular atrophy V (distal motor involvement exclusively)
Variants listed in the table have been provided by the authors.
There are two isoforms of
## Molecular Pathogenesis
The molecular pathology that underlies the spectrum of neuromuscular and sensory phenotypes observed in
The protein GARS, which functions as a homodimer, is a member of the ubiquitously expressed aminoacyl-tRNA synthetase family whose key function is charging tRNA with glycine. GARS comprises an N-terminal appended WHEP-TRS domain, a catalytic core, and a C-terminal anticodon binding domain. Variants in
While absence of phenotypes in heterozygous null variants in mice provides evidence against haploinsufficiency [
An overview of the gene-disease association can be found
Notable
CMT2D = Charcot-Marie-Tooth neuropathy type 2D (distal motor and sensory involvement); dSMA-V = distal spinal muscular atrophy V (distal motor involvement exclusively)
Variants listed in the table have been provided by the authors.
There are two isoforms of
## Chapter Notes
Anthony Antonellis, PhD; University of Michigan Medical School (2018-2021)Rajarshi Ghosh, PhD (2021-present)Lev G Goldfarb, MD; National Institute of Neurological Disorders and Stroke (2006-2021)Timothy Lotze, MD (2021-present)Rebecca Markovitz, MD, PhD (2021-present)Lorraine Potocki, MD (2021-present)Kumaraswamy Sivakumar, MD; Barrow Neurological Institute, Phoenix (2006-2021)
22 July 2021 (bp) Comprehensive update posted live
29 November 2018 (ha) Comprehensive update posted live
25 August 2011 (me) Comprehensive update posted live
30 January 2007 (lgg) Revision: sequence analysis clinically available for mutations in
8 November 2006 (me) Review posted live
24 February 2006 (lgg) Original submission
• 22 July 2021 (bp) Comprehensive update posted live
• 29 November 2018 (ha) Comprehensive update posted live
• 25 August 2011 (me) Comprehensive update posted live
• 30 January 2007 (lgg) Revision: sequence analysis clinically available for mutations in
• 8 November 2006 (me) Review posted live
• 24 February 2006 (lgg) Original submission
## Author History
Anthony Antonellis, PhD; University of Michigan Medical School (2018-2021)Rajarshi Ghosh, PhD (2021-present)Lev G Goldfarb, MD; National Institute of Neurological Disorders and Stroke (2006-2021)Timothy Lotze, MD (2021-present)Rebecca Markovitz, MD, PhD (2021-present)Lorraine Potocki, MD (2021-present)Kumaraswamy Sivakumar, MD; Barrow Neurological Institute, Phoenix (2006-2021)
## Revision History
22 July 2021 (bp) Comprehensive update posted live
29 November 2018 (ha) Comprehensive update posted live
25 August 2011 (me) Comprehensive update posted live
30 January 2007 (lgg) Revision: sequence analysis clinically available for mutations in
8 November 2006 (me) Review posted live
24 February 2006 (lgg) Original submission
• 22 July 2021 (bp) Comprehensive update posted live
• 29 November 2018 (ha) Comprehensive update posted live
• 25 August 2011 (me) Comprehensive update posted live
• 30 January 2007 (lgg) Revision: sequence analysis clinically available for mutations in
• 8 November 2006 (me) Review posted live
• 24 February 2006 (lgg) Original submission
## References
## Literature Cited
Distribution of muscle weakness and atrophy in individuals with two major clinical phenotypes of
A. Thenar and first dorsal interosseus muscle wasting with relatively preserved hypothenar in an individual with dSMA-V phenotype
B. Peroneal atrophy,
Reprinted from
Hematoxylin and eosin stain of quadriceps muscle of an infant with
A. Low power magnification demonstrates small atrophied fibers with marked variation in fiber size. Inflammatory cells are absent, and there is no increase in endomysial connective tissue.
B. Higher power magnification demonstrates clusters of large hypertrophied muscle fibers among large groups of small often rounded, atrophic muscle fibers.
|
[
"A Abe, K Hayasaka. The GARS gene is rarely mutated in Japanese patients with Charcot-Marie-Tooth neuropathy.. J Hum Genet. 2009;54:310-2",
"A Antonellis, RE Ellsworth, N Sambuughin, I Puls, A Abel, SQ Lee-Lin, A Jordanova, I Kremensky, K Christodoulou, LT Middleton, K Sivakumar, V Ionasescu, B Funalot, JM Vance, LG Goldfarb, KH Fischbeck, ED Green. Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V.. Am J Hum Genet 2003;72:1293-9",
"CG Bönnemann, CH Wang, S Quijano-Roy, N Deconinck, E Bertini, A Ferreiro, F Muntoni, C Sewry, C Béroud, KD Mathews, SA Moore, J Bellini, A Rutkowski, KN North. Members of International Standard of Care Committee for Congenital Muscular Dystrophies. Diagnostic approach to the congenital muscular dystrophies.. Neuromuscul Disord. 2014;24:289-311",
"K Christodoulou, T Kyriakides, AH Hristova, DM Georgiou, L Kalaydjieva, B Yshpekova, T Ivanova, JL Weber, LT Middleton. Mapping of a distal form of spinal muscular atrophy with upper limb predominance to chromosome 7p.. Hum Mol Genet. 1995;4:1629-32",
"A Cortese, JE Wilcox, JM Polke, R Poh, M Skorupinska, AM Rossor, M Laura, PJ Tomaselli, H Houlden, ME Shy, MM Reilly. Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease.. Neurology. 2020;94:e51-e61",
"R Del Bo, F Locatelli, S Corti, M Scarlato, S Ghezzi, A Prelle, G Fagiolari, M Moggio, M Carpo, N Bresolin, GP Comi. Coexistence of CMT-2D and distal SMA-V phenotypes in an Italian family with a GARS gene mutation.. Neurology 2006;66:752-4",
"O Dubourg, H Azzedine, RB Yaou, J Pouget, A Barois, V Meininger, D Bouteiller, M Ruberg, A Brice, E LeGuern. The G526R glycyl-tRNA synthetase gene mutation in distal hereditary motor neuropathy type V.. Neurology 2006;66:1721-6",
"JM Eskuri, CM Stanley, SA Moore, KD Mathews. Infantile onset CMT2D/dSMA V in monozygotic twins due to a mutation in the anticodon-binding domain of GARS.. J Peripher Nerv Syst. 2012;17:132-4",
"LB Griffin, R Sakaguchi, D McGuigan, MA Gonzalez, C Searby, S Züchner, YM Hou, A Antonellis. Impaired function is a common feature of neuropathy-associated glycyl-tRNA synthetase mutations.. Hum Mutat. 2014;35:1363-71",
"UP Guenther, R Varon, M Schlicke, V Dutrannoy, A Volk, C Hübner, K von Au, M Schuelke. Clinical and mutational profile in spinal muscular atrophy with respiratory distress (SMARD): defining novel phenotypes through hierarchical cluster analysis.. Hum Mutat. 2007;28:808-15",
"W He, G Bai, H Zhou, N Wei, NM White, J Lauer, H Liu, Y Shi, CD Dumitru, K Lettieri, V Shubayev, A Jordanova, V Guergueltcheva, PR Griffin, RW Burgess, SL Pfaff, XL Yang. CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase.. Nature. 2015;526:710-4",
"PA James, MZ Cader, F Muntoni, AM Childs, YJ Crow, K Talbit. Severe childhood SMA and axonal CMT due to anticodon binding domain mutations in the GARS gene.. Neurology 2006;67:1710-2",
"L Kong, DO Valdivia, CM Simon, CW Hassinan, N Delestrée, DM Ramos, JH Park, CM Pilato, X Xu, M Crowder, CC Grzyb, ZA King, M Petrillo, KJ Swoboda, C Davis, CM Lutz, AH Stephan, X Zhao, M Weetall, NA Naryshkin, TO Crawford, GZ Mentis, CJ Sumner. Sci. Transl. Med. 2021;13",
"YC Liao, YT Liu, PC Tsai, CC Chang, YH Huang, BW Soong, YC Lee. Two Novel De Novo GARS mutations cause early-onset axonal Charcot-Marie-Tooth disease.. PLoS One. 2015;10",
"S Lin, LQ Xu, GR Xu, LL Guo, BJ Lin, WJ Chen, N Wang, Y Lin, J He. Whole exome sequencing reveals a broader variant spectrum of Charcot-Marie-Tooth disease type 2.. Neurogenetics. 2020;21:79-86",
"MJ MacLeod, JE Taylor, PW Lunt, CG Mathew, SA Robb. Prenatal onset spinal muscular atrophy.. Eur J Paediatr Neurol. 1999;3:65-72",
"L Magy, S Mathis, G Le Masson, C Goizet, M Tazir, JM Vallat. Updating the classification of inherited neuropathies: results of an international survey.. Neurology. 2018;90:e870-e876",
"N Malissovas, LB Griffin, A Antonellis, D Beis. Dimerization is required for GARS-mediated neurotoxicity in dominant CMT disease.. Hum Mol Genet. 2016;25:1528-42",
"R Markovitz, R Ghosh, ME Kuo, W Hong, J Lim, S Bernes, S Manberg, K Crosby, P Tanpaiboon, D Bharucha-Goebel, C Bonnemann, CA Mohila, E Mizerik, S Woodbury, B Weimin, T Lotze, A Antonellis, R Xiao, L Potocki. GARS-related disease in infantile spinal muscular atrophy: implications for diagnosis and treatment.. Am J Med Genet Part A. 2020;182:1167-76",
"R Meyer-Schuman, A. Antonellis. Emerging mechanisms of aminoacyl-tRNA synthetase mutations in recessive and dominant human disease.. Hum Mol Genet 2017;26:R114-R127",
"T Nishikawa, K Kawakami, T Kumamoto, S Tonooka, A Abe, K Hayasaka, Y Okamoto, Y Kawano. Severe neurotoxicities in a case of Charcot-Marie-Tooth disease type 2 caused by vincristine for acute lymphoblastic leukemia.. J Pediatr Hematol Oncol. 2008;30:519-21",
"SN Oprescu, X Chepa-Lotrea, R Takase, G Golas, TC Markello, DR Adams, C Toro, AL Gropman, YM Hou, MCV Malicdan, WA Gahl, CJ Tifft, A Antonellis. Compound heterozygosity for loss-of-function GARS variants results in a multisystem developmental syndrome that includes severe growth retardation.. Hum Mutat. 2017;38:1412-20",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"N Sambuughin, K Sivakumar, B Selenge, HS Lee, D Friedlich, D Baasanjav, MC Dalakas, LG Goldfarb. Autosomal dominant distal spinal muscular atrophy type V (dSMA-V) and Charcot-Marie-Tooth disease type 2D (CMT2D) segregate within a single large kindred and map to a refined region on chromosome 7p15.. J Neurol Sci 1998;161:23-8",
"KL Seburn, KH Morelli, A Jordanova, RW Burgess. Lack of neuropathy-related phenotypes in hint1 knockout mice.. J Neuropathol Exp Neurol. 2014;73:693-701",
"K Sivakumar, T Kyriakides, I Puls, GA Nicholson, B Funalot, A Antonellis, N Sambuughin, K Ellsworth, JL Beggs, E Zamba-Papanicolaou, V Ionasescu, MC Dalakas, ED Green, KH Fischbeck, LG Goldfarb. Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations.. Brain 2005;128:2304-14",
"PD Stenson, M Mort, EV Ball, K Evans, M Hayden, S Heywood, M Hussain, AD Phillips, DN Cooper. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies.. Hum Genet. 2017;136:665-77"
] |
8/11/2006
|
22/7/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
cmt2e
|
cmt2e
|
[
"CMT2E/1F",
"CMT 2E/1F",
"Neurofilament light polypeptide",
"NEFL",
"CMT2E/1F"
] |
Charcot-Marie-Tooth Neuropathy Type 2E/1F – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Peter De Jonghe, Albena K Jordanova
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Summary Charcot-Marie-Tooth neuropathy type 2E/1F (CMT2E/1F) is characterized by a progressive peripheral motor and sensory neuropathy with variable clinical and electrophysiologic expression. Disease onset ranges from the first to the fifth decade of life; in some cases disease onset can be in infancy. Affected individuals have difficulty walking and running because of progressive distal weakness and wasting of the muscles of the lower limbs. Paresis in the distal part of the lower limbs varies from mild weakness to a complete paralysis of the distal muscle groups. Tendon reflexes are diminished or absent. Sensory signs are not prominent but are present in all affected individuals. In most individuals, nerve conduction velocities (NCVs) are severely to moderately reduced and fall within the CMT1 range (i.e., <38 m/sec for the motor median nerve), although near-normal NCVs have been described. CMT2E/1F is usually inherited in an autosomal dominant manner; on rare occasion it can be inherited in an autosomal recessive manner. Prenatal testing for pregnancies at increased risk for both autosomal dominant and autosomal recessive CMT2E/1F is possible if the pathogenic variant(s) in the family are known.
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## Diagnosis
Charcot-Marie-Tooth neuropathy type 2E/1F (CMT2E/1F) is suspected in individuals with a progressive peripheral motor and sensory neuropathy.
To date, deletion or duplication of exons or of the entire gene has not been reported.
Molecular Genetic Testing Used in Charcot-Marie-Tooth Neuropathy Type 2E/1F
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
## Clinical Diagnosis
Charcot-Marie-Tooth neuropathy type 2E/1F (CMT2E/1F) is suspected in individuals with a progressive peripheral motor and sensory neuropathy.
## Molecular Genetic Testing
To date, deletion or duplication of exons or of the entire gene has not been reported.
Molecular Genetic Testing Used in Charcot-Marie-Tooth Neuropathy Type 2E/1F
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
## Testing Strategy
## Clinical Characteristics
CMT2E/1F is a progressive peripheral motor and sensory neuropathy with variable clinical and electrophysiologic expression. The disease onset is within the first five decades of life and presents with a broad clinical phenotype – from an early-onset severe phenotype to milder forms.
Some affected individuals have onset in infancy or early childhood and may display hypotonia and mildly delayed motor milestones. The presenting symptoms in most individuals are difficulties in walking and running as a result of progressive distal weakness and wasting of the lower limbs. Paresis in the distal part of the lower limbs varies from mild weakness to a complete paralysis of the distal muscle groups. In the most severely affected people, mild-to-moderate proximal arm and shoulder girdle weakness can be observed.
Tendon reflexes are diminished or absent.
Sensory signs are not prominent but are present in all affected individuals.
Cerebellar dysfunction, tremor, and hearing loss are occasionally observed.
Ambulation is generally preserved during life. Only one individual is reported to be wheelchair bound.
Affected individuals do not have palpably enlarged nerves, ulcerated feet, or paralysis of the vocal cords and/or diaphragm.
There are no obvious genotype/phenotype correlations, mainly because of the small number of reported individuals with
Individuals with autosomal recessive CMT2E/1F usually have more a severe phenotype, diagnosed as CMT1F.
Penetrance is most likely to be complete.
No clear evidence of anticipation is available in the literature.
In the first reported family, NCVs were within the CMT2 range; thus this CMT variant was initially described as CMT2E [
CMT1F is characterized by slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, hollow feet, and reduced nerve conduction velocities (<38 m per sec). Onset is in early infancy or childhood and the course is usually more severe. These individuals are often diagnosed as having Dejerine-Sottas syndrome (DSS), a term that refers to this phenotype and can be observed in individuals with pathogenic variants in a number of genes; thus, the term DSS has become more confusing than helpful when considering the nosology of CMT.
The reported autosomal dominant as well as autosomal recessive mode of inheritance of the disease further complicates the nosologic classification.
The true prevalence of CMT2E/1F is not known. Preliminary data indicate that
## Clinical Description
CMT2E/1F is a progressive peripheral motor and sensory neuropathy with variable clinical and electrophysiologic expression. The disease onset is within the first five decades of life and presents with a broad clinical phenotype – from an early-onset severe phenotype to milder forms.
Some affected individuals have onset in infancy or early childhood and may display hypotonia and mildly delayed motor milestones. The presenting symptoms in most individuals are difficulties in walking and running as a result of progressive distal weakness and wasting of the lower limbs. Paresis in the distal part of the lower limbs varies from mild weakness to a complete paralysis of the distal muscle groups. In the most severely affected people, mild-to-moderate proximal arm and shoulder girdle weakness can be observed.
Tendon reflexes are diminished or absent.
Sensory signs are not prominent but are present in all affected individuals.
Cerebellar dysfunction, tremor, and hearing loss are occasionally observed.
Ambulation is generally preserved during life. Only one individual is reported to be wheelchair bound.
Affected individuals do not have palpably enlarged nerves, ulcerated feet, or paralysis of the vocal cords and/or diaphragm.
## Genotype-Phenotype Correlations
There are no obvious genotype/phenotype correlations, mainly because of the small number of reported individuals with
Individuals with autosomal recessive CMT2E/1F usually have more a severe phenotype, diagnosed as CMT1F.
## Penetrance
Penetrance is most likely to be complete.
## Anticipation
No clear evidence of anticipation is available in the literature.
## Nomenclature
In the first reported family, NCVs were within the CMT2 range; thus this CMT variant was initially described as CMT2E [
CMT1F is characterized by slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, hollow feet, and reduced nerve conduction velocities (<38 m per sec). Onset is in early infancy or childhood and the course is usually more severe. These individuals are often diagnosed as having Dejerine-Sottas syndrome (DSS), a term that refers to this phenotype and can be observed in individuals with pathogenic variants in a number of genes; thus, the term DSS has become more confusing than helpful when considering the nosology of CMT.
The reported autosomal dominant as well as autosomal recessive mode of inheritance of the disease further complicates the nosologic classification.
## Prevalence
The true prevalence of CMT2E/1F is not known. Preliminary data indicate that
## Genetically Related (Allelic) Disorders
CMT2E/1F is the only disorder associated with pathogenic variants in
## Differential Diagnosis
The clinical and electrophysiologic phenotype of CMT2E/1F is undistinguishable from other forms of CMT/DSS (see
## Management
To establish the extent of disease in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 2E/1F (CMT2E/1F), the following evaluations are recommended:
Physical examination to determine extent of weakness and atrophy,
NCV to help distinguish demyelinating, axonal, and mixed neuropathies
Complete family history
Consultation with a cinical geneticist and/or genetic counselor
Treatment is symptomatic and affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [
Special shoes, including those with good ankle support, may be needed.
Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.
Affected individuals often require ankle/foot orthoses (AFO) to correct foot drop and aid walking.
Orthopedic surgery may be required to correct severe
Some individuals require forearm crutches or canes for gait stability; fewer than 5% need wheelchairs.
Exercise is encouraged within the individual's capability and many individuals remain physically active.
Career and employment choices may be influenced by persistent weakness of hands and/or feet.
Pain should be treated symptomatically [
Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.
Monitoring of gait and condition of feet to determine need for bracing, special shoes, surgery is appropriate.
Obesity is to be avoided because it makes walking more difficult.
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
See
Search
• Physical examination to determine extent of weakness and atrophy,
• NCV to help distinguish demyelinating, axonal, and mixed neuropathies
• Complete family history
• Consultation with a cinical geneticist and/or genetic counselor
• Special shoes, including those with good ankle support, may be needed.
• Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.
• Affected individuals often require ankle/foot orthoses (AFO) to correct foot drop and aid walking.
• Orthopedic surgery may be required to correct severe
• Some individuals require forearm crutches or canes for gait stability; fewer than 5% need wheelchairs.
• Exercise is encouraged within the individual's capability and many individuals remain physically active.
• Career and employment choices may be influenced by persistent weakness of hands and/or feet.
• Pain should be treated symptomatically [
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 2E/1F (CMT2E/1F), the following evaluations are recommended:
Physical examination to determine extent of weakness and atrophy,
NCV to help distinguish demyelinating, axonal, and mixed neuropathies
Complete family history
Consultation with a cinical geneticist and/or genetic counselor
• Physical examination to determine extent of weakness and atrophy,
• NCV to help distinguish demyelinating, axonal, and mixed neuropathies
• Complete family history
• Consultation with a cinical geneticist and/or genetic counselor
## Treatment of Manifestations
Treatment is symptomatic and affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [
Special shoes, including those with good ankle support, may be needed.
Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.
Affected individuals often require ankle/foot orthoses (AFO) to correct foot drop and aid walking.
Orthopedic surgery may be required to correct severe
Some individuals require forearm crutches or canes for gait stability; fewer than 5% need wheelchairs.
Exercise is encouraged within the individual's capability and many individuals remain physically active.
Career and employment choices may be influenced by persistent weakness of hands and/or feet.
Pain should be treated symptomatically [
• Special shoes, including those with good ankle support, may be needed.
• Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.
• Affected individuals often require ankle/foot orthoses (AFO) to correct foot drop and aid walking.
• Orthopedic surgery may be required to correct severe
• Some individuals require forearm crutches or canes for gait stability; fewer than 5% need wheelchairs.
• Exercise is encouraged within the individual's capability and many individuals remain physically active.
• Career and employment choices may be influenced by persistent weakness of hands and/or feet.
• Pain should be treated symptomatically [
## Prevention of Secondary Complications
Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.
## Surveillance
Monitoring of gait and condition of feet to determine need for bracing, special shoes, surgery is appropriate.
## Agents/Circumstances to Avoid
Obesity is to be avoided because it makes walking more difficult.
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Charcot-Marie-Tooth neuropathy type 2E/1F is typically inherited in an autosomal dominant manner.
To date, two families with autosomal recessive CMT2E/1F (caused by homozygous nonsense variants) have been reported [
Most individuals with autosomal dominant CMT2E/1F have an affected parent.
Occasionally, family history may be negative because the proband has a
Recommendations for the evaluation of parents of a simplex case (i.e., an individual with no family history of the disorder) include neurologic and electrophysiologic examination and, if the pathogenic variant in the proband has been identified, molecular genetic testing.
Note: Although most individuals diagnosed with autosomal dominant CMT2E/1F have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
The risk to sibs depends on the genetic status of the proband's parents.
If a parent has a autosomal dominant pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
The presence of a
If the pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, it is most likely caused by a
Each child of an individual with CMT2E/1F has a 50% chance of inheriting the pathogenic variant.
The presence of a
Individuals who are severely affected may not reproduce.
Parents of a proband with CMT2E/1F inherited in an autosomal recessive manner are obligate heterozygotes and therefore carry one mutated allele.
Heterozygotes (carriers) are asymptomatic.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
The offspring of a proband with autosomal recessive CMT2E/1F are obligate heterozygotes (carriers).
In the rare instance that an unrelated reproductive partner is a carrier, the offspring are at a 50% risk of being affected and a 50% risk of being carriers.
Carrier testing for autosomal recessive CMT2E/1F is possible once the
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk.
Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
• Most individuals with autosomal dominant CMT2E/1F have an affected parent.
• Occasionally, family history may be negative because the proband has a
• Recommendations for the evaluation of parents of a simplex case (i.e., an individual with no family history of the disorder) include neurologic and electrophysiologic examination and, if the pathogenic variant in the proband has been identified, molecular genetic testing.
• The risk to sibs depends on the genetic status of the proband's parents.
• If a parent has a autosomal dominant pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• The presence of a
• If the pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, it is most likely caused by a
• Each child of an individual with CMT2E/1F has a 50% chance of inheriting the pathogenic variant.
• The presence of a
• Individuals who are severely affected may not reproduce.
• Parents of a proband with CMT2E/1F inherited in an autosomal recessive manner are obligate heterozygotes and therefore carry one mutated allele.
• Heterozygotes (carriers) are asymptomatic.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.
• The offspring of a proband with autosomal recessive CMT2E/1F are obligate heterozygotes (carriers).
• In the rare instance that an unrelated reproductive partner is a carrier, the offspring are at a 50% risk of being affected and a 50% risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk.
## Mode of Inheritance
Charcot-Marie-Tooth neuropathy type 2E/1F is typically inherited in an autosomal dominant manner.
To date, two families with autosomal recessive CMT2E/1F (caused by homozygous nonsense variants) have been reported [
## Autosomal Dominant Inheritance – Risk to Family Members
Most individuals with autosomal dominant CMT2E/1F have an affected parent.
Occasionally, family history may be negative because the proband has a
Recommendations for the evaluation of parents of a simplex case (i.e., an individual with no family history of the disorder) include neurologic and electrophysiologic examination and, if the pathogenic variant in the proband has been identified, molecular genetic testing.
Note: Although most individuals diagnosed with autosomal dominant CMT2E/1F have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
The risk to sibs depends on the genetic status of the proband's parents.
If a parent has a autosomal dominant pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
The presence of a
If the pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, it is most likely caused by a
Each child of an individual with CMT2E/1F has a 50% chance of inheriting the pathogenic variant.
The presence of a
Individuals who are severely affected may not reproduce.
• Most individuals with autosomal dominant CMT2E/1F have an affected parent.
• Occasionally, family history may be negative because the proband has a
• Recommendations for the evaluation of parents of a simplex case (i.e., an individual with no family history of the disorder) include neurologic and electrophysiologic examination and, if the pathogenic variant in the proband has been identified, molecular genetic testing.
• The risk to sibs depends on the genetic status of the proband's parents.
• If a parent has a autosomal dominant pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• The presence of a
• If the pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, it is most likely caused by a
• Each child of an individual with CMT2E/1F has a 50% chance of inheriting the pathogenic variant.
• The presence of a
• Individuals who are severely affected may not reproduce.
## Autosomal Recessive Inheritance
Parents of a proband with CMT2E/1F inherited in an autosomal recessive manner are obligate heterozygotes and therefore carry one mutated allele.
Heterozygotes (carriers) are asymptomatic.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
The offspring of a proband with autosomal recessive CMT2E/1F are obligate heterozygotes (carriers).
In the rare instance that an unrelated reproductive partner is a carrier, the offspring are at a 50% risk of being affected and a 50% risk of being carriers.
Carrier testing for autosomal recessive CMT2E/1F is possible once the
• Parents of a proband with CMT2E/1F inherited in an autosomal recessive manner are obligate heterozygotes and therefore carry one mutated allele.
• Heterozygotes (carriers) are asymptomatic.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.
• The offspring of a proband with autosomal recessive CMT2E/1F are obligate heterozygotes (carriers).
• In the rare instance that an unrelated reproductive partner is a carrier, the offspring are at a 50% risk of being affected and a 50% risk of being carriers.
## Risk to Family Members
Parents of a proband with CMT2E/1F inherited in an autosomal recessive manner are obligate heterozygotes and therefore carry one mutated allele.
Heterozygotes (carriers) are asymptomatic.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
The offspring of a proband with autosomal recessive CMT2E/1F are obligate heterozygotes (carriers).
In the rare instance that an unrelated reproductive partner is a carrier, the offspring are at a 50% risk of being affected and a 50% risk of being carriers.
• Parents of a proband with CMT2E/1F inherited in an autosomal recessive manner are obligate heterozygotes and therefore carry one mutated allele.
• Heterozygotes (carriers) are asymptomatic.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.
• The offspring of a proband with autosomal recessive CMT2E/1F are obligate heterozygotes (carriers).
• In the rare instance that an unrelated reproductive partner is a carrier, the offspring are at a 50% risk of being affected and a 50% risk of being carriers.
## Carrier (Heterozygote) Detection
Carrier testing for autosomal recessive CMT2E/1F is possible once the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
## Resources
France
PO Box 105
Glenolden PA 19036
Department of Molecular Genetics
University of Antwerp
Antwerp Antwerpen B-2610
Belgium
432 Park Avenue South
4th Floor
New York NY 10016
Institute of Genetic Medicine
University of Newcastle upon Tyne
International Centre for Life
Newcastle upon Tyne NE1 3BZ
United Kingdom
1 Rue de l'International
BP59
Evry cedex 91002
France
Lt Gen van Heutszlaan 6
3743 JN Baarn
Netherlands
222 South Riverside Plaza
Suite 1500
Chicago IL 60606
61A Great Suffolk Street
London SE1 0BU
United Kingdom
•
• France
•
•
• PO Box 105
• Glenolden PA 19036
•
•
• Department of Molecular Genetics
• University of Antwerp
• Antwerp Antwerpen B-2610
• Belgium
•
• 432 Park Avenue South
• 4th Floor
• New York NY 10016
•
•
•
•
•
•
•
•
• Institute of Genetic Medicine
• University of Newcastle upon Tyne
• International Centre for Life
• Newcastle upon Tyne NE1 3BZ
• United Kingdom
•
•
• 1 Rue de l'International
• BP59
• Evry cedex 91002
• France
•
•
• Lt Gen van Heutszlaan 6
• 3743 JN Baarn
• Netherlands
•
•
• 222 South Riverside Plaza
• Suite 1500
• Chicago IL 60606
•
•
• 61A Great Suffolk Street
• London SE1 0BU
• United Kingdom
•
•
•
## Molecular Genetics
Charcot-Marie-Tooth Neuropathy Type 2E/1F: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Charcot-Marie-Tooth Neuropathy Type 2E/1F (
The cytoskeleton of neuronal cells is mainly composed of three kinds of filaments: microtubules, neurofilaments, and actin filaments [
Neurofilaments in vertebrates are composed of three different protein subunits, referred to as neurofilament light chain (NEFL, 68 kd), neurofilament medium chain (NEFM, 160 kd), and neurofilament heavy chain (NEFH, 210 kd), each of these encoded by different genes [
Disruption of axonal transport of NFs resulting in neurofilament accumulations is a major pathologic hallmark during the early stages of many human motor neuron diseases, including
Selected
Variants listed in the table have been provided by the authors.
p. = designates that protein has not been analyzed, but no change is expected.
Variant designation that does not conform to current naming conventions
Pathogenic variants that result in autosomal recessive inheritance
The effect of dominant
Two transgenic mouse CMT2E models have been generated to date, expressing p.Pro22Ser and p.Glu396Lys pathogenic variants respectively [
## Molecular Pathogenesis
The cytoskeleton of neuronal cells is mainly composed of three kinds of filaments: microtubules, neurofilaments, and actin filaments [
Neurofilaments in vertebrates are composed of three different protein subunits, referred to as neurofilament light chain (NEFL, 68 kd), neurofilament medium chain (NEFM, 160 kd), and neurofilament heavy chain (NEFH, 210 kd), each of these encoded by different genes [
Disruption of axonal transport of NFs resulting in neurofilament accumulations is a major pathologic hallmark during the early stages of many human motor neuron diseases, including
Selected
Variants listed in the table have been provided by the authors.
p. = designates that protein has not been analyzed, but no change is expected.
Variant designation that does not conform to current naming conventions
Pathogenic variants that result in autosomal recessive inheritance
The effect of dominant
Two transgenic mouse CMT2E models have been generated to date, expressing p.Pro22Ser and p.Glu396Lys pathogenic variants respectively [
## References
## Literature Cited
## Chapter Notes
15 August 2019 (ma) Chapter retired: covered in
27 October 2011 (me) Comprehensive update posted live
15 June 2006 (ca) Comprehensive update posted live
1 April 2004 (me) Review posted live
6 October 2003 (pdj) Original submission
• 15 August 2019 (ma) Chapter retired: covered in
• 27 October 2011 (me) Comprehensive update posted live
• 15 June 2006 (ca) Comprehensive update posted live
• 1 April 2004 (me) Review posted live
• 6 October 2003 (pdj) Original submission
## Revision History
15 August 2019 (ma) Chapter retired: covered in
27 October 2011 (me) Comprehensive update posted live
15 June 2006 (ca) Comprehensive update posted live
1 April 2004 (me) Review posted live
6 October 2003 (pdj) Original submission
• 15 August 2019 (ma) Chapter retired: covered in
• 27 October 2011 (me) Comprehensive update posted live
• 15 June 2006 (ca) Comprehensive update posted live
• 1 April 2004 (me) Review posted live
• 6 October 2003 (pdj) Original submission
|
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"A Al-Chalabi, PM Andersen, P Nilsson, B Chioza, JL Andersson, C Russ, CE Shaw, JF Powell, PN Leigh. Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis.. Hum Mol Genet 1999;8:157-64",
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"J Brownlees, S Ackerley, AJ Grierson, NJ Jacobsen, K Shea, BH Anderton, PN Leigh, CE Shaw, CC Miller. Charcot-Marie-Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport.. Hum Mol Genet 2002;11:2837-44",
"DA Carpenter, W Ip. Neurofilament triplet protein interactions: evidence for the preferred formation of NF-L-containing dimers and a putative function for the end domains.. J Cell Sci 1996;109:2493-8",
"BO Choi, MS Lee, SH Shin, JH Hwang, KG Choi, WK Kim, IN Sunwoo, NK Kim, KW Chung. Mutational analysis of PMP22, MPZ, GJB1, EGR2 and NEFL in Korean Charcot-Marie-Tooth neuropathy patients.. Hum Mutat 2004;24:185-6",
"C Cifuentes-Diaz, S Nicole, ME Velasco, C Borra-Cebrian, C Panozzo, T Frugier, G Millet, N Roblot, V Joshi, J Melki. Neurofilament accumulation at the motor endplate and lack of axonal sprouting in a spinal muscular atrophy mouse model.. Hum Mol Genet 2002;11:1439-47",
"P De Jonghe, I Mersivanova, E Nelis, J Del Favero, JJ Martin, C Van Broeckhoven, O Evgrafov, V Timmerman. Further evidence that neurofilament light chain gene mutations can cause Charcot-Marie-Tooth disease type 2E.. Ann Neurol 2001;49:245-9",
"F Dequen, M Filali, RC Larivière, R Perrot, S Hisanaga, JP Julien. Reversal of neuropathy phenotypes in conditional mouse model of Charcot-Marie-Tooth disease type 2E.. Hum Mol Genet. 2010;19:2616-29",
"M Dubois, C Strazielle, JP Julien, R Lalonde. Mice with the deleted neurofilament of low molecular weight (Nefl) gene: 2. Effects on motor functions and spatial orientation.. J Neurosci Res 2005;80:751-8",
"GM Fabrizi, T Cavallaro, C Angiari, L Bertolasi, I Cabrini, M Ferrarini, N Rizzuto. Giant axon and neurofilament accumulation in Charcot-Marie-Tooth disease type 2E.. Neurology 2004;62:1429-31",
"GM Fabrizi, T Cavallaro, C Angiari, I Cabrini, F Taioli, G Malerba, L Bertolasi, N Rizzuto. Charcot-Marie-Tooth disease type 2E, a disorder of the cytoskeleton.. Brain. 2007;130:394-403",
"DA Figlewicz, A Krizus, MG Martinoli, V Meininger, M Dib, GA Rouleau, JP Julien. Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis.. Hum Mol Genet 1994;3:1757-61",
"KM Flanigan, TO Crawford, JW Griffin, HH Goebel, A Kohlschutter, J Ranells, PR Camfield, LJ Ptacek. Localization of the giant axonal neuropathy gene to chromosome 16q24.. Ann Neurol 1998;43:143-8",
"RL Friede, T Samorajski. Axon caliber related to neurofilaments and microtubules in sciatic nerve fibers of rats and mice.. Anat Rec 1970;167:379-87",
"F Gemignani, G Melli, S Alfieri, C Inglese, A Marbini. Sensory manifestations in Charcot-Marie-Tooth disease.. J Peripher Nerv Syst 2004;9:7-14",
"DM Georgiou, J Zidar, M Korosec, LT Middleton, T Kyriakides, K Christodoulou. A novel NF-L mutation Pro22Ser is associated with CMT2 in a large Slovenian family.. Neurogenetics 2002;4:93-6",
"JE Goldman, SH Yen, FC Chiu, NS Peress. Lewy bodies of Parkinson's disease contain neurofilament antigens.. Science 1983;221:1082-4",
"M Grandis, ME Shy. Current therapy for Charcot-Marie-Tooth disease.. Curr Treat Options Neurol 2005;7:23-31",
"GP Guyton, RA Mann. The pathogenesis and surgical management of foot deformity in Charcot-Marie-Tooth disease.. Foot Ankle Clin 2000;5:317-26",
"JR Holmes, ST Hansen. Foot and ankle manifestations of Charcot-Marie-Tooth disease.. Foot Ankle 1993;14:476-86",
"A Jordanova, P De Jonghe, CF Boerkoel, H Takashima, E De Vriendt, C Ceuterick, JJ Martin, IJ Butler, P Mancias, SCh Papasozomenos, D Terespolsky, L Potocki, CW Brown, M Shy, DA Rita, I Tournev, I Kremensky, JR Lupski, V Timmerman. Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease.. Brain 2003;126:590-7",
"JP Julien. A role for neurofilaments in the pathogenesis of amyotrophic lateral sclerosis.. Biochem Cell Biol 1995;73:593-7",
"JP Julien. Neurofilament functions in health and disease.. Curr Opin Neurobiol 1999;9:554-60",
"SK Kim, H Kim, YR Yang, PG Suh, JS Chang. Phosphatidylinositol phosphates directly bind to neurofilament light chain (NF-L) for the regulation of NF-L self assembly.. Exp Mol Med. 2011;43:153-60",
"W Luo, B Tang, G Zhao, Q Li, J Xiao, Q Yang, J Xia. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2003;20:169-70",
"IV Mersiyanova, AV Perepelov, AV Polyakov, VF Sitnikov, EL Dadali, RB Oparin, AN Petrin, OV Evgrafov. A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene.. Am J Hum Genet 2000;67:37-46",
"G Miltenberger-Miltenyi, AR Janecke, JV Wanschitz, V Timmerman, C Windpassinger, M Auer-Grumbach, WN Löscher. Clinical and electrophysiological features in Charcot-Marie-Tooth disease with mutations in the NEFL gene.. Arch Neurol. 2007;64:966-70",
"R Pérez-Ollé, ST Jones, RK Liem. Phenotypic analysis of neurofilament light gene mutations linked to Charcot-Marie-Tooth disease in cell culture models.. Hum Mol Genet 2004;13:2207-20",
"R Pérez-Ollé, CL Leung, RK Liem. Effects of Charcot-Marie-Tooth-linked mutations of the neurofilament light subunit on intermediate filament formation.. J Cell Sci 2002;115:4937-46",
"R Pérez-Ollé, MA Lopez-Toledano, D Goryunov, N Cabrera-Poch, L Stefanis, K Brown, RK Liem. Mutations in the neurofilament light gene linked to Charcot-Marie-Tooth disease cause defects in transport.. J Neurochem 2005;93:861-74",
"SC Previtali, B Zerega, DL Sherman, PJ Brophy, G Dina, RH King, MM Salih, L Feltri, A Quattrini, R Ravazzolo, L Wrabetz, AP Monaco, A Bolino. Myotubularin-related 2 protein phosphatase and neurofilament light chain protein, both mutated in CMT neuropathies, interact in peripheral nerve.. Hum Mol Genet 2003;12:1713-23",
"T Sasaki, T Gotow, M Shiozaki, F Sakaue, T Saito, JP Julien, Y Uchiyama, S Hisanaga. Aggregate formation and phosphorylation of neurofilament-L Pro22 Charcot-Marie-Tooth disease mutants.. Hum Mol Genet 2006;15:943-52",
"H Shen, DM Barry, JM Dale, VB Garcia, NA Calcutt, ML Garcia. Muscle pathology without severe nerve pathology in a new mouse model of Charcot-Marie-Tooth disease type 2E.. Hum Mol Genet. 2011;20:2535-48",
"CE Shepherd, H McCann, E Thiel, GM Halliday. Neurofilament-immunoreactive neurons in Alzheimer's disease and dementia with Lewy bodies.. Neurobiol Dis 2002;9:249-57",
"S Tokutake. On the assembly mechanism of neurofilaments.. Int J Biochem 1990;22:1-6",
"J Tomkins, P Usher, JY Slade, PG Ince, A Curtis, K Bushby, PJ Shaw. Novel insertion in the KSP region of the neurofilament heavy gene in amyotrophic lateral sclerosis (ALS).. Neuroreport 1998;9:3967-70",
"JD Vechio, LI Bruijn, Z Xu, RH Brown, DW Cleveland. Sequence variants in human neurofilament proteins: absence of linkage to familial amyotrophic lateral sclerosis.. Ann Neurol 1996;40:603-10",
"M Yamamoto, T Yoshihara, N Hattori, G Sobue. Glu528del in NEFL is a polymorphic variant rather than a disease-causing mutation for Charcot-Marie-Tooth disease in Japan.. Neurogenetics 2004;5:75-7",
"T Yoshihara, M Yamamoto, N Hattori, K Misu, K Mori, H Koike, G Sobue. Identification of novel sequence variants in the neurofilament-light gene in a Japanese population: analysis of Charcot-Marie-Tooth disease patients and normal individuals.. J Peripher Nerv Syst 2002;7:221-4",
"SW Yum, J Zhang, K Mo, J Li, SS Scherer. A novel recessive Nefl mutation causes a severe, early-onset axonal neuropathy.. Ann Neurol. 2009;66:759-70",
"J Zhai, H Lin, JP Julien, WW Schlaepfer. Disruption of neurofilament network with aggregation of light neurofilament protein: a common pathway leading to motor neuron degeneration due to Charcot-Marie-Tooth disease-linked mutations in NFL and HSPB1.. Hum Mol Genet. 2007;16:3103-16",
"S Züchner, M Vorgerd, E Sindern, JM Schroder. The novel neurofilament light (NEFL) mutation Glu397Lys is associated with a clinically and morphologically heterogeneous type of Charcot-Marie-Tooth neuropathy.. Neuromuscul Disord 2004;14:147-57"
] |
1/4/2004
|
27/10/2011
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
cmt4
|
cmt4
|
[
"CMT4",
"CMT 4",
"CMT4",
"Charcot-Marie-Tooth Neuropathy Type 4A (CMT4A)",
"Charcot-Marie-Tooth Neuropathy Type 4B1 (CMT4B1)",
"Charcot-Marie-Tooth Neuropathy Type 4B2 (CMT4B2)",
"Charcot-Marie-Tooth Neuropathy Type 4C",
"Charcot-Marie-Tooth Neuropathy Type 4D (CMT4D)",
"Charcot-Marie-Tooth Neuropathy Type 4E (CMT4E)",
"Charcot-Marie-Tooth Neuropathy Type 4F (CMT4F)",
"Charcot-Marie-Tooth Neuropathy Type 4H (CMT4H)",
"Charcot-Marie-Tooth Neuropathy Type 4J (CMT4J)",
"Charcot-Marie-Tooth Neuropathy Type 4B3 (CMT4B3)",
"Charcot-Marie-Tooth Neuropathy Type 4G (CMT4G)",
"E3 SUMO-protein ligase EGR2",
"FYVE, RhoGEF and PH domain-containing protein 4",
"Ganglioside-induced differentiation-associated protein 1",
"Hexokinase-1",
"Myotubularin-related protein 13",
"Myotubularin-related protein 2",
"Myotubularin-related protein 5",
"Periaxin",
"Polyphosphoinositide phosphatase",
"Protein NDRG1",
"SH3 domain and tetratricopeptide repeat-containing protein 2",
"EGR2",
"FGD4",
"FIG4",
"GDAP1",
"HK1",
"MTMR2",
"NDRG1",
"PRX",
"SBF1",
"SBF2",
"SH3TC2",
"Charcot-Marie-Tooth Neuropathy Type 4"
] |
Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Thomas D Bird
|
Summary Charcot-Marie-Tooth neuropathy type 4 (CMT4) is a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance. Affected individuals have the typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and, frequently, The diagnosis of CMT4 subtypes is based on clinical findings, neurophysiologic studies, and molecular genetic testing. Detection of biallelic pathogenic variants in one of the following 11 genes establishes the diagnosis: The CMT4 subtypes are inherited in an autosomal recessive manner. Parents of an affected individual are obligate carriers of the CMT4-related pathogenic variant present in their family. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in an affected family member are known.
|
CMT4A
CMT4B1
CMT4B2
CMT4B3
CMT4C
CMT4D
CMT4E
CMT4F
CMT4G
CMT4H
CMT4J
For synonyms and outdated names see
• CMT4A
• CMT4B1
• CMT4B2
• CMT4B3
• CMT4C
• CMT4D
• CMT4E
• CMT4F
• CMT4G
• CMT4H
• CMT4J
## Diagnosis
Charcot-Marie-Tooth neuropathy type 4 (CMT4)
Progressive weakness of the distal muscles in the feet and/or hands
High-arched feet
Weak ankle dorsiflexion
Atrophic distal muscles
Depressed or absent tendon reflexes
Distal sensory loss
The diagnosis of CMT4
Molecular testing approaches can include
Molecular Genetics of CMT4
See
See
Genetic abnormalities identified in 3312 of 17,880 individuals referred to a commercial genetic testing laboratory [
197 individuals tested for CMT [
96 cases (axonal) [
Genetic abnormalities identified in 35 of 77 individuals tested [
1206 individuals tested for CMT [
449 cases (demyelinating) [
• Progressive weakness of the distal muscles in the feet and/or hands
• High-arched feet
• Weak ankle dorsiflexion
• Atrophic distal muscles
• Depressed or absent tendon reflexes
• Distal sensory loss
## Suggestive Findings
Charcot-Marie-Tooth neuropathy type 4 (CMT4)
Progressive weakness of the distal muscles in the feet and/or hands
High-arched feet
Weak ankle dorsiflexion
Atrophic distal muscles
Depressed or absent tendon reflexes
Distal sensory loss
• Progressive weakness of the distal muscles in the feet and/or hands
• High-arched feet
• Weak ankle dorsiflexion
• Atrophic distal muscles
• Depressed or absent tendon reflexes
• Distal sensory loss
## Establishing the Diagnosis
The diagnosis of CMT4
Molecular testing approaches can include
Molecular Genetics of CMT4
See
See
Genetic abnormalities identified in 3312 of 17,880 individuals referred to a commercial genetic testing laboratory [
197 individuals tested for CMT [
96 cases (axonal) [
Genetic abnormalities identified in 35 of 77 individuals tested [
1206 individuals tested for CMT [
449 cases (demyelinating) [
## Clinical Characteristics
The clinical findings of a peripheral neuropathy, slow NCV, mode of inheritance, and biallelic pathogenic variants in a specific gene have been the basis for classification for the majority of CMT subtypes.
Individuals with CMT4 usually have the clinical characteristics of the CMT phenotype, including distal muscle weakness and atrophy, sensory loss, and, often,
The autosomal recessive neuropathies tend to have an earlier onset (early childhood) and more severe progression than the autosomal dominant varieties. Except in the case of consanguinity, they also appear only in sibs or as simplex cases.
Some families with CMT4A have features of a demyelinating neuropathy, whereas others have features of axonal neuropathy [
Mild sensory loss, absent tendon reflexes, skeletal deformities, and scoliosis can be observed. Vocal cord paresis may occur [
Nerve biopsy reveals hypomyelination with onion bulbs composed of basal laminae [
Cerebrospinal fluid protein concentration is normal.
Adults who are affected are seriously handicapped and frequently require wheelchairs by age 20 years. Duration of illness ranges from age 27 to 39 years and death occurs in the fourth or fifth decade. Intellect is normal.
Two families were reported by
In a family with an
Auditory evoked potentials are abnormal.
NCVs are very slow (15-17 m/s) and often undetectable.
Sural nerve biopsy reveals irregular redundant loops of focally folded myelin.
A Japanese family with neuropathy and nerve pathology showing irregular redundant loops and folding of the myelin sheath has been associated with juvenile onset of glaucoma [
Severe kyphoscoliosis and cranial nerve involvement were found in ten cases reported by
Affected individuals have motor and sensory neuropathy in the lower limbs and slow median NCV (mean is 24 m/s).
Nerve biopsy shows an increase of basal membranes around demyelinated and unmyelinated axons, relatively few classic onion bulbs, and large cytoplasmic extensions of the Schwann cells [
CMT4D has the distinguishing clinical characteristic of sensorineural deafness, with onset usually in the third decade. Tongue atrophy has also been described.
A non-Gypsy family with CNS white matter lesions has been reported [
Nerve biopsy shows a hypertrophic onion bulb change.
A child had delayed motor milestones and marked weakness. Additional families are described by
A more benign phenotype with later age of onset (7-12 years) but with marked spine deformities was reported by
Prominent sensory loss occurred in one family [
Sural nerve pathology showed demyelination, onion bulbs, and focal myelin thickening.
Two sibs in Ireland remained ambulatory into middle age [
An Algerian and a Lebanese affected individual had marked slowing of nerve conductions [
In general, no specific consistent genotype-phenotype correlations are known.
Severe neuropathy with slow NCVs and onset in early childhood is often called the Déjérine-Sottas syndrome (DSS). This is a descriptive clinical term that does not refer to a specific disease because it is caused by pathogenic variants in multiple genes [
The overall prevalence of hereditary neuropathies is estimated to be approximately 30:100,000 population. More than half of these cases are CMT type 1 (15:100,000).
The autosomal recessive forms of CMT are quite rare and often limited to specific ethnic groups (e.g., in North Africa), where they may be relatively common.
Three founder pathogenic variants are found in CMT4 in subgroups of the European Gypsy population [
CMT4C (
CMT4D (
CMT4G (
• CMT4C (
• CMT4D (
• CMT4G (
## Clinical Description
The clinical findings of a peripheral neuropathy, slow NCV, mode of inheritance, and biallelic pathogenic variants in a specific gene have been the basis for classification for the majority of CMT subtypes.
Individuals with CMT4 usually have the clinical characteristics of the CMT phenotype, including distal muscle weakness and atrophy, sensory loss, and, often,
The autosomal recessive neuropathies tend to have an earlier onset (early childhood) and more severe progression than the autosomal dominant varieties. Except in the case of consanguinity, they also appear only in sibs or as simplex cases.
Some families with CMT4A have features of a demyelinating neuropathy, whereas others have features of axonal neuropathy [
Mild sensory loss, absent tendon reflexes, skeletal deformities, and scoliosis can be observed. Vocal cord paresis may occur [
Nerve biopsy reveals hypomyelination with onion bulbs composed of basal laminae [
Cerebrospinal fluid protein concentration is normal.
Adults who are affected are seriously handicapped and frequently require wheelchairs by age 20 years. Duration of illness ranges from age 27 to 39 years and death occurs in the fourth or fifth decade. Intellect is normal.
Two families were reported by
In a family with an
Auditory evoked potentials are abnormal.
NCVs are very slow (15-17 m/s) and often undetectable.
Sural nerve biopsy reveals irregular redundant loops of focally folded myelin.
A Japanese family with neuropathy and nerve pathology showing irregular redundant loops and folding of the myelin sheath has been associated with juvenile onset of glaucoma [
Severe kyphoscoliosis and cranial nerve involvement were found in ten cases reported by
Affected individuals have motor and sensory neuropathy in the lower limbs and slow median NCV (mean is 24 m/s).
Nerve biopsy shows an increase of basal membranes around demyelinated and unmyelinated axons, relatively few classic onion bulbs, and large cytoplasmic extensions of the Schwann cells [
CMT4D has the distinguishing clinical characteristic of sensorineural deafness, with onset usually in the third decade. Tongue atrophy has also been described.
A non-Gypsy family with CNS white matter lesions has been reported [
Nerve biopsy shows a hypertrophic onion bulb change.
A child had delayed motor milestones and marked weakness. Additional families are described by
A more benign phenotype with later age of onset (7-12 years) but with marked spine deformities was reported by
Prominent sensory loss occurred in one family [
Sural nerve pathology showed demyelination, onion bulbs, and focal myelin thickening.
Two sibs in Ireland remained ambulatory into middle age [
An Algerian and a Lebanese affected individual had marked slowing of nerve conductions [
## Genotype-Phenotype Correlations
In general, no specific consistent genotype-phenotype correlations are known.
## Nomenclature
Severe neuropathy with slow NCVs and onset in early childhood is often called the Déjérine-Sottas syndrome (DSS). This is a descriptive clinical term that does not refer to a specific disease because it is caused by pathogenic variants in multiple genes [
## Prevalence
The overall prevalence of hereditary neuropathies is estimated to be approximately 30:100,000 population. More than half of these cases are CMT type 1 (15:100,000).
The autosomal recessive forms of CMT are quite rare and often limited to specific ethnic groups (e.g., in North Africa), where they may be relatively common.
Three founder pathogenic variants are found in CMT4 in subgroups of the European Gypsy population [
CMT4C (
CMT4D (
CMT4G (
• CMT4C (
• CMT4D (
• CMT4G (
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
See
## Management
To establish the extent of disease and needs in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 4 (CMT4), the following evaluations are recommended:
Physical examination to determine extent of weakness and atrophy,
NCV to help determine whether the disease is axonal, demyelinating, or mixed
Detailed family history
Consultation with a clinical geneticist and/or genetic counselor
The affected individual is often managed by a multidisciplinary team that includes a neurologist, physiatrist, orthopedic surgeon, and physical and occupational therapists [
Treatment is symptomatic and may include the following:
Special shoes, including those with good ankle support
Ankle/foot orthoses to correct foot drop and aid walking
Orthopedic surgery to correct severe
Forearm crutches or canes for gait stability; fewer than 5% of affected individuals need wheelchairs.
Exercise within the individual's capability to remain physically active
Daily heel cord stretching exercises are helpful in preventing Achilles' tendon shortening.
Children's feet should be watched at regular intervals to provide for properly fitting shoes and avoid sores and skin breakdown.
It is appropriate to monitor gait and condition of feet to determine need for bracing, special shoes, and/or surgery.
Obesity is to be avoided because it makes walking more difficult.
Medications which are toxic or potentially toxic to persons with CMT comprise a range of risk from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
See
No specific pregnancy management recommendations have been published. However, weight gain during pregnancy may produce additional gait disability.
Search
Career and employment may be influenced by the persistent weakness of hands and/or feet.
• Physical examination to determine extent of weakness and atrophy,
• NCV to help determine whether the disease is axonal, demyelinating, or mixed
• Detailed family history
• Consultation with a clinical geneticist and/or genetic counselor
• Special shoes, including those with good ankle support
• Ankle/foot orthoses to correct foot drop and aid walking
• Orthopedic surgery to correct severe
• Forearm crutches or canes for gait stability; fewer than 5% of affected individuals need wheelchairs.
• Exercise within the individual's capability to remain physically active
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 4 (CMT4), the following evaluations are recommended:
Physical examination to determine extent of weakness and atrophy,
NCV to help determine whether the disease is axonal, demyelinating, or mixed
Detailed family history
Consultation with a clinical geneticist and/or genetic counselor
• Physical examination to determine extent of weakness and atrophy,
• NCV to help determine whether the disease is axonal, demyelinating, or mixed
• Detailed family history
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
The affected individual is often managed by a multidisciplinary team that includes a neurologist, physiatrist, orthopedic surgeon, and physical and occupational therapists [
Treatment is symptomatic and may include the following:
Special shoes, including those with good ankle support
Ankle/foot orthoses to correct foot drop and aid walking
Orthopedic surgery to correct severe
Forearm crutches or canes for gait stability; fewer than 5% of affected individuals need wheelchairs.
Exercise within the individual's capability to remain physically active
• Special shoes, including those with good ankle support
• Ankle/foot orthoses to correct foot drop and aid walking
• Orthopedic surgery to correct severe
• Forearm crutches or canes for gait stability; fewer than 5% of affected individuals need wheelchairs.
• Exercise within the individual's capability to remain physically active
## Prevention of Secondary Complications
Daily heel cord stretching exercises are helpful in preventing Achilles' tendon shortening.
## Surveillance
Children's feet should be watched at regular intervals to provide for properly fitting shoes and avoid sores and skin breakdown.
It is appropriate to monitor gait and condition of feet to determine need for bracing, special shoes, and/or surgery.
## Agents/Circumstances to Avoid
Obesity is to be avoided because it makes walking more difficult.
Medications which are toxic or potentially toxic to persons with CMT comprise a range of risk from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
## Evaluation of Relatives at Risk
See
## Pregnancy Management
No specific pregnancy management recommendations have been published. However, weight gain during pregnancy may produce additional gait disability.
## Therapies Under Investigation
Search
## Other
Career and employment may be influenced by the persistent weakness of hands and/or feet.
## Genetic Counseling
All of the Charcot-Marie-Tooth neuropathy type 4 (CMT4) subtypes discussed in this
Parents of an affected individual are obligate heterozygotes and therefore carriers of one of the CMT4 subtype-related pathogenic variants present in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing CMT.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being unaffected and a carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier of one of the CMT4 subtype-related pathogenic variants present in the proband is 2/3.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CMT4 are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
• Parents of an affected individual are obligate heterozygotes and therefore carriers of one of the CMT4 subtype-related pathogenic variants present in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing CMT.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being unaffected and a carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier of one of the CMT4 subtype-related pathogenic variants present in the proband is 2/3.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
All of the Charcot-Marie-Tooth neuropathy type 4 (CMT4) subtypes discussed in this
## Risk to Family Members
Parents of an affected individual are obligate heterozygotes and therefore carriers of one of the CMT4 subtype-related pathogenic variants present in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing CMT.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being unaffected and a carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier of one of the CMT4 subtype-related pathogenic variants present in the proband is 2/3.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Parents of an affected individual are obligate heterozygotes and therefore carriers of one of the CMT4 subtype-related pathogenic variants present in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing CMT.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being unaffected and a carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier of one of the CMT4 subtype-related pathogenic variants present in the proband is 2/3.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier (Heterozygote) Detection
Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CMT4 are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
## Resources
France
PO Box 105
Glenolden PA 19036
Department of Molecular Genetics
University of Antwerp
Antwerp Antwerpen B-2610
Belgium
432 Park Avenue South
4th Floor
New York NY 10016
Institute of Genetic Medicine
University of Newcastle upon Tyne
International Centre for Life
Newcastle upon Tyne NE1 3BZ
United Kingdom
1 Rue de l'International
BP59
Evry cedex 91002
France
Lt Gen van Heutszlaan 6
3743 JN Baarn
Netherlands
222 South Riverside Plaza
Suite 1500
Chicago IL 60606
61A Great Suffolk Street
London SE1 0BU
United Kingdom
•
• France
•
•
• PO Box 105
• Glenolden PA 19036
•
•
• Department of Molecular Genetics
• University of Antwerp
• Antwerp Antwerpen B-2610
• Belgium
•
• 432 Park Avenue South
• 4th Floor
• New York NY 10016
•
•
•
•
•
•
• Institute of Genetic Medicine
• University of Newcastle upon Tyne
• International Centre for Life
• Newcastle upon Tyne NE1 3BZ
• United Kingdom
•
•
• 1 Rue de l'International
• BP59
• Evry cedex 91002
• France
•
•
• Lt Gen van Heutszlaan 6
• 3743 JN Baarn
• Netherlands
•
•
• 222 South Riverside Plaza
• Suite 1500
• Chicago IL 60606
•
•
• 61A Great Suffolk Street
• London SE1 0BU
• United Kingdom
•
•
•
## Molecular Genetics
Charcot-Marie-Tooth Neuropathy Type 4: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Charcot-Marie-Tooth Neuropathy Type 4 (
For a detailed summary of gene and protein information for the following genes, see
Selected
Variants listed in the table have been provided by the author.
Associated with autosomal dominant inheritance; see
Selected
Variants listed in the table have been provided by the author.
Selected
Variants listed in the table have been provided by the author.
A founder variant in Spanish Gypsies [
Selected
Variants listed in the table have been provided by the author.
Selected
Variants listed in the table have been provided by the author.
Selected
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
Variant occurs in a novel alternative untranslated exon in
See
Published designation of variant [
Selected
Variants listed in the table have been provided by the author.
H indicates sequence ambiguity; could be A, C, or T nucleotide.
Selected
Variants listed in the table have been provided by the author.
## References
## Literature Cited
## Suggested Reading
## Chapter Notes
5 July 2018 (ma) Chapter retired: covered in
14 April 2016 (tb) Revision:
20 August 2015 (me) Comprehensive update posted live
17 April 2014 (tb) Revision: edits to
20 February 2014 (tb) Revision: Ylikallio et al 2013 reference added describing one person with an unclassified recessive neuropathy
26 September 2013 (tb) Revision: to Differential Diagnosis -- information on SURF1 deficiency [Echaniz-Laguna et al 2103]
8 August 2013 (tb) Revision: addition of add
11 October 2012 (tb) Revision: hereditary neuropathy with neuromyotonia (caused by mutations in
13 September 2012 (me) Comprehensive update posted live
27 May 2010 (cd) Revision: edits to Agents/Circumstances to Avoid
22 April 2010 (me) Comprehensive update posted live
30 April 2009 (cd) Revision: sequence analysis available clinically for CMT4H
12 June 2008 (cd) Revision: sequence analysis of entire
6 September 2007 (me) Comprehensive update posted live
15 April 2005 (me) Comprehensive update posted live
19 December 2003 (tb) Author revisions
24 October 2003 (cd,tb) Revision: change in test availability
21 August 2003 (cd,tb) Revision: change in gene name
29 May 2003 (tb) Author revisions
4 April 2003 (me) Comprehensive update posted live
8 November 2001 (tb) Author revisions
27 June 2001 (tb) Author revisions
22 June 2001 (tb) Author revisions
11 April 2001 (tb) Author revisions
25 September 2000 (tb) Author revisions
25 August 2000 (me) Comprehensive update posted live
15 June 2000 (tb) Author revisions
15 May 2000 (tb) Author revisions
14 January 2000 (tb) Author revisions
24 September 1999 (tb) Author revisions
31 August 1999 (tb) Author revisions
18 June 1999 (tb) Author revisions
8 April 1999 (tb) Author revisions
24 September 1998 (tb) Review posted live
April 1996 (tb) Original submission
• 5 July 2018 (ma) Chapter retired: covered in
• 14 April 2016 (tb) Revision:
• 20 August 2015 (me) Comprehensive update posted live
• 17 April 2014 (tb) Revision: edits to
• 20 February 2014 (tb) Revision: Ylikallio et al 2013 reference added describing one person with an unclassified recessive neuropathy
• 26 September 2013 (tb) Revision: to Differential Diagnosis -- information on SURF1 deficiency [Echaniz-Laguna et al 2103]
• 8 August 2013 (tb) Revision: addition of add
• 11 October 2012 (tb) Revision: hereditary neuropathy with neuromyotonia (caused by mutations in
• 13 September 2012 (me) Comprehensive update posted live
• 27 May 2010 (cd) Revision: edits to Agents/Circumstances to Avoid
• 22 April 2010 (me) Comprehensive update posted live
• 30 April 2009 (cd) Revision: sequence analysis available clinically for CMT4H
• 12 June 2008 (cd) Revision: sequence analysis of entire
• 6 September 2007 (me) Comprehensive update posted live
• 15 April 2005 (me) Comprehensive update posted live
• 19 December 2003 (tb) Author revisions
• 24 October 2003 (cd,tb) Revision: change in test availability
• 21 August 2003 (cd,tb) Revision: change in gene name
• 29 May 2003 (tb) Author revisions
• 4 April 2003 (me) Comprehensive update posted live
• 8 November 2001 (tb) Author revisions
• 27 June 2001 (tb) Author revisions
• 22 June 2001 (tb) Author revisions
• 11 April 2001 (tb) Author revisions
• 25 September 2000 (tb) Author revisions
• 25 August 2000 (me) Comprehensive update posted live
• 15 June 2000 (tb) Author revisions
• 15 May 2000 (tb) Author revisions
• 14 January 2000 (tb) Author revisions
• 24 September 1999 (tb) Author revisions
• 31 August 1999 (tb) Author revisions
• 18 June 1999 (tb) Author revisions
• 8 April 1999 (tb) Author revisions
• 24 September 1998 (tb) Review posted live
• April 1996 (tb) Original submission
## Revision History
5 July 2018 (ma) Chapter retired: covered in
14 April 2016 (tb) Revision:
20 August 2015 (me) Comprehensive update posted live
17 April 2014 (tb) Revision: edits to
20 February 2014 (tb) Revision: Ylikallio et al 2013 reference added describing one person with an unclassified recessive neuropathy
26 September 2013 (tb) Revision: to Differential Diagnosis -- information on SURF1 deficiency [Echaniz-Laguna et al 2103]
8 August 2013 (tb) Revision: addition of add
11 October 2012 (tb) Revision: hereditary neuropathy with neuromyotonia (caused by mutations in
13 September 2012 (me) Comprehensive update posted live
27 May 2010 (cd) Revision: edits to Agents/Circumstances to Avoid
22 April 2010 (me) Comprehensive update posted live
30 April 2009 (cd) Revision: sequence analysis available clinically for CMT4H
12 June 2008 (cd) Revision: sequence analysis of entire
6 September 2007 (me) Comprehensive update posted live
15 April 2005 (me) Comprehensive update posted live
19 December 2003 (tb) Author revisions
24 October 2003 (cd,tb) Revision: change in test availability
21 August 2003 (cd,tb) Revision: change in gene name
29 May 2003 (tb) Author revisions
4 April 2003 (me) Comprehensive update posted live
8 November 2001 (tb) Author revisions
27 June 2001 (tb) Author revisions
22 June 2001 (tb) Author revisions
11 April 2001 (tb) Author revisions
25 September 2000 (tb) Author revisions
25 August 2000 (me) Comprehensive update posted live
15 June 2000 (tb) Author revisions
15 May 2000 (tb) Author revisions
14 January 2000 (tb) Author revisions
24 September 1999 (tb) Author revisions
31 August 1999 (tb) Author revisions
18 June 1999 (tb) Author revisions
8 April 1999 (tb) Author revisions
24 September 1998 (tb) Review posted live
April 1996 (tb) Original submission
• 5 July 2018 (ma) Chapter retired: covered in
• 14 April 2016 (tb) Revision:
• 20 August 2015 (me) Comprehensive update posted live
• 17 April 2014 (tb) Revision: edits to
• 20 February 2014 (tb) Revision: Ylikallio et al 2013 reference added describing one person with an unclassified recessive neuropathy
• 26 September 2013 (tb) Revision: to Differential Diagnosis -- information on SURF1 deficiency [Echaniz-Laguna et al 2103]
• 8 August 2013 (tb) Revision: addition of add
• 11 October 2012 (tb) Revision: hereditary neuropathy with neuromyotonia (caused by mutations in
• 13 September 2012 (me) Comprehensive update posted live
• 27 May 2010 (cd) Revision: edits to Agents/Circumstances to Avoid
• 22 April 2010 (me) Comprehensive update posted live
• 30 April 2009 (cd) Revision: sequence analysis available clinically for CMT4H
• 12 June 2008 (cd) Revision: sequence analysis of entire
• 6 September 2007 (me) Comprehensive update posted live
• 15 April 2005 (me) Comprehensive update posted live
• 19 December 2003 (tb) Author revisions
• 24 October 2003 (cd,tb) Revision: change in test availability
• 21 August 2003 (cd,tb) Revision: change in gene name
• 29 May 2003 (tb) Author revisions
• 4 April 2003 (me) Comprehensive update posted live
• 8 November 2001 (tb) Author revisions
• 27 June 2001 (tb) Author revisions
• 22 June 2001 (tb) Author revisions
• 11 April 2001 (tb) Author revisions
• 25 September 2000 (tb) Author revisions
• 25 August 2000 (me) Comprehensive update posted live
• 15 June 2000 (tb) Author revisions
• 15 May 2000 (tb) Author revisions
• 14 January 2000 (tb) Author revisions
• 24 September 1999 (tb) Author revisions
• 31 August 1999 (tb) Author revisions
• 18 June 1999 (tb) Author revisions
• 8 April 1999 (tb) Author revisions
• 24 September 1998 (tb) Review posted live
• April 1996 (tb) Original submission
|
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"T Kiwaki, F Umehara, H Takashima, M Nakagawa, K Kamimura, N Kashio, Y Sakamoto, K Unoki, Y Nobuhara, K Michizono, O Watanabe, H Arimura, M Osame. Hereditary motor and sensory neuropathy with myelin folding and juvenile onset glaucoma.. Neurology 2000;55:392-7",
"A Leal, B Morera, G Del Valle, D Heuss, C Kayser, M Berghoff, R Villegas, E Hernandez, M Mendez, HC Hennies, B Neundorfer, R Barrantes, A Reis, B Rautenstrauss. A second locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 19q13.3.. Am J Hum Genet 2001;68:269-74",
"GM Lenk, CJ Ferguson, CY Chow, N Jin, JM Jones, AE Grant, SN Zolov, JJ Winters, RJ Giger, JJ Dowling, LS Weisman, MH Meisler. Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J.. PLoS Genet. 2011;7",
"X Li, Z Hu, L Liu, Y Xie, Y Zhan, X Zi, J Wang, L Wu, K Xia, B Tang, R Zhang. A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy.. Neurology 2015;84:2430-7",
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"FL Robinson, IR Niesman, KK Beiswenger, JE Dixon. Loss of the inactive myotubularin-related phosphatase Mtmr13 leads to a Charcot-Marie-Tooth 4B2-like peripheral neuropathy in mice.. Proc Natl Acad Sci U S A 2008;105:4916-21",
"T Rogers, D Chandler, D Angelicheva, PK Thomas, B Youl, I Tournev, V Gergelcheva, L Kalaydjieva. A novel locus for autosomal recessive peripheral neuropathy in the EGR2 region on 10q23.. Am J Hum Genet 2000;67:664-71",
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"GM Saifi, K Szigeti, GJ Snipes, CA Garcia, JR Lupski. Molecular mechanisms, diagnosis, and rational approaches to management of and therapy for Charcot-Marie-Tooth disease and related peripheral neuropathies.. J Investig Med 2003;51:261-83",
"AS Saporta, SL Sottile, LJ Miller, SM Feely, CE Siskind, ME Shy. Charcot Marie Tooth (CMT) subtypes and genetic testing strategies.. Ann Neurol. 2011;69:22-33",
"M Schabhüttl, T Wieland, J Senderek, J Baets, V Timmerman, P De Jonghe, MM Reilly, K Stieglbauer, E Laich, R Windhager, W Erwa, S Trajanoski, TM Strom, M Auer-Grumbach. Whole-exome sequencing in patients with inherited neuropathies: outcome and challenges.. J Neurol. 2014;261:970-82",
"J Senderek, C Bergmann, VT Ramaekers, E Nelis, G Bernert, A Makowski, S Zuchner, P De Jonghe, S Rudnik-Schöneborn, K Zerres, JM Schroder. Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy.. Brain 2003a;126:642-9",
"J Senderek, C Bergmann, C Stendel, J Kirfel, N Verpoorten, P De Jonghe, V Timmerman, R H G Chrast, M Verheijen, G Lemke, E Battaloglu, Y Parman, S Erdem, E Tan, H Topaloglu, A Hahn, W Muller-Felber, N Rizzuto, GM Fabrizi, M Stuhrmann, S Rudnik-Schöneborn, S Zuchner, J Michael Schroder, E Buchheim, V Straub, J Klepper, K Huehne, B Rautenstrauss, R Buttner, E Nelis, K Zerres. Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy.. Am J Hum Genet 2003b;73:1106-19",
"J Senderek, C Bergmann, S Weber, UP Ketelsen, H Schorle, S Rudnik-Schoneborn, R Buttner, E Buchheim, K Zerres. Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot-Marie-Tooth neuropathy type 4B2/11p15.. Hum Mol Genet 2003c;12:349-56",
"T Sevilla, A Cuesta, MJ Chumillas, F Mayordomo, L Pedrola, F Palau, JJ Vilchez. Clinical, electrophysiological and morphological findings of Charcot-Marie-Tooth neuropathy with vocal cord palsy and mutations in the GDAP1 gene.. Brain 2003;126:2023-33",
"T Sevilla, T Jaijo, D Nauffal, D Collado, MJ Chumillas, JJ Vilchez, N Muelas, L Bataller, R Domenech, C Espinós, F Palau. Vocal cord paresis and diaphragmatic dysfunction are severe and frequent symptoms of GDAP1-associated neuropathy.. Brain 2008;131:3051-61",
"T Sevilla, D Martínez-Rubio, C Márquez, C Paradas, J Colomer, T Jaijo, JM Millán, F Palau, C Espinós. Genetics of the Charcot-Marie-Tooth disease in the Spanish Gypsy population: the hereditary motor and sensory neuropathy-Russe in depth.. Clin Genet. 2013;83:565-70",
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"T Stojkovic, P Latour, G Viet, J de Seze, JF Hurtevent, A Vandenberghe, P Vermersch. Vocal cord and diaphragm paralysis, as clinical features of a French family with autosomal recessive Charcot-Marie-Tooth disease, associated with a new mutation in the GDAP1 gene.. Neuromuscul Disord 2004;14:261-4",
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] |
24/9/1998
|
20/8/2015
|
14/4/2016
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cmt4c
|
cmt4c
|
[
"Charcot-Marie-Tooth Disease Type 4C",
"CMT4C",
"SH3TC2-HMSN",
"SH3TC2-Related Charcot-Marie-Tooth Neuropathy",
"Charcot-Marie-Tooth Disease Type 4C (CMT4C)",
"SH3TC2-HMSN",
"SH3TC2-Related Charcot-Marie-Tooth Neuropathy",
"SH3 domain and tetratricopeptide repeat-containing protein 2",
"SH3TC2",
"SH3TC2-Related Hereditary Motor and Sensory Neuropathy"
] |
Hamid Azzedine, Mustafa A Salih
|
Summary The diagnosis of
|
## Diagnosis
No consensus clinical diagnostic criteria for
Early and severe scoliosis, the presenting sign in most individuals
Neuropathy, usually developing in the first decade or adolescence, but occasionally manifesting as delay in onset of independent ambulation in early childhood
Slowly progressive neuropathy, with some individuals becoming wheelchair dependent because of involvement of the proximal lower limbs
MNCV of the median nerve is typically 4-37 m/sec, with a mean of 22 m/sec.
MNCV is not correlated with disease duration.
In some cases, electroneuromyographic examination is incomplete or does not allow measurement of MNCVs because of the severity of the secondary axonal loss.
The diagnosis of
Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
When the diagnosis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No causative deletions or duplications involving
• Early and severe scoliosis, the presenting sign in most individuals
• Neuropathy, usually developing in the first decade or adolescence, but occasionally manifesting as delay in onset of independent ambulation in early childhood
• Slowly progressive neuropathy, with some individuals becoming wheelchair dependent because of involvement of the proximal lower limbs
• MNCV of the median nerve is typically 4-37 m/sec, with a mean of 22 m/sec.
• MNCV is not correlated with disease duration.
• In some cases, electroneuromyographic examination is incomplete or does not allow measurement of MNCVs because of the severity of the secondary axonal loss.
## Suggestive Findings
Early and severe scoliosis, the presenting sign in most individuals
Neuropathy, usually developing in the first decade or adolescence, but occasionally manifesting as delay in onset of independent ambulation in early childhood
Slowly progressive neuropathy, with some individuals becoming wheelchair dependent because of involvement of the proximal lower limbs
MNCV of the median nerve is typically 4-37 m/sec, with a mean of 22 m/sec.
MNCV is not correlated with disease duration.
In some cases, electroneuromyographic examination is incomplete or does not allow measurement of MNCVs because of the severity of the secondary axonal loss.
• Early and severe scoliosis, the presenting sign in most individuals
• Neuropathy, usually developing in the first decade or adolescence, but occasionally manifesting as delay in onset of independent ambulation in early childhood
• Slowly progressive neuropathy, with some individuals becoming wheelchair dependent because of involvement of the proximal lower limbs
• MNCV of the median nerve is typically 4-37 m/sec, with a mean of 22 m/sec.
• MNCV is not correlated with disease duration.
• In some cases, electroneuromyographic examination is incomplete or does not allow measurement of MNCVs because of the severity of the secondary axonal loss.
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
When the diagnosis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No causative deletions or duplications involving
## Option 1
For an introduction to multigene panels click
## Option 2
When the diagnosis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No causative deletions or duplications involving
## Clinical Characteristics
Based on
See
See
Foot deformities (
Spine deformities (scoliosis or kyphoscoliosis) were observed between ages two and ten years in most individuals [
Cumulative data indicate that scoliosis occurs in 73% of persons with
– = not done or not documented
Authors did not specify type of deformities.
Authors did not specify the foot deformity in the one person who had surgery.
Unknown for 12 of 14 persons
Authors did not indicate whether they evaluated for kyphoscoliosis and/or lordosis.
Onset of scoliosis in infancy; age not reported
Age documented in four persons only
See
Abnormal pupillary light reflexes, facial paresis, hypoventilation/respiratory insufficiency, lingual fasciculation, head tremor, sensory ataxia, and diabetes mellitus were also reported.
In individuals with
Facial pain in a woman age 80 years [
Trigeminal neuralgia in an affected person age 55 years [
– = not done or not documented
Only 14 of 18 ipersons were examined for cranial nerve involvement.
Dropped head syndrome in one individual [
Cerebellar atrophy together with mild cerebellar ataxia in 1/5 and thickening of cranial nerves in another 1/5 [
Vestibular areflexia in 7/10 Spanish individuals [
Nerve biopsies – no longer required to suspect the diagnosis of
Loss of myelinated fibers
Relatively few and small classic onion bulbs, as observed in CMT1A, caused by heterozygous pathogenic variants in
Basal membrane onion bulbs, consisting of concentric Schwann cell lamellae intermingled with single or double basal membranes or concentric basal membranes alone
Schwann cells of unmyelinated axons, often with very thin processes and connecting links between axons
No genotype-phenotype correlations have been identified: to date, intra- and interfamilial variability is consistently observed [
Hereditary motor and sensory neuropathy is most commonly referred to by the eponymous name "Charcot-Marie-Tooth (CMT) neuropathy" or "Charcot-Marie-Tooth disease."
Based on an older classification system in which subtypes were defined by clinical findings, the mode of inheritance, neuropathy type (defined by electrophysiologic findings), pathologic finding (when available), and involved gene,
For further review of nomenclature, see the
Three more recent studies revealed the following:
Testing for 14 genes (
Evaluation of 612 index cases with a Charcot-Marie-Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a panel of 80 genes associated with autosomal recessive, autosomal dominant, and X-linked neuropathy identified
In a cohort of 50 Greek individuals with autosomal recessive demyelinating CMT,
Romani from Spain and Turkey [
The
• Facial pain in a woman age 80 years [
• Trigeminal neuralgia in an affected person age 55 years [
• Dropped head syndrome in one individual [
• Cerebellar atrophy together with mild cerebellar ataxia in 1/5 and thickening of cranial nerves in another 1/5 [
• Vestibular areflexia in 7/10 Spanish individuals [
• Loss of myelinated fibers
• Relatively few and small classic onion bulbs, as observed in CMT1A, caused by heterozygous pathogenic variants in
• Basal membrane onion bulbs, consisting of concentric Schwann cell lamellae intermingled with single or double basal membranes or concentric basal membranes alone
• Schwann cells of unmyelinated axons, often with very thin processes and connecting links between axons
• Testing for 14 genes (
• Evaluation of 612 index cases with a Charcot-Marie-Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a panel of 80 genes associated with autosomal recessive, autosomal dominant, and X-linked neuropathy identified
• In a cohort of 50 Greek individuals with autosomal recessive demyelinating CMT,
• Romani from Spain and Turkey [
• The
## Clinical Description
Based on
See
See
Foot deformities (
Spine deformities (scoliosis or kyphoscoliosis) were observed between ages two and ten years in most individuals [
Cumulative data indicate that scoliosis occurs in 73% of persons with
– = not done or not documented
Authors did not specify type of deformities.
Authors did not specify the foot deformity in the one person who had surgery.
Unknown for 12 of 14 persons
Authors did not indicate whether they evaluated for kyphoscoliosis and/or lordosis.
Onset of scoliosis in infancy; age not reported
Age documented in four persons only
See
Abnormal pupillary light reflexes, facial paresis, hypoventilation/respiratory insufficiency, lingual fasciculation, head tremor, sensory ataxia, and diabetes mellitus were also reported.
In individuals with
Facial pain in a woman age 80 years [
Trigeminal neuralgia in an affected person age 55 years [
– = not done or not documented
Only 14 of 18 ipersons were examined for cranial nerve involvement.
Dropped head syndrome in one individual [
Cerebellar atrophy together with mild cerebellar ataxia in 1/5 and thickening of cranial nerves in another 1/5 [
Vestibular areflexia in 7/10 Spanish individuals [
Nerve biopsies – no longer required to suspect the diagnosis of
Loss of myelinated fibers
Relatively few and small classic onion bulbs, as observed in CMT1A, caused by heterozygous pathogenic variants in
Basal membrane onion bulbs, consisting of concentric Schwann cell lamellae intermingled with single or double basal membranes or concentric basal membranes alone
Schwann cells of unmyelinated axons, often with very thin processes and connecting links between axons
• Facial pain in a woman age 80 years [
• Trigeminal neuralgia in an affected person age 55 years [
• Dropped head syndrome in one individual [
• Cerebellar atrophy together with mild cerebellar ataxia in 1/5 and thickening of cranial nerves in another 1/5 [
• Vestibular areflexia in 7/10 Spanish individuals [
• Loss of myelinated fibers
• Relatively few and small classic onion bulbs, as observed in CMT1A, caused by heterozygous pathogenic variants in
• Basal membrane onion bulbs, consisting of concentric Schwann cell lamellae intermingled with single or double basal membranes or concentric basal membranes alone
• Schwann cells of unmyelinated axons, often with very thin processes and connecting links between axons
## Foot and Spine Deformities
See
Foot deformities (
Spine deformities (scoliosis or kyphoscoliosis) were observed between ages two and ten years in most individuals [
Cumulative data indicate that scoliosis occurs in 73% of persons with
– = not done or not documented
Authors did not specify type of deformities.
Authors did not specify the foot deformity in the one person who had surgery.
Unknown for 12 of 14 persons
Authors did not indicate whether they evaluated for kyphoscoliosis and/or lordosis.
Onset of scoliosis in infancy; age not reported
Age documented in four persons only
## Other Clinical Findings
See
Abnormal pupillary light reflexes, facial paresis, hypoventilation/respiratory insufficiency, lingual fasciculation, head tremor, sensory ataxia, and diabetes mellitus were also reported.
In individuals with
Facial pain in a woman age 80 years [
Trigeminal neuralgia in an affected person age 55 years [
– = not done or not documented
Only 14 of 18 ipersons were examined for cranial nerve involvement.
Dropped head syndrome in one individual [
Cerebellar atrophy together with mild cerebellar ataxia in 1/5 and thickening of cranial nerves in another 1/5 [
Vestibular areflexia in 7/10 Spanish individuals [
• Facial pain in a woman age 80 years [
• Trigeminal neuralgia in an affected person age 55 years [
• Dropped head syndrome in one individual [
• Cerebellar atrophy together with mild cerebellar ataxia in 1/5 and thickening of cranial nerves in another 1/5 [
• Vestibular areflexia in 7/10 Spanish individuals [
## Histopathology
Nerve biopsies – no longer required to suspect the diagnosis of
Loss of myelinated fibers
Relatively few and small classic onion bulbs, as observed in CMT1A, caused by heterozygous pathogenic variants in
Basal membrane onion bulbs, consisting of concentric Schwann cell lamellae intermingled with single or double basal membranes or concentric basal membranes alone
Schwann cells of unmyelinated axons, often with very thin processes and connecting links between axons
• Loss of myelinated fibers
• Relatively few and small classic onion bulbs, as observed in CMT1A, caused by heterozygous pathogenic variants in
• Basal membrane onion bulbs, consisting of concentric Schwann cell lamellae intermingled with single or double basal membranes or concentric basal membranes alone
• Schwann cells of unmyelinated axons, often with very thin processes and connecting links between axons
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified: to date, intra- and interfamilial variability is consistently observed [
## Nomenclature
Hereditary motor and sensory neuropathy is most commonly referred to by the eponymous name "Charcot-Marie-Tooth (CMT) neuropathy" or "Charcot-Marie-Tooth disease."
Based on an older classification system in which subtypes were defined by clinical findings, the mode of inheritance, neuropathy type (defined by electrophysiologic findings), pathologic finding (when available), and involved gene,
For further review of nomenclature, see the
## Prevalence
Three more recent studies revealed the following:
Testing for 14 genes (
Evaluation of 612 index cases with a Charcot-Marie-Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a panel of 80 genes associated with autosomal recessive, autosomal dominant, and X-linked neuropathy identified
In a cohort of 50 Greek individuals with autosomal recessive demyelinating CMT,
Romani from Spain and Turkey [
The
• Testing for 14 genes (
• Evaluation of 612 index cases with a Charcot-Marie-Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a panel of 80 genes associated with autosomal recessive, autosomal dominant, and X-linked neuropathy identified
• In a cohort of 50 Greek individuals with autosomal recessive demyelinating CMT,
• Romani from Spain and Turkey [
• The
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
See
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Tone, weakness, atrophy, sensory loss, joint contractures
Foot &/or hand involvement
Spine involvement
Cranial nerve involvement
Ataxia
Gait stability using CMT Infant Scale
Pain w/attention to distinguishing between neuropathic & mechanical pain
Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Need for AFOs, specialized shoes
Mobility, ADL, & need for adaptive devices/durable equipment
Need for handicapped parking
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
To incl eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; AFOs = ankle-foot orthotics; CMT = Charcot-Marie-Tooth; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment is symptomatic. Affected individuals are often managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, physical and occupational therapists, audiologists/otolaryngologists, speech and language therapists, and pulmonologists (
Treatment of Manifestations in Individuals with
PT to preserve flexibility
Bracing when possible
Daily heel cord stretching to help w/flexibility & prevent contractures
Other activities to help person remain as physically active as possible
ASM = anti-seizure medication; AFOs = ankle-foot orthotics; PT = physical therapy
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Recommended Surveillance for Individuals with
OT: Monitor hand function.
PT: Monitor strength, mobility.
Both: Monitor ADL.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
ADL = activities of daily living; OT = occupational therapy; PT = physical therapy
Obesity is to be avoided because it makes walking more difficult.
Medications that are toxic or potentially toxic to persons with Charcot-Marie-Tooth (CMT) disease comprise a range of risks ranging from definite high risk to negligible risk [
Although it had no adverse effects in 41 persons with CMT [
Blockers of the neuromuscular junction should be used with caution.
Local/regional anesthesia, especially epidural analgesia at childbirth, has been used without problems in CMT. This use of anesthesia should be discussed on a case-by-case basis with the anesthesiologist.
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual in order to identify as early as possible those who would benefit from awareness of
See
There are no guidelines for pregnancy management in CMT of any type; the following general statements are offered as possible considerations.
CMT appears to be an independent risk factor for complications during pregnancy and delivery.
The symptoms of CMT can worsen during pregnancy; in particular: cramps, subjective sensitivity (e.g., paresthesias), difficulty walking, and fatigue.
In rare instances, crises occurring during pregnancy do not subside post partum.
A retrospective study in Norway between 1967 and 2002 comparing 108 births to mothers with CMT with 2.1 million births to mothers without CMT determined that mothers with CMT more frequently needed interventions during delivery [
It has been postulated that fetal presentation tends to be abnormal because of the combination of CMT in the mother and fetus [
Note: Because
Search
• Tone, weakness, atrophy, sensory loss, joint contractures
• Foot &/or hand involvement
• Spine involvement
• Cranial nerve involvement
• Ataxia
• Gait stability using CMT Infant Scale
• Pain w/attention to distinguishing between neuropathic & mechanical pain
• Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Need for AFOs, specialized shoes
• Mobility, ADL, & need for adaptive devices/durable equipment
• Need for handicapped parking
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• PT to preserve flexibility
• Bracing when possible
• Daily heel cord stretching to help w/flexibility & prevent contractures
• Other activities to help person remain as physically active as possible
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• OT: Monitor hand function.
• PT: Monitor strength, mobility.
• Both: Monitor ADL.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Although it had no adverse effects in 41 persons with CMT [
• Blockers of the neuromuscular junction should be used with caution.
• Local/regional anesthesia, especially epidural analgesia at childbirth, has been used without problems in CMT. This use of anesthesia should be discussed on a case-by-case basis with the anesthesiologist.
• The symptoms of CMT can worsen during pregnancy; in particular: cramps, subjective sensitivity (e.g., paresthesias), difficulty walking, and fatigue.
• In rare instances, crises occurring during pregnancy do not subside post partum.
• A retrospective study in Norway between 1967 and 2002 comparing 108 births to mothers with CMT with 2.1 million births to mothers without CMT determined that mothers with CMT more frequently needed interventions during delivery [
• It has been postulated that fetal presentation tends to be abnormal because of the combination of CMT in the mother and fetus [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Tone, weakness, atrophy, sensory loss, joint contractures
Foot &/or hand involvement
Spine involvement
Cranial nerve involvement
Ataxia
Gait stability using CMT Infant Scale
Pain w/attention to distinguishing between neuropathic & mechanical pain
Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Need for AFOs, specialized shoes
Mobility, ADL, & need for adaptive devices/durable equipment
Need for handicapped parking
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
To incl eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; AFOs = ankle-foot orthotics; CMT = Charcot-Marie-Tooth; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Tone, weakness, atrophy, sensory loss, joint contractures
• Foot &/or hand involvement
• Spine involvement
• Cranial nerve involvement
• Ataxia
• Gait stability using CMT Infant Scale
• Pain w/attention to distinguishing between neuropathic & mechanical pain
• Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Need for AFOs, specialized shoes
• Mobility, ADL, & need for adaptive devices/durable equipment
• Need for handicapped parking
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment is symptomatic. Affected individuals are often managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, physical and occupational therapists, audiologists/otolaryngologists, speech and language therapists, and pulmonologists (
Treatment of Manifestations in Individuals with
PT to preserve flexibility
Bracing when possible
Daily heel cord stretching to help w/flexibility & prevent contractures
Other activities to help person remain as physically active as possible
ASM = anti-seizure medication; AFOs = ankle-foot orthotics; PT = physical therapy
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• PT to preserve flexibility
• Bracing when possible
• Daily heel cord stretching to help w/flexibility & prevent contractures
• Other activities to help person remain as physically active as possible
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Surveillance
Recommended Surveillance for Individuals with
OT: Monitor hand function.
PT: Monitor strength, mobility.
Both: Monitor ADL.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
ADL = activities of daily living; OT = occupational therapy; PT = physical therapy
• OT: Monitor hand function.
• PT: Monitor strength, mobility.
• Both: Monitor ADL.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Agents/Circumstances to Avoid
Obesity is to be avoided because it makes walking more difficult.
Medications that are toxic or potentially toxic to persons with Charcot-Marie-Tooth (CMT) disease comprise a range of risks ranging from definite high risk to negligible risk [
Although it had no adverse effects in 41 persons with CMT [
Blockers of the neuromuscular junction should be used with caution.
Local/regional anesthesia, especially epidural analgesia at childbirth, has been used without problems in CMT. This use of anesthesia should be discussed on a case-by-case basis with the anesthesiologist.
• Although it had no adverse effects in 41 persons with CMT [
• Blockers of the neuromuscular junction should be used with caution.
• Local/regional anesthesia, especially epidural analgesia at childbirth, has been used without problems in CMT. This use of anesthesia should be discussed on a case-by-case basis with the anesthesiologist.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual in order to identify as early as possible those who would benefit from awareness of
See
## Pregnancy Management
There are no guidelines for pregnancy management in CMT of any type; the following general statements are offered as possible considerations.
CMT appears to be an independent risk factor for complications during pregnancy and delivery.
The symptoms of CMT can worsen during pregnancy; in particular: cramps, subjective sensitivity (e.g., paresthesias), difficulty walking, and fatigue.
In rare instances, crises occurring during pregnancy do not subside post partum.
A retrospective study in Norway between 1967 and 2002 comparing 108 births to mothers with CMT with 2.1 million births to mothers without CMT determined that mothers with CMT more frequently needed interventions during delivery [
It has been postulated that fetal presentation tends to be abnormal because of the combination of CMT in the mother and fetus [
Note: Because
• The symptoms of CMT can worsen during pregnancy; in particular: cramps, subjective sensitivity (e.g., paresthesias), difficulty walking, and fatigue.
• In rare instances, crises occurring during pregnancy do not subside post partum.
• A retrospective study in Norway between 1967 and 2002 comparing 108 births to mothers with CMT with 2.1 million births to mothers without CMT determined that mothers with CMT more frequently needed interventions during delivery [
• It has been postulated that fetal presentation tends to be abnormal because of the combination of CMT in the mother and fetus [
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of an affected individual are typically heterozygotes (i.e., carriers of one
In families in which the parents are of the same ethnic origin, where endogamy is frequent, a parent of the proband may have signs of
The carrier frequency of
Because a parent with biallelic
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent of a proband with
One of the pathogenic variants identified in the proband occurred as a
One of the pathogenic variants identified in the proband was inherited from a mosaic parent [
The proband inherited a chromosome or a particular chromosomal region from only one of the proband's parents (if the chromosome or the chromosomal region encompasses an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Intrafamilial clinical variability may be observed in sibs who inherit biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are typically heterozygotes (i.e., carriers of one
• In families in which the parents are of the same ethnic origin, where endogamy is frequent, a parent of the proband may have signs of
• The carrier frequency of
• Because a parent with biallelic
• The carrier frequency of
• Because a parent with biallelic
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent of a proband with
• One of the pathogenic variants identified in the proband occurred as a
• One of the pathogenic variants identified in the proband was inherited from a mosaic parent [
• The proband inherited a chromosome or a particular chromosomal region from only one of the proband's parents (if the chromosome or the chromosomal region encompasses an
• One of the pathogenic variants identified in the proband occurred as a
• One of the pathogenic variants identified in the proband was inherited from a mosaic parent [
• The proband inherited a chromosome or a particular chromosomal region from only one of the proband's parents (if the chromosome or the chromosomal region encompasses an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The carrier frequency of
• Because a parent with biallelic
• One of the pathogenic variants identified in the proband occurred as a
• One of the pathogenic variants identified in the proband was inherited from a mosaic parent [
• The proband inherited a chromosome or a particular chromosomal region from only one of the proband's parents (if the chromosome or the chromosomal region encompasses an
• If both parents are known to be heterozygous for an
• Intrafamilial clinical variability may be observed in sibs who inherit biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
## Risk to Family Members
The parents of an affected individual are typically heterozygotes (i.e., carriers of one
In families in which the parents are of the same ethnic origin, where endogamy is frequent, a parent of the proband may have signs of
The carrier frequency of
Because a parent with biallelic
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent of a proband with
One of the pathogenic variants identified in the proband occurred as a
One of the pathogenic variants identified in the proband was inherited from a mosaic parent [
The proband inherited a chromosome or a particular chromosomal region from only one of the proband's parents (if the chromosome or the chromosomal region encompasses an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Intrafamilial clinical variability may be observed in sibs who inherit biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing
• The parents of an affected individual are typically heterozygotes (i.e., carriers of one
• In families in which the parents are of the same ethnic origin, where endogamy is frequent, a parent of the proband may have signs of
• The carrier frequency of
• Because a parent with biallelic
• The carrier frequency of
• Because a parent with biallelic
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent of a proband with
• One of the pathogenic variants identified in the proband occurred as a
• One of the pathogenic variants identified in the proband was inherited from a mosaic parent [
• The proband inherited a chromosome or a particular chromosomal region from only one of the proband's parents (if the chromosome or the chromosomal region encompasses an
• One of the pathogenic variants identified in the proband occurred as a
• One of the pathogenic variants identified in the proband was inherited from a mosaic parent [
• The proband inherited a chromosome or a particular chromosomal region from only one of the proband's parents (if the chromosome or the chromosomal region encompasses an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The carrier frequency of
• Because a parent with biallelic
• One of the pathogenic variants identified in the proband occurred as a
• One of the pathogenic variants identified in the proband was inherited from a mosaic parent [
• The proband inherited a chromosome or a particular chromosomal region from only one of the proband's parents (if the chromosome or the chromosomal region encompasses an
• If both parents are known to be heterozygous for an
• Intrafamilial clinical variability may be observed in sibs who inherit biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Department of Molecular Genetics
University of Antwerp
Antwerp Antwerpen B-2610
Belgium
Institute of Translational and Clinical Research
University of Newcastle upon Tyne
International Centre for Life
Newcastle upon Tyne NE1 3BZ
United Kingdom
France
United Kingdom
•
•
•
• Department of Molecular Genetics
• University of Antwerp
• Antwerp Antwerpen B-2610
• Belgium
•
•
•
•
•
• Institute of Translational and Clinical Research
• University of Newcastle upon Tyne
• International Centre for Life
• Newcastle upon Tyne NE1 3BZ
• United Kingdom
•
•
• France
•
•
•
•
•
•
• United Kingdom
•
•
•
## Molecular Genetics
SH3TC2-Related Hereditary Motor and Sensory Neuropathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SH3TC2-Related Hereditary Motor and Sensory Neuropathy (
The SH3TC2 protein has been reported to contain Src homology-3 (SH3) domains and tetratricopeptide repeat (TPR) domains (see
SH3 domains are highly conserved in eukaryotes, prokaryotes, and viruses, and mediate interactions with enzymes (tyrosine kinases, phospholipases cγ [PLCγ], and PLCγ, phosphoinositide 3-kinase, and the NADPH-oxidase complex), cytoskeleton molecules (spectrin and nebulin), and myosins. They play important roles in cell-to-cell communication and signal transduction from the cell surface to the nucleus [
Proteins with TPR domains are involved in many cellular processes through protein-protein interactions: in mitosis and RNA synthesis by their association in multi-protein complexes controlling cell-cycle or transcription machinery, in protein transport, and in chaperone functions [
Notable
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (
• SH3 domains are highly conserved in eukaryotes, prokaryotes, and viruses, and mediate interactions with enzymes (tyrosine kinases, phospholipases cγ [PLCγ], and PLCγ, phosphoinositide 3-kinase, and the NADPH-oxidase complex), cytoskeleton molecules (spectrin and nebulin), and myosins. They play important roles in cell-to-cell communication and signal transduction from the cell surface to the nucleus [
• Proteins with TPR domains are involved in many cellular processes through protein-protein interactions: in mitosis and RNA synthesis by their association in multi-protein complexes controlling cell-cycle or transcription machinery, in protein transport, and in chaperone functions [
## Molecular Pathogenesis
The SH3TC2 protein has been reported to contain Src homology-3 (SH3) domains and tetratricopeptide repeat (TPR) domains (see
SH3 domains are highly conserved in eukaryotes, prokaryotes, and viruses, and mediate interactions with enzymes (tyrosine kinases, phospholipases cγ [PLCγ], and PLCγ, phosphoinositide 3-kinase, and the NADPH-oxidase complex), cytoskeleton molecules (spectrin and nebulin), and myosins. They play important roles in cell-to-cell communication and signal transduction from the cell surface to the nucleus [
Proteins with TPR domains are involved in many cellular processes through protein-protein interactions: in mitosis and RNA synthesis by their association in multi-protein complexes controlling cell-cycle or transcription machinery, in protein transport, and in chaperone functions [
Notable
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (
• SH3 domains are highly conserved in eukaryotes, prokaryotes, and viruses, and mediate interactions with enzymes (tyrosine kinases, phospholipases cγ [PLCγ], and PLCγ, phosphoinositide 3-kinase, and the NADPH-oxidase complex), cytoskeleton molecules (spectrin and nebulin), and myosins. They play important roles in cell-to-cell communication and signal transduction from the cell surface to the nucleus [
• Proteins with TPR domains are involved in many cellular processes through protein-protein interactions: in mitosis and RNA synthesis by their association in multi-protein complexes controlling cell-cycle or transcription machinery, in protein transport, and in chaperone functions [
## Chapter Notes
For more than two decades, our work has been mainly devoted to peripheral neuropathies and related disorders, especially the autosomal recessive forms. We intended to identify the genetic basis of these disorders, to establish genotype-phenotype correlations, if any, and to better characterize each clinical phenotype. We are also interested in the pathophysiology underlying the different phenotypes encountered in this highly variable genetic disorder. This work leads to a better knowledge of the disease and paves the way for therapeutic research.
Contact: Dr Hamid Azzedine Email:
This work was supported by the Association Française contre les Myopathies (AFM).
Hamid Azzedine, PhD (2008-present)Luc Bontoux, MD; Centre Hospitalier Universitaire d'Angers (2008-2015)Eric LeGuern, MD, PhD; La Pitié-Salpêtrière Hospital (2008-2021)Mustafa A Salih, MD, Dr Med Sci, FRCPCH, FAAN (2015-present)
11 March 2021 (bp) Comprehensive update posted live
15 October 2015 (me) Comprehensive update posted live
6 July 2010 (cd) Revision: edits to
31 March 2008 (me) Review posted live
10 February 2006 (ha) Original submission
• 11 March 2021 (bp) Comprehensive update posted live
• 15 October 2015 (me) Comprehensive update posted live
• 6 July 2010 (cd) Revision: edits to
• 31 March 2008 (me) Review posted live
• 10 February 2006 (ha) Original submission
## Author Notes
For more than two decades, our work has been mainly devoted to peripheral neuropathies and related disorders, especially the autosomal recessive forms. We intended to identify the genetic basis of these disorders, to establish genotype-phenotype correlations, if any, and to better characterize each clinical phenotype. We are also interested in the pathophysiology underlying the different phenotypes encountered in this highly variable genetic disorder. This work leads to a better knowledge of the disease and paves the way for therapeutic research.
Contact: Dr Hamid Azzedine Email:
## Acknowledgments
This work was supported by the Association Française contre les Myopathies (AFM).
## Author History
Hamid Azzedine, PhD (2008-present)Luc Bontoux, MD; Centre Hospitalier Universitaire d'Angers (2008-2015)Eric LeGuern, MD, PhD; La Pitié-Salpêtrière Hospital (2008-2021)Mustafa A Salih, MD, Dr Med Sci, FRCPCH, FAAN (2015-present)
## Revision History
11 March 2021 (bp) Comprehensive update posted live
15 October 2015 (me) Comprehensive update posted live
6 July 2010 (cd) Revision: edits to
31 March 2008 (me) Review posted live
10 February 2006 (ha) Original submission
• 11 March 2021 (bp) Comprehensive update posted live
• 15 October 2015 (me) Comprehensive update posted live
• 6 July 2010 (cd) Revision: edits to
• 31 March 2008 (me) Review posted live
• 10 February 2006 (ha) Original submission
## References
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"C Fischer, S Trajanoski, L Papić, C Windpassinger, G Bernert, M Freilinger, M Schabhüttl, M Arslan-Kirchner, P Javaher-Haghighi, B Plecko, J Senderek, C Rauscher, WN Löscher, TR Pieber, AR Janecke, M Auer-Grumbach. SNP array-based whole genome homozygosity mapping as the first step to a molecular diagnosis in patients with Charcot-Marie-Tooth disease.. J Neurol. 2012;259:515-23",
"A Gabreëls-Festen, S van Beersum, L Eshuis, E LeGuern, F Gabreëls, B van Engelen, E Mariman. Study on the gene and phenotypic characterisation of autosomal recessive demyelinating motor and sensory neuropathy (Charcot-Marie-Tooth disease) with a gene locus on chromosome 5q23-q33.. J Neurol Neurosurg Psychiatry 1999;66:569-74",
"R Gooding, J Colomer, R King, D Angelicheva, L Marns, Y Parman, D Chandler, J Bertranpetit, L Kalaydjieva. A novel Gypsy founder mutation, p.Arg1109X in the CMT4C gene, causes variable peripheral neuropathy phenotypes.. J Med Genet 2005;42",
"I Gosselin, I Thiffault, M Tétreault, V Chau, MJ Dicaire, L Loisel, M Emond, J Senderek, J Mathieu, N Dupré, M Vanasse, J Puymirat, B Brais. Founder SH3TC2 mutations are responsible for a CMT4C French-Canadians cluster.. Neuromuscul Disord. 2008;18:483-92",
"A Guilbot, M Kessali, N Ravisé, T Hammadouche, A Bouhouche, T Maisonobe, D Grid, A Brice, E LeGuern. The autosomal recessive form of CMT disease linked to 5q31-q33.. Ann N Y Acad Sci 1999;883:453-6",
"GP Guyton, RA Mann. The pathogenesis and surgical management of foot deformity in Charcot-Marie-Tooth disease.. Foot Ankle Clin 2000;5:317-26",
"JM Hoff, NE Gilhus, AK Daltveit. Pregnancies and deliveries in patients with Charcot-Marie-Tooth disease.. Neurology 2005;64:459-62",
"H Houlden, M Laura, L Ginsberg, H Jungbluth, SA Robb, J Blake, S Robinson, RH King, MM Reilly. The phenotype of Charcot-Marie-Tooth disease type 4C due to SH3TC2 mutations and possible predisposition to an inflammatory neuropathy.. Neuromuscul Disord. 2009;19:264-9",
"M Iguchi, A Hashiguchi, E Ito, K Toda, M Urano, Y Shimizu, C Takeuchi, K Saito, H Takashima, S. Uchiyama. Charcot-Marie-Tooth disease type 4C in Japan: report of a case.. Muscle Nerve. 2013;47:283-6",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"M Kessali, R Zemmouri, A Guilbot, T Maisonobe, A Brice, E LeGuern, D Grid. A clinical, electrophysiologic, neuropathologic, and genetic study of two large Algerian families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease.. Neurology 1997;48:867-73",
"Z Kontogeorgiou, K Nikolaou, C Kartanou, M Breza, M Panas, G Karadima, G Koutsis. Mutational screening of the SH3TC2 gene in Greek patients with suspected demyelinating recessive Charcot-Marie-Tooth disease reveals a varied and unusual phenotypic spectrum.. J Peripher Nerv Syst. 2019;24:125-30",
"P Laššuthová, R Mazanec, P Vondráček, D Sišková, J Haberlová, J Sabová, P. Seeman. High frequency of SH3TC2 mutations in Czech HMSN I patients.. Clin Genet. 2011;80:334-45",
"E LeGuern, A Guilbot, M Kessali, N Ravisé, J Tassin, T Maisonobe, D Grid, A Brice. Homozygosity mapping of an autosomal recessive form of demyelinating Charcot-Marie-Tooth disease to chromosome 5q23-q33.. Hum Mol Genet 1996;5:1685-8",
"MR Mandarakas, MP Menezes, KJ Rose, R Shy, K Eichinger, M Foscan, T Estilow, R Kennedy, K Herbert, P Bray, K Refshauge, MM Ryan, EM Yiu, M Farrar, H Sampaio, I Moroni, E Pagliano, D Pareyson, SW Yum, DN Herrmann, G Acsadi, ME Shy, J Burns, O Sanmaneechai. Development and validation of the Charcot-Marie-Tooth Disease Infant Scale.. Brain. 2018;141:3319-30",
"L Padua, T Cavallaro, D Pareyson, A Quattrone, G Vita, A Schenone, CMT Italian. QoL Study Group. Charcot-Marie-Tooth and pain: correlations with neurophysiological, clinical, and disability findings.. Neurol Sci. 2008;29:193-4",
"H Pérez-Garrigues, R Sivera, JJ Vílchez, C Espinós, F Palau, T Sevilla. Vestibular impairment in Charcot-Marie-tooth disease type 4C.. J Neurol Neurosurg Psychiatry. 2014;85:824-7",
"G Piscosquito, P Saveri, S Magri, C Ciano, C Gandioli, M Morbin, DD Bella, I Moroni, F Taroni, D Pareyson. Screening for SH3TC2 gene mutations in a series of demyelinating recessive Charcot-Marie-tooth disease (CMT4).. J Peripher Nerv Syst. 2016;21:142-9",
"J Rayl, PJ Gibson, DE Hickok. A population-based case-control study of risk factors for breech presentation.. Am J Obstet Gynecol 1996;174:28-32",
"RC Roberts, AA Peden, F Buss, NA Bright, M Latouche, MM Reilly, J Kendrick-Jones, JP Luzio. Mistargeting of SH3TC2 away from the recycling endosome causes Charcot-Marie-Tooth disease type 4C.. Hum Mol Genet. 2010;19:1009-18",
"J Senderek, C Bergmann, C Stendel, J Kirfel, N Verpoorten, P De Jonghe, V Timmerman, R Chrast, MH Verheijen, G Lemke, E Battaloglu, Y Parman, S Erdem, E Tan, H Topaloglu, A Hahn, W Muller-Felber, N Rizzuto, GM Fabrizi, M Stuhrmann, S Rudnik-Schoneborn, S Zuchner, J Michael Schroder, E Buchheim, V Straub, J Klepper, K Huehne, B Rautenstrauss, R Buttner, E Nelis, K Zerres. Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy.. Am J Hum Genet 2003;73:1106-19",
"H Skott, C Muntean-Firanescu, K Samuelsson, L Verrecchia, P Svenningsson, H Malmgren, C Cananau, AJ Espay, R Press, G Solders, M Paucar. The cerebellar phenotype of Charcot-Marie-Tooth neuropathy type 4C.. Cerebellum Ataxias. 2019;6:9",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"V Tiffreau, G Viet, A Thévenon. Pain and neuromuscular disease: the results of a survey.. Am J Phys Med Rehabil. 2006;85:756-66",
"JC Whisstock, AM Lesk. SH3 domains in prokaryotes.. Trends Biochem Sci 1999;24:132-3",
"M Yger, T Stojkovic, S Tardieu, T Maisonobe, A Brice, A Echaniz-Laguna, Y Alembik, S Girard, C Cazeneuve, E Leguern, O Dubourg. Characteristics of clinical and electrophysiological pattern of Charcot-Marie-Tooth 4C.. J Peripher Nerv Syst. 2012;17:112-22"
] |
31/3/2008
|
11/3/2021
|
6/7/2010
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
cmt4h
|
cmt4h
|
[
"Charcot-Marie-Tooth Disease Type 4H",
"CMT4H",
"CMT4H",
"Charcot-Marie-Tooth Disease Type 4H",
"CMT 4H",
"FYVE, RhoGEF and PH domain-containing protein 4",
"FGD4",
"Charcot-Marie-Tooth Neuropathy Type 4H (CMT4H)"
] |
Charcot-Marie-Tooth Neuropathy Type 4H – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Valérie Delague
|
Summary Charcot-Marie-Tooth neuropathy type 4H (CMT4H) is a demyelinating form of CMT that is characterized by early onset (usually before age 3 years; range: birth to age 10 years) and slow progression. The degree of distal muscle weakness and amyotrophy varies between affected individuals as does the presence or absence and severity of foot deformities, scoliosis, and sensory involvement. Neuropathic pain has not been reported. To date, findings in18 individuals with molecularly confirmed CMT4H from 13 families have been reported. CMT4H is suspected in individuals with typical findings of CMT (distal amyotrophy, foot deformities), early onset, and slow progression. Motor nerve conduction velocities (MNCVs) and sensory nerve conduction velocities (SNCVs) are abnormal. The diagnosis is established by the presence of biallelic CMT4H is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.
|
## Diagnosis
Formal diagnostic guidelines for Charcot-Marie-Tooth type 4H (CMT4H) do not exist.
Note: Although the CMT Neuropathy Score (CMTNS) and CMTNS version 2 (CMTNS2) are widely used in the diagnosis of CMT [
Early onset. The imprecise retrospective data available indicate that symptoms typically appear before age three years, with a range presumed to be birth to ten years.
Slow progression. Despite early onset, the disease is stable with only very slow progression.
Scoliosis; onset before age ten years (observed in some, but not all, affected individuals)
Abnormal motor nerve conduction velocities (MNCVs) and sensory nerve conduction velocities (SNCVs). In the lower limbs, MNCVs were non-recordable in 8/9 individuals tested and severely reduced in one; SNCVs were non-recordable in 8/8 individuals tested. In the upper limbs, MNCVs were non-recordable in 3/16 and severely reduced in 13/16; SNCVs were non-recordable in 8/9 and reduced in one (for details see
Family history consistent with autosomal recessive inheritance. Parental consanguinity is common; parents are not affected unless multigenerational consanguinity exists. Note: Disease severity and disability vary even within the same family (i.e., among individuals with the same pathogenic variants).
Molecular Genetic Testing Used in Charcot-Marie-Tooth Neuropathy Type 4H
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
The test method does not allow detection or large genomic rearrangements within
Individuals with CMT4H or autosomal recessive demyelinating CMT with clinical signs consistent with CMT4H [
Note: When molecular genetic testing is not available, sural nerve biopsy can be considered; however, histologic findings are not specific to CMT4H, and thus not confirmatory.
• Early onset. The imprecise retrospective data available indicate that symptoms typically appear before age three years, with a range presumed to be birth to ten years.
• Slow progression. Despite early onset, the disease is stable with only very slow progression.
• Scoliosis; onset before age ten years (observed in some, but not all, affected individuals)
• Abnormal motor nerve conduction velocities (MNCVs) and sensory nerve conduction velocities (SNCVs). In the lower limbs, MNCVs were non-recordable in 8/9 individuals tested and severely reduced in one; SNCVs were non-recordable in 8/8 individuals tested. In the upper limbs, MNCVs were non-recordable in 3/16 and severely reduced in 13/16; SNCVs were non-recordable in 8/9 and reduced in one (for details see
• Family history consistent with autosomal recessive inheritance. Parental consanguinity is common; parents are not affected unless multigenerational consanguinity exists. Note: Disease severity and disability vary even within the same family (i.e., among individuals with the same pathogenic variants).
## Clinical Diagnosis
Formal diagnostic guidelines for Charcot-Marie-Tooth type 4H (CMT4H) do not exist.
Note: Although the CMT Neuropathy Score (CMTNS) and CMTNS version 2 (CMTNS2) are widely used in the diagnosis of CMT [
Early onset. The imprecise retrospective data available indicate that symptoms typically appear before age three years, with a range presumed to be birth to ten years.
Slow progression. Despite early onset, the disease is stable with only very slow progression.
Scoliosis; onset before age ten years (observed in some, but not all, affected individuals)
Abnormal motor nerve conduction velocities (MNCVs) and sensory nerve conduction velocities (SNCVs). In the lower limbs, MNCVs were non-recordable in 8/9 individuals tested and severely reduced in one; SNCVs were non-recordable in 8/8 individuals tested. In the upper limbs, MNCVs were non-recordable in 3/16 and severely reduced in 13/16; SNCVs were non-recordable in 8/9 and reduced in one (for details see
Family history consistent with autosomal recessive inheritance. Parental consanguinity is common; parents are not affected unless multigenerational consanguinity exists. Note: Disease severity and disability vary even within the same family (i.e., among individuals with the same pathogenic variants).
Molecular Genetic Testing Used in Charcot-Marie-Tooth Neuropathy Type 4H
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
The test method does not allow detection or large genomic rearrangements within
Individuals with CMT4H or autosomal recessive demyelinating CMT with clinical signs consistent with CMT4H [
Note: When molecular genetic testing is not available, sural nerve biopsy can be considered; however, histologic findings are not specific to CMT4H, and thus not confirmatory.
• Early onset. The imprecise retrospective data available indicate that symptoms typically appear before age three years, with a range presumed to be birth to ten years.
• Slow progression. Despite early onset, the disease is stable with only very slow progression.
• Scoliosis; onset before age ten years (observed in some, but not all, affected individuals)
• Abnormal motor nerve conduction velocities (MNCVs) and sensory nerve conduction velocities (SNCVs). In the lower limbs, MNCVs were non-recordable in 8/9 individuals tested and severely reduced in one; SNCVs were non-recordable in 8/8 individuals tested. In the upper limbs, MNCVs were non-recordable in 3/16 and severely reduced in 13/16; SNCVs were non-recordable in 8/9 and reduced in one (for details see
• Family history consistent with autosomal recessive inheritance. Parental consanguinity is common; parents are not affected unless multigenerational consanguinity exists. Note: Disease severity and disability vary even within the same family (i.e., among individuals with the same pathogenic variants).
## Clinical Characteristics
Charcot-Marie-Tooth neuropathy type 4H (CMT4H), an autosomal recessive demyelinating form of CMT, is characterized by early onset and slow progression. The most common findings observed in published reports of 18 affected individuals from 13 families with molecularly confirmed CMT4H are summarized in
The degree of distal muscle weakness and amyotrophy varies between affected individuals as does the presence or absence and severity of foot deformities, scoliosis, and sensory involvement.
Although individuals with CMT do experience neuropathic pain that is usually moderate, preferentially located in the extremities, and symmetric [
Clinical Characteristics of CMT4H in 18 Individuals from 13 Families
For further information see
Roman numerals = family; letters = sibs
- = not affected; + = mild in the lower extremities; ++ = marked in the lower extremities; +++ = also affected the hands and forearms
- = affected; + = mild; ++ = severe
- = no deformities; + = pes cavus and hammer toes; ++ = pes equinus and toes retraction
- = none; + = mild; ++ = severe; +++ = surgery required
- = no deficit; + = decreased sensibility; +++ = no sensibility
Patients Ia, Ib, and Ic are from three different branches of the same Lebanese family. See also
Difficulty running and poor balance
Clumsiness
No genotype-phenotype correlations can be established in the 18 affected individuals from 13 families with molecularly confirmed CMT4H; remarkably, individuals homozygous for nonsense or frameshift variants do not have more severe manifestations than individuals with missense variants (summarized in detail in
CMT4H is rare and it is difficult to estimate its prevalence. Only 13 families with molecularly confirmed CMT4H have been published to date.
Proportion of Individuals with CMT4H in Published Studies
The proportion of CMT4H is probably higher than indicated, as a number of individuals in this series have autosomal dominant inheritance.
All affected individuals had (1) demyelinating sensorimotor neuropathy with onset in the first decade and (2) at least one of the following: (a) parental consanguinity or at least one other affected sib; (b) severely slowed NCVs (<15 m/s for the motor median nerve); (c) prominent scoliosis; and (d) myelin outfoldings on nerve biopsy. No parents of affected individuals had clinical or neurophysiologic findings of CMT.
## Clinical Description
Charcot-Marie-Tooth neuropathy type 4H (CMT4H), an autosomal recessive demyelinating form of CMT, is characterized by early onset and slow progression. The most common findings observed in published reports of 18 affected individuals from 13 families with molecularly confirmed CMT4H are summarized in
The degree of distal muscle weakness and amyotrophy varies between affected individuals as does the presence or absence and severity of foot deformities, scoliosis, and sensory involvement.
Although individuals with CMT do experience neuropathic pain that is usually moderate, preferentially located in the extremities, and symmetric [
Clinical Characteristics of CMT4H in 18 Individuals from 13 Families
For further information see
Roman numerals = family; letters = sibs
- = not affected; + = mild in the lower extremities; ++ = marked in the lower extremities; +++ = also affected the hands and forearms
- = affected; + = mild; ++ = severe
- = no deformities; + = pes cavus and hammer toes; ++ = pes equinus and toes retraction
- = none; + = mild; ++ = severe; +++ = surgery required
- = no deficit; + = decreased sensibility; +++ = no sensibility
Patients Ia, Ib, and Ic are from three different branches of the same Lebanese family. See also
Difficulty running and poor balance
Clumsiness
## Genotype-Phenotype Correlations
No genotype-phenotype correlations can be established in the 18 affected individuals from 13 families with molecularly confirmed CMT4H; remarkably, individuals homozygous for nonsense or frameshift variants do not have more severe manifestations than individuals with missense variants (summarized in detail in
## Prevalence
CMT4H is rare and it is difficult to estimate its prevalence. Only 13 families with molecularly confirmed CMT4H have been published to date.
Proportion of Individuals with CMT4H in Published Studies
The proportion of CMT4H is probably higher than indicated, as a number of individuals in this series have autosomal dominant inheritance.
All affected individuals had (1) demyelinating sensorimotor neuropathy with onset in the first decade and (2) at least one of the following: (a) parental consanguinity or at least one other affected sib; (b) severely slowed NCVs (<15 m/s for the motor median nerve); (c) prominent scoliosis; and (d) myelin outfoldings on nerve biopsy. No parents of affected individuals had clinical or neurophysiologic findings of CMT.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
See
## Management
To establish the extent of disease and needs in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 4H (CMT4H), the following evaluations are recommended:
Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, sensory loss, and skeletal deformities. In children with CMT, one should use the CMTPedS score defined by
Although the CMT Neuropathy Score (CMTNS) and CMTNS version 2 (CMTNS2) are widely used in the diagnosis of CMT [
The transition from the CMTPedS in childhood to the CMTNS2 in adulthood has been evaluated [
Orthopedic consultation to evaluate skeletal deformities such as foot deformities (pes cavus) and scoliosis and to determine the need for a surgery and/or ankle/foot orthoses
Clinical genetics consultation and/or pediatric neurology consultation
Individuals with CMT4H are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [
Treatment is symptomatic and may include the following:
Ankle/foot orthoses (AFOs) to correct foot drop and aid walking [
Physiotherapy with daily heel cord stretching exercises to help prevent Achilles' tendon shortening and physical activity adapted to the abilities of each individual to prevent contractures and help preserve flexibility
Orthopedic surgery to correct severe pes cavus deformity [
Surgery to correct spine deformities
Forearm crutches or canes for gait stability
Wheelchairs as needed because of gait instability
Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) [
Appropriate surveillance includes annual evaluation by a team comprising physiatrists, neurologists, and physical and occupational therapists to determine neurologic status and functional disability.
Obesity is to be avoided because it makes walking more difficult.
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
See
Search
• Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, sensory loss, and skeletal deformities. In children with CMT, one should use the CMTPedS score defined by
• Although the CMT Neuropathy Score (CMTNS) and CMTNS version 2 (CMTNS2) are widely used in the diagnosis of CMT [
• The transition from the CMTPedS in childhood to the CMTNS2 in adulthood has been evaluated [
• Orthopedic consultation to evaluate skeletal deformities such as foot deformities (pes cavus) and scoliosis and to determine the need for a surgery and/or ankle/foot orthoses
• Clinical genetics consultation and/or pediatric neurology consultation
• Ankle/foot orthoses (AFOs) to correct foot drop and aid walking [
• Physiotherapy with daily heel cord stretching exercises to help prevent Achilles' tendon shortening and physical activity adapted to the abilities of each individual to prevent contractures and help preserve flexibility
• Orthopedic surgery to correct severe pes cavus deformity [
• Surgery to correct spine deformities
• Forearm crutches or canes for gait stability
• Wheelchairs as needed because of gait instability
• Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 4H (CMT4H), the following evaluations are recommended:
Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, sensory loss, and skeletal deformities. In children with CMT, one should use the CMTPedS score defined by
Although the CMT Neuropathy Score (CMTNS) and CMTNS version 2 (CMTNS2) are widely used in the diagnosis of CMT [
The transition from the CMTPedS in childhood to the CMTNS2 in adulthood has been evaluated [
Orthopedic consultation to evaluate skeletal deformities such as foot deformities (pes cavus) and scoliosis and to determine the need for a surgery and/or ankle/foot orthoses
Clinical genetics consultation and/or pediatric neurology consultation
• Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, sensory loss, and skeletal deformities. In children with CMT, one should use the CMTPedS score defined by
• Although the CMT Neuropathy Score (CMTNS) and CMTNS version 2 (CMTNS2) are widely used in the diagnosis of CMT [
• The transition from the CMTPedS in childhood to the CMTNS2 in adulthood has been evaluated [
• Orthopedic consultation to evaluate skeletal deformities such as foot deformities (pes cavus) and scoliosis and to determine the need for a surgery and/or ankle/foot orthoses
• Clinical genetics consultation and/or pediatric neurology consultation
## Treatment of Manifestations
Individuals with CMT4H are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [
Treatment is symptomatic and may include the following:
Ankle/foot orthoses (AFOs) to correct foot drop and aid walking [
Physiotherapy with daily heel cord stretching exercises to help prevent Achilles' tendon shortening and physical activity adapted to the abilities of each individual to prevent contractures and help preserve flexibility
Orthopedic surgery to correct severe pes cavus deformity [
Surgery to correct spine deformities
Forearm crutches or canes for gait stability
Wheelchairs as needed because of gait instability
Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) [
• Ankle/foot orthoses (AFOs) to correct foot drop and aid walking [
• Physiotherapy with daily heel cord stretching exercises to help prevent Achilles' tendon shortening and physical activity adapted to the abilities of each individual to prevent contractures and help preserve flexibility
• Orthopedic surgery to correct severe pes cavus deformity [
• Surgery to correct spine deformities
• Forearm crutches or canes for gait stability
• Wheelchairs as needed because of gait instability
• Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) [
## Surveillance
Appropriate surveillance includes annual evaluation by a team comprising physiatrists, neurologists, and physical and occupational therapists to determine neurologic status and functional disability.
## Agents/Circumstances to Avoid
Obesity is to be avoided because it makes walking more difficult.
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Charcot-Marie-Tooth neuropathy type 4H (CMT4H) is inherited in an autosomal recessive manner.
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one mutant allele).
Heterozygotes (carriers) are asymptomatic.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CMT4H are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While decisions regarding prenatal testing are the choice of the parents, discussion of these issues is appropriate.
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one mutant allele).
• Heterozygotes (carriers) are asymptomatic.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Charcot-Marie-Tooth neuropathy type 4H (CMT4H) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one mutant allele).
Heterozygotes (carriers) are asymptomatic.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one mutant allele).
• Heterozygotes (carriers) are asymptomatic.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.
## Carrier (Heterozygote) Detection
Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CMT4H are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While decisions regarding prenatal testing are the choice of the parents, discussion of these issues is appropriate.
## Resources
France
PO Box 105
Glenolden PA 19036
Department of Molecular Genetics
University of Antwerp
Antwerp Antwerpen B-2610
Belgium
432 Park Avenue South
4th Floor
New York NY 10016
Institute of Genetic Medicine
University of Newcastle upon Tyne
International Centre for Life
Newcastle upon Tyne NE1 3BZ
United Kingdom
1 Rue de l'International
BP59
Evry cedex 91002
France
Lt Gen van Heutszlaan 6
3743 JN Baarn
Netherlands
222 South Riverside Plaza
Suite 1500
Chicago IL 60606
61A Great Suffolk Street
London SE1 0BU
United Kingdom
•
• France
•
•
• PO Box 105
• Glenolden PA 19036
•
•
• Department of Molecular Genetics
• University of Antwerp
• Antwerp Antwerpen B-2610
• Belgium
•
• 432 Park Avenue South
• 4th Floor
• New York NY 10016
•
•
•
•
•
•
•
•
• Institute of Genetic Medicine
• University of Newcastle upon Tyne
• International Centre for Life
• Newcastle upon Tyne NE1 3BZ
• United Kingdom
•
•
• 1 Rue de l'International
• BP59
• Evry cedex 91002
• France
•
•
• Lt Gen van Heutszlaan 6
• 3743 JN Baarn
• Netherlands
•
•
• 222 South Riverside Plaza
• Suite 1500
• Chicago IL 60606
•
•
• 61A Great Suffolk Street
• London SE1 0BU
• United Kingdom
•
•
•
## Molecular Genetics
Charcot-Marie-Tooth Neuropathy Type 4H: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Charcot-Marie-Tooth Neuropathy Type 4H (
See
For further information see
Reference sequences:
Variant designation that does not conform to current naming conventions
Two individuals from different branches of the same Lebanese family
DH domains were first identified in the Dbl protein (and are present in many proteins where they play a key role in the catalysis of GDP to GTP exchange); while PH and FYVE domains are mainly involved in interactions with different forms of phosphoinositides.
FRABIN is a Rho GDP/GTP nucleotide exchange factor (RhoGEF), specific for Cdc42, a member of the Rho family of small GTP binding proteins (Rho GTPases) [
The role of FRABIN in peripheral nerve is not well known; however, overexpression of Frabin in embryonic rat spinal motoneurons and rat RT4 schwannoma cells showed that Frabin colocalizes with F-actin in neurite tips and growth cones, and induces the formation of filopodia-like microspikes [
Also, a recent study in a mouse model of CMT4H [
## References
## Literature Cited
## Chapter Notes
My team leads translational research in the field of Inherited Peripheral Neuropathies (mostly Charcot-Marie-Tooth disease), a group of neuromuscular disorders affecting peripheral nerve. Our aim is to better understand the genetics and physiopathology of this group of diseases. We focus our research on autosomal recessive forms of these diseases, by studying large consanguineous families. By using traditional positional cloning strategies, combined to high-throughput Next Generation Sequencing strategies, we identify new defective genes in Inherited Peripheral Neuropathies. We further study the physiopathology of these diseases, by developing different models, in order to identify potential therapeutic strategies for these diseases. We study in particular two CMT subtypes: CMT4H, caused by pathogenic variants in
In close relationship with the Molecular Genetics Department of The Children’s Hospital "La Timone," we develop innovative diagnosis strategies.
19 September 2019 (ma) Chapter retired: Covered in
8 August 2013 (me) Review posted live
1 April 2013 (vd) Original submission
• 19 September 2019 (ma) Chapter retired: Covered in
• 8 August 2013 (me) Review posted live
• 1 April 2013 (vd) Original submission
## Author Notes
My team leads translational research in the field of Inherited Peripheral Neuropathies (mostly Charcot-Marie-Tooth disease), a group of neuromuscular disorders affecting peripheral nerve. Our aim is to better understand the genetics and physiopathology of this group of diseases. We focus our research on autosomal recessive forms of these diseases, by studying large consanguineous families. By using traditional positional cloning strategies, combined to high-throughput Next Generation Sequencing strategies, we identify new defective genes in Inherited Peripheral Neuropathies. We further study the physiopathology of these diseases, by developing different models, in order to identify potential therapeutic strategies for these diseases. We study in particular two CMT subtypes: CMT4H, caused by pathogenic variants in
In close relationship with the Molecular Genetics Department of The Children’s Hospital "La Timone," we develop innovative diagnosis strategies.
## Revision History
19 September 2019 (ma) Chapter retired: Covered in
8 August 2013 (me) Review posted live
1 April 2013 (vd) Original submission
• 19 September 2019 (ma) Chapter retired: Covered in
• 8 August 2013 (me) Review posted live
• 1 April 2013 (vd) Original submission
|
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"H Houlden, S Hammans, H Katifi, MM Reilly. A novel Frabin (FGD4) nonsense mutation p.R275X associated with phenotypic variability in CMT4H.. Neurology. 2009;72:617-20",
"AB Jaffe, A Hall. Rho GTPases: biochemistry and biology.. Annu Rev Cell Dev Biol. 2005;21:247-69",
"H Obaishi, H Nakanishi, K Mandai, K Satoh, A Satoh, K Takahashi, M Miyahara, H Nishioka, K Takaishi, Y. Takai. Frabin, a novel FGD1-related actin filament-binding protein capable of changing cell shape and activating c-Jun N-terminal kinase.. J Biol Chem. 1998;273:18697-700",
"SM Murphy, DN Herrmann, MP McDermott, SS Scherer, ME Shy, MM Reilly, D Pareyson. Reliability of the CMT neuropathy score (second version) in Charcot-Marie-Tooth disease.. J Peripher Nerv Syst. 2011;16:191-8",
"E Pagliano, I Moroni, G Baranello, A Magro, A Marchi, S Bulgheroni, M Ferrarin, D. Pareyson. Outcome measures for Charcot-Marie-Tooth disease: clinical and neurofunctional assessment in children.. J Peripher Nerv Syst. 2011;16:237-42",
"KL Reddy, JM Zullo, E Bertolino, H Singh. Transcriptional repression mediated by repositioning of genes to the nuclear lamina.. Nature. 2008;452:243-7",
"C Ribiere, M Bernardin, S Sacconi, E Delmont, M Fournier-Mehouas, H Rauscent, M Benchortane, P Staccini, M Lantéri-Minet, C. Desnuelle. Pain assessment in Charcot-Marie-Tooth (CMT) disease.. Ann Phys Rehabil Med. 2012;55:160-73",
"C Stendel, A Roos, T Deconinck, J Pereira, F Castagner, A Niemann, J Kirschner, R Korinthenberg, UP Ketelsen, E Battaloglu, Y Parman, G Nicholson, R Ouvrier, J Seeger, P De Jonghe, J Weis, A Krüttgen, S Rudnik-Schöneborn, C Bergmann, U Suter, K Zerres, V Timmerman, JB Relvas, J Senderek. Peripheral nerve demyelination caused by a mutant Rho GTPase guanine nucleotide exchange factor, frabin/FGD4.. Am J Hum Genet. 2007;81:158-64",
"ME Shy, J Blake, K Krajewski, DR Fuerst, M Laura, AF Hahn, J Li, RA Lewis, M Reilly. Reliability and validity of the CMT neuropathy score as a measure of disability.. Neurology. 2005;64:1209-14",
"M Umikawa, H Obaishi, H Nakanishi, K Satoh-Horikawa, K Takahashi, I Hotta, Y Matsuura, Y Takai. Association of frabin with the actin cytoskeleton is essential for microspike formation through activation of Cdc42 small G protein.. J Biol Chem. 1999;274:25197-200",
"CM Ward, LA Dolan, DL Bennett, JA Morcuende, RR Cooper. Long-term results of reconstruction for treatment of a flexible cavovarus foot in Charcot-Marie-Tooth disease.. J Bone Joint Surg Am. 2008;90:2631-42"
] |
8/8/2013
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
cmt4j
|
cmt4j
|
[
"Charcot-Marie-Tooth Disease Type 4J",
"CMT4J",
"CMT4J",
"Charcot-Marie-Tooth Disease Type 4J",
"CMT 4J",
"Charcot-Marie-Tooth Disease, Autosomal Recessive, Type 4J",
"Polyphosphoinositide phosphatase",
"FIG4",
"Charcot-Marie-Tooth Neuropathy Type 4J (CMT4J)"
] |
Charcot-Marie-Tooth Neuropathy Type 4J – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Jun Li
|
Summary Charcot-Marie-Tooth neuropathy type 4J (CMT4J) is a peripheral neuropathy characterized by childhood onset (manifest as clumsy gait) with accelerated limb weakness and muscle atrophy during the teen or adult years that is typically asymmetric and can involve both distal and proximal limb muscles. Although sensory symptoms are minimal, examination may reveal decreased response to touch, pin prick, or vibration distally. Bulbar and cranial nerve functions are often spared; intellect is normal. The diagnosis is established by neurologic findings, nerve conduction studies (NCS) that are decreased but not uniformly so and can vary within the same limb, electromyogram (EMG) that often shows diffuse denervation, and detection of biallelic pathogenic variants in CMT4J is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.
|
## Diagnosis
No diagnostic criteria have been established for Charcot-Marie-Tooth neuropathy type 4J (CMT4J).
Mild motor symptoms during childhood, such as clumsy gait or difficulties with sports in school
Accelerated limb weakness and muscle atrophy during the teen years or adulthood
Asymmetric involvement that may include proximal muscles. Examination typically shows asymmetric muscle weakness and atrophy in both distal and proximal muscles.
Usually minimal sensory complaints. Examination may reveal decreased response to touch, pin prick, or vibration in distal limbs [
Diminished or absent deep tendon reflexes
Family history consistent with autosomal recessive inheritance
Nerve conduction studies (NCS) that are decreased but not uniformly so. In contrast to the uniform slowing of conduction velocities observed in most individuals with CMT type I [
Needle electromyogram (EMG). Despite clear evidence of sensory nerve conduction abnormalities, needle EMG often shows diffuse denervation, suggesting severe axonal loss or motor neuron degeneration [
Note: A high index of suspicion is necessary, particularly in individuals who manifest rapidly progressive and asymmetric limb weakness and evidence of sensory abnormalities on physical examination.
Thus far, all pathogenic variants are biallelic, and are usually compound heterozygous variants with one missense variant and one truncating variant. A common pathogenic missense variant occurs in individuals of European descent (see
Molecular Genetic Testing Used in Charcot-Marie-Tooth Neuropathy Type 4J
See
See
The ability of the test method used to detect a pathogenic variant that is present in the indicated gene
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
• Mild motor symptoms during childhood, such as clumsy gait or difficulties with sports in school
• Accelerated limb weakness and muscle atrophy during the teen years or adulthood
• Asymmetric involvement that may include proximal muscles. Examination typically shows asymmetric muscle weakness and atrophy in both distal and proximal muscles.
• Usually minimal sensory complaints. Examination may reveal decreased response to touch, pin prick, or vibration in distal limbs [
• Diminished or absent deep tendon reflexes
• Family history consistent with autosomal recessive inheritance
• Nerve conduction studies (NCS) that are decreased but not uniformly so. In contrast to the uniform slowing of conduction velocities observed in most individuals with CMT type I [
• Needle electromyogram (EMG). Despite clear evidence of sensory nerve conduction abnormalities, needle EMG often shows diffuse denervation, suggesting severe axonal loss or motor neuron degeneration [
• Note: A high index of suspicion is necessary, particularly in individuals who manifest rapidly progressive and asymmetric limb weakness and evidence of sensory abnormalities on physical examination.
## Clinical Characteristics
Findings of Charcot-Marie-Tooth neuropathy type 4J (CMT4J) during childhood include clumsy gait, tripping, and difficulties with sports in school. These findings are usually mild and typically not sufficient to bring affected children to medical attention.
Instances of early childhood onset are very rare.
A majority of affected individuals with biallelic pathogenic variants show accelerated limb weakness and atrophy during teenage years or adulthood with asymmetric involvement of both distal and proximal muscles. These findings are often rapidly progressive, resulting in severe paralysis.
Bulbar or cranial nerve functions are often spared clinically and on physical examination.
While readily detected on physical examination, sensory abnormalities are usually not included in the complaints of patients. Thus, this clinical constellation at presentation resembles
No obvious cognitive dysfunction has been reported in CMT4J.
Severe weakness may prevent independent ambulation depending on the speed of progression. In some patients, respiratory functions may be compromised.
Thus far, no epidemiologic data document life expectancy in CMT4J.
About 22 individuals with CMT4J have been reported. No other information regarding prevalence of CMT4J is available.
## Clinical Description
Findings of Charcot-Marie-Tooth neuropathy type 4J (CMT4J) during childhood include clumsy gait, tripping, and difficulties with sports in school. These findings are usually mild and typically not sufficient to bring affected children to medical attention.
Instances of early childhood onset are very rare.
A majority of affected individuals with biallelic pathogenic variants show accelerated limb weakness and atrophy during teenage years or adulthood with asymmetric involvement of both distal and proximal muscles. These findings are often rapidly progressive, resulting in severe paralysis.
Bulbar or cranial nerve functions are often spared clinically and on physical examination.
While readily detected on physical examination, sensory abnormalities are usually not included in the complaints of patients. Thus, this clinical constellation at presentation resembles
No obvious cognitive dysfunction has been reported in CMT4J.
Severe weakness may prevent independent ambulation depending on the speed of progression. In some patients, respiratory functions may be compromised.
Thus far, no epidemiologic data document life expectancy in CMT4J.
## Genotype-Phenotype Correlations
## Prevalence
About 22 individuals with CMT4J have been reported. No other information regarding prevalence of CMT4J is available.
## Genetically Related (Allelic) Disorders
In a subset of affected individuals, clinical presentation may include (in addition to severe neurologic deficits) severe skeletal abnormalities, such as
To date, there is no evidence that heterozygous
## Differential Diagnosis
See
Two clinical scenarios in which CMT4J needs to be considered:
Individuals presenting with an amyotrophic lateral sclerosis-like phenotype and abnormalities in sensory nerves
Individuals presenting with a clinical and electrophysiologic phenotype of chronic inflammatory demyelination polyneuropathy (CIDP) in whom weakness is asymmetric and rapidly progressive
• Individuals presenting with an amyotrophic lateral sclerosis-like phenotype and abnormalities in sensory nerves
• Individuals presenting with a clinical and electrophysiologic phenotype of chronic inflammatory demyelination polyneuropathy (CIDP) in whom weakness is asymmetric and rapidly progressive
## Management
To establish the extent of disease and needs in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 4J (CMT4J), the following evaluations are recommended:
Pulmonary function tests to determine whether respiratory functions are compromised
Skeletal survey to determine if any of the skeletal abnormalities typically observed in Yunis-Varón syndrome (YVS) are evident. Non-neural deficits are often severe and overshadow neurologic symptoms. Thus far, no neuromuscular involvement has been identified in persons with YVS.
Consultation with a clinical geneticist and/or genetic counselor
No specific treatment reverses the manifestations of CMT4J.
Affected individuals are often managed by a multidisciplinary team that includes a neurologist, physiatrist, orthopedic surgeon, and physical and occupational therapists [
Treatment is symptomatic and may include the following:
Special shoes, including those with good ankle support
Ankle/foot orthoses to correct foot drop and aid walking [
Orthopedic surgery to correct severe
Forearm crutches or canes for gait stability; severely affected individuals need wheelchairs.
Exercise within the individual's capability to remain physically active
BIPAP for those with respiratory muscle weakness
Ankle braces can help prevent tripping and falling or ankle injuries.
The following are appropriate:
Annual follow up with a neurologist for overall evaluation of neurologic deficits
Annual follow up with occupational therapy and physical therapy to assess fine motor and gross motor function
Annual follow up with a pulmonologist for evaluation of respiratory function
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
See
Search
Because the segmental demyelination in patients with CMT4J is similar to that observed in acquired demyelinating neuropathies, a few patients have been treated with intravenous immunoglobin [
• Pulmonary function tests to determine whether respiratory functions are compromised
• Skeletal survey to determine if any of the skeletal abnormalities typically observed in Yunis-Varón syndrome (YVS) are evident. Non-neural deficits are often severe and overshadow neurologic symptoms. Thus far, no neuromuscular involvement has been identified in persons with YVS.
• Consultation with a clinical geneticist and/or genetic counselor
• Special shoes, including those with good ankle support
• Ankle/foot orthoses to correct foot drop and aid walking [
• Orthopedic surgery to correct severe
• Forearm crutches or canes for gait stability; severely affected individuals need wheelchairs.
• Exercise within the individual's capability to remain physically active
• BIPAP for those with respiratory muscle weakness
• Annual follow up with a neurologist for overall evaluation of neurologic deficits
• Annual follow up with occupational therapy and physical therapy to assess fine motor and gross motor function
• Annual follow up with a pulmonologist for evaluation of respiratory function
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 4J (CMT4J), the following evaluations are recommended:
Pulmonary function tests to determine whether respiratory functions are compromised
Skeletal survey to determine if any of the skeletal abnormalities typically observed in Yunis-Varón syndrome (YVS) are evident. Non-neural deficits are often severe and overshadow neurologic symptoms. Thus far, no neuromuscular involvement has been identified in persons with YVS.
Consultation with a clinical geneticist and/or genetic counselor
• Pulmonary function tests to determine whether respiratory functions are compromised
• Skeletal survey to determine if any of the skeletal abnormalities typically observed in Yunis-Varón syndrome (YVS) are evident. Non-neural deficits are often severe and overshadow neurologic symptoms. Thus far, no neuromuscular involvement has been identified in persons with YVS.
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
No specific treatment reverses the manifestations of CMT4J.
Affected individuals are often managed by a multidisciplinary team that includes a neurologist, physiatrist, orthopedic surgeon, and physical and occupational therapists [
Treatment is symptomatic and may include the following:
Special shoes, including those with good ankle support
Ankle/foot orthoses to correct foot drop and aid walking [
Orthopedic surgery to correct severe
Forearm crutches or canes for gait stability; severely affected individuals need wheelchairs.
Exercise within the individual's capability to remain physically active
BIPAP for those with respiratory muscle weakness
• Special shoes, including those with good ankle support
• Ankle/foot orthoses to correct foot drop and aid walking [
• Orthopedic surgery to correct severe
• Forearm crutches or canes for gait stability; severely affected individuals need wheelchairs.
• Exercise within the individual's capability to remain physically active
• BIPAP for those with respiratory muscle weakness
## Prevention of Secondary Complications
Ankle braces can help prevent tripping and falling or ankle injuries.
## Surveillance
The following are appropriate:
Annual follow up with a neurologist for overall evaluation of neurologic deficits
Annual follow up with occupational therapy and physical therapy to assess fine motor and gross motor function
Annual follow up with a pulmonologist for evaluation of respiratory function
• Annual follow up with a neurologist for overall evaluation of neurologic deficits
• Annual follow up with occupational therapy and physical therapy to assess fine motor and gross motor function
• Annual follow up with a pulmonologist for evaluation of respiratory function
## Agents/Circumstances to Avoid
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Other
Because the segmental demyelination in patients with CMT4J is similar to that observed in acquired demyelinating neuropathies, a few patients have been treated with intravenous immunoglobin [
## Genetic Counseling
Charcot-Marie-Tooth neuropathy type 4J (CMT4J) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutated allele).
Heterozygotes (carriers) are asymptomatic.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
The offspring of an individual with CMT4J are obligate heterozygotes (carriers) for a pathogenic variant in
Unless an individual with CMT4J has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutated allele).
• Heterozygotes (carriers) are asymptomatic.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.
• The offspring of an individual with CMT4J are obligate heterozygotes (carriers) for a pathogenic variant in
• Unless an individual with CMT4J has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Charcot-Marie-Tooth neuropathy type 4J (CMT4J) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutated allele).
Heterozygotes (carriers) are asymptomatic.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
The offspring of an individual with CMT4J are obligate heterozygotes (carriers) for a pathogenic variant in
Unless an individual with CMT4J has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutated allele).
• Heterozygotes (carriers) are asymptomatic.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.
• The offspring of an individual with CMT4J are obligate heterozygotes (carriers) for a pathogenic variant in
• Unless an individual with CMT4J has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
## Carrier (Heterozygote) Detection
Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
## Resources
PO Box 105
Glenolden PA 19036
Department of Molecular Genetics
University of Antwerp
Antwerp Antwerpen B-2610
Belgium
432 Park Avenue South
4th Floor
New York NY 10016
Institute of Genetic Medicine
University of Newcastle upon Tyne
International Centre for Life
Newcastle upon Tyne NE1 3BZ
United Kingdom
222 South Riverside Plaza
Suite 1500
Chicago IL 60606
61A Great Suffolk Street
London SE1 0BU
United Kingdom
•
• PO Box 105
• Glenolden PA 19036
•
•
• Department of Molecular Genetics
• University of Antwerp
• Antwerp Antwerpen B-2610
• Belgium
•
• 432 Park Avenue South
• 4th Floor
• New York NY 10016
•
•
•
•
•
•
•
•
• Institute of Genetic Medicine
• University of Newcastle upon Tyne
• International Centre for Life
• Newcastle upon Tyne NE1 3BZ
• United Kingdom
•
•
• 222 South Riverside Plaza
• Suite 1500
• Chicago IL 60606
•
•
• 61A Great Suffolk Street
• London SE1 0BU
• United Kingdom
•
•
•
## Molecular Genetics
Charcot-Marie-Tooth Neuropathy Type 4J: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Charcot-Marie-Tooth Neuropathy Type 4J (
Variants listed in the table have been provided by the author.
Fig4/SAC3 is a SAC-domain phosphoinositide phosphatase with specificity toward the 5'-phosphate of PI(3,5)P
In order for Fig4/Sac3 to exert its biologic function, it typically complexes with a scaffolding protein known as Vac14/ArPIKfyve and a 5'-kinase of PI3P known as Fab1/PIKfyve. This regulatory complex (PAS) is thought to localize on early endosomal membranes during the transition from early endosomes to late endosomes. Alongside the myriad of endosomal maturation processes that occur at this time, the PAS complex is thought to mediate the conversion of early endosomal PI3P to late endosomal PI(3,5)P
Based on the current literature, the author proposes a hypothetic mechanism [
The
Once PI(3,5)P
Given these findings, one could speculate that the deficiency of Fig4/SAC3 and PI(3,5)P
## References
## Literature Cited
## Chapter Notes
The author specializes in neuromuscular diseases with particular research interest in inherited neuropathies (also called Charcot-Marie-Tooth disease or CMT) and myelin biology. Disabilities in many neurologic diseases, including inherited neuropathies, are usually caused by one of the two pathophysiologic processes: de-/dysmyelination and/or axonal degeneration. Our laboratory investigates the molecular mechanisms underlying the two pathologic processes at different levels of biologic system, including primary culture neurons/Schwann cells, genetically manipulated rodent models, and human subjects with inherited neuropathies.
Our laboratory research is currently funded by the National Institutes of Health, Muscular Dystrophy Association, and Veterans Affairs.
The author's
This work is, in part, supported by grants from NINDS (R01NS066927 and R21NS081364).
19 September 2019 (ma) Chapter retired: Covered in
14 November 2013 (me) Review posted live
17 August 2013 (jl) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 19 September 2019 (ma) Chapter retired: Covered in
• 14 November 2013 (me) Review posted live
• 17 August 2013 (jl) Original submission
## Author Notes
The author specializes in neuromuscular diseases with particular research interest in inherited neuropathies (also called Charcot-Marie-Tooth disease or CMT) and myelin biology. Disabilities in many neurologic diseases, including inherited neuropathies, are usually caused by one of the two pathophysiologic processes: de-/dysmyelination and/or axonal degeneration. Our laboratory investigates the molecular mechanisms underlying the two pathologic processes at different levels of biologic system, including primary culture neurons/Schwann cells, genetically manipulated rodent models, and human subjects with inherited neuropathies.
Our laboratory research is currently funded by the National Institutes of Health, Muscular Dystrophy Association, and Veterans Affairs.
The author's
## Acknowledgments
This work is, in part, supported by grants from NINDS (R01NS066927 and R21NS081364).
## Revision History
19 September 2019 (ma) Chapter retired: Covered in
14 November 2013 (me) Review posted live
17 August 2013 (jl) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 19 September 2019 (ma) Chapter retired: Covered in
• 14 November 2013 (me) Review posted live
• 17 August 2013 (jl) Original submission
|
[
"PM Campeau, GM Lenk, JT Lu, Y Bae, L Burrage, P Turnpenny, J Román Corona-Rivera, L Morandi, M Mora, H Reutter, AT Vulto-van Silfhout, L Faivre, E Haan, RA Gibbs, MH Meisler, BH Lee. Yunis-Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase.. Am J Hum Genet. 2013;92:781-91",
"GT Carter, RT Abresch, WM Fowler, ER Johnson, DD Kilmer, CM McDonald. Profiles of neuromuscular diseases. Hereditary motor and sensory neuropathy, types I and II.. Am J Phys Med Rehabil. 1995;74:S140-9",
"CY Chow, JE Landers, SK Bergren, PC Sapp, AE Grant, JM Jones, L Everett, GM Lenk, DM McKenna-Yasek, LS Weisman, D Figlewicz, RH Brown, MH Meisler. Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS.. Am J Hum Genet. 2009;84:85-8",
"CY Chow, Y Zhang, JJ Dowling, N Jin, M Adamska, K Shiga, K Szigeti, ME Shy, J Li, X Zhang, JR Lupski, LS Weisman, MH Meisler. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J.. Nature. 2007;448:68-72",
"E Cottenie, MP Menezes, AM Rossor, JM Morrow, TA Yousry, DJ Dick, JR Anderson, Z Jaunmuktane, S Brandner, JC Blake, H Houlden, MM Reilly. Rapidly progressive asymmetrical weakness in Charcot-Marie-Tooth disease type 4J resembles chronic inflammatory demyelinating polyneuropathy.. Neuromuscul Disord. 2013;23:399-403",
"SK Dove, K Dong, T Kobayashi, FK Williams, RH Michell. Phosphatidylinositol 3,5-bisphosphate and Fab1p/PIKfyve underPPIn endo-lysosome function.. Biochem J. 2009;419:1-13",
"GP Guyton, RA Mann. The pathogenesis and surgical management of foot deformity in Charcot-Marie-Tooth disease.. Foot Ankle Clin. 2000;5:317-26",
"N Jin, CY Chow, L Liu, SN Zolov, R Bronson, M Davisson, JL Petersen, Y Zhang, S Park, JE Duex, D Goldowitz, MH Meisler, LS Weisman. VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse.. EMBO J. 2008;27:3221-34",
"I Katona, X Zhang, Y Bai, ME Shy, J Guo, Q Yan, J Hatfield, WJ Kupsky, J Li. Distinct pathogenic processes between Fig4-deficient motor and sensory neurons.. Eur J Neurosci. 2011;33:1401-10",
"RA Lewis, AJ Sumner, ME Shy. Electrophysiological features of inherited demyelinating neuropathies: A reappraisal in the era of molecular diagnosis.. Muscle Nerve. 2000;23:1472-87",
"A Manford, T Xia, AK Saxena, C Stefan, F Hu, SD Emr, Y Mao. Crystal structure of the yeast Sac1: implications for its phosphoinositide phosphatase function.. EMBO J. 2010;29:1489-98",
"C Martyn, J. Li. Fig4 deficiency: a newly emerged lysosomal storage disorder?. Prog Neurobiol. 2013;101-102:35-45",
"G Nicholson, GM Lenk, SW Reddel, AE Grant, CF Towne, CJ Ferguson, E Simpson, A Scheuerle, M Yasick, S Hoffman, R Blouin, C Brandt, G Coppola, LG Biesecker, SD Batish, MH Meisler. Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P. Brain. 2011;134:1959-71",
"D Pareyson, C Marchesi. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease.. Lancet Neurol. 2009;8:654-67",
"MM Reilly, ME Shy. Diagnosis and new treatments in genetic neuropathies.. J Neurol Neurosurg Psychiatry. 2009;80:1304-14",
"CM Ward, LA Dolan, DL Bennett, JA Morcuende, RR Cooper. Long-term results of reconstruction for treatment of a flexible cavovarus foot in Charcot-Marie-Tooth disease.. J Bone Joint Surg Am. 2008;90:2631-42",
"X Zhang, CY Chow, Z Sahenk, ME Shy, MH Meisler, J Li. Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration.. Brain. 2008;131:1990-2001"
] |
14/11/2013
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
cmtc
|
cmtc
|
[
"Van Lohuizen Syndrome",
"Van Lohuizen Syndrome",
"Guanine nucleotide-binding protein subunit alpha-11",
"GNA11",
"Isolated and Classic Cutis Marmorata Telangiectatica Congenita (CMTC)"
] |
Isolated and Classic Cutis Marmorata Telangiectatica Congenita
|
Joan Tamburro, Elias I Traboulsi, Millan S Patel
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Summary Isolated and classic cutis marmorata telangiectatica congenita (CMTC) are characterized by congenital skin changes including erythematous-to-violaceous, reticulated, net-like or marbled-appearing patches of skin that do not mostly or completely resolve with warming or any other acute intervention. Individuals with isolated CMTC have no other syndromic features, and skin lesions tend to fade or resolve. Those with classic CMTC may have accompanying hemihypoplasia with body asymmetry, skin atrophy or ulceration, other vascular malformations, and occasional ocular issues (early-onset glaucoma and/or peripheral retinal vascular attenuation) but do not have other malformations, dysmorphic features, or cognitive impairment. The most common location for the CMTC lesions is on the legs. An affected limb may also display weakness or be unusually susceptible to cold compared to an unaffected limb. In more than half of affected individuals, skin lesions will generally fade across a wide range in age (6 weeks to 26 years), most commonly in the first year of life, but may not resolve completely. A molecular diagnosis can be established in a proband with suggestive cutaneous findings if a mosaic heterozygous pathogenic variant in Isolated and classic CMTC are typically not inherited. Most affected individuals represent simplex cases. Vertical transmission of a Rarely, autosomal dominant inheritance has been reported in families with a clinical diagnosis of isolated or classic CMTC (i.e., families in which a Because vertical transmission of a mosaic
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## Diagnosis
Isolated and classic cutis marmorata telangiectatica congenita (CMTC) are considered capillary malformations by the International Society for the Study of Vascular Anomalies. Clinically, CMTC is diagnosed by characteristic congenital erythematous-to-violaceous net-like or marbled areas of skin (
Isolated and classic CMTC
Persistent cutis marmorata that is more prominent or florid than physiologic cutis marmorata AND:
Typically affects specific body areas with clear demarcation
May be accompanied by ulceration and/or atrophy of the involved skin
Vascular telangiectasia (spider veins)
Dilated, tortuous superficial veins
Body asymmetry in the form of hemihypoplasia
While there are no universally accepted clinical diagnostic criteria, the authors suggest that an affected individual should have all three of the following:
Congenital, net-like pattern of red-to-purplish cutaneous erythema that is obvious at rest
Erythema that does not mostly or completely resolve with warming or any other acute intervention
No other features of syndromes in which CMTC or CMTC-like lesions are present (See
Note: These proposed clinical diagnostic criteria have not been validated.
A molecular diagnosis of isolated and classic CMTC can be established in a proband with suggestive cutaneous findings if a mosaic heterozygous pathogenic (or likely pathogenic) variant in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Because the few reported individuals with a molecular diagnosis have a
Experience suggests that sequence analysis of DNA derived from affected skin or subcutaneous tissue has a higher detection rate than that of peripheral blood-derived DNA, where the variant is often absent.
Because CMTC is a focal disorder, pathogenic variants may only be detectable in affected tissues.
Failure to detect a
Sensitivity to detect low-level mosaicism of a
Molecular Genetic Testing Used in Isolated and Classic Cutis Marmorata Telangiectatica Congenita
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Most identified
Next-generation sequencing of affected tissues has failed to detect
• Persistent cutis marmorata that is more prominent or florid than physiologic cutis marmorata AND:
• Typically affects specific body areas with clear demarcation
• May be accompanied by ulceration and/or atrophy of the involved skin
• Typically affects specific body areas with clear demarcation
• May be accompanied by ulceration and/or atrophy of the involved skin
• Vascular telangiectasia (spider veins)
• Dilated, tortuous superficial veins
• Body asymmetry in the form of hemihypoplasia
• Typically affects specific body areas with clear demarcation
• May be accompanied by ulceration and/or atrophy of the involved skin
• Congenital, net-like pattern of red-to-purplish cutaneous erythema that is obvious at rest
• Erythema that does not mostly or completely resolve with warming or any other acute intervention
• No other features of syndromes in which CMTC or CMTC-like lesions are present (See
• Experience suggests that sequence analysis of DNA derived from affected skin or subcutaneous tissue has a higher detection rate than that of peripheral blood-derived DNA, where the variant is often absent.
• Because CMTC is a focal disorder, pathogenic variants may only be detectable in affected tissues.
• Failure to detect a
• Sensitivity to detect low-level mosaicism of a
## Suggestive Findings
Isolated and classic CMTC
Persistent cutis marmorata that is more prominent or florid than physiologic cutis marmorata AND:
Typically affects specific body areas with clear demarcation
May be accompanied by ulceration and/or atrophy of the involved skin
Vascular telangiectasia (spider veins)
Dilated, tortuous superficial veins
Body asymmetry in the form of hemihypoplasia
• Persistent cutis marmorata that is more prominent or florid than physiologic cutis marmorata AND:
• Typically affects specific body areas with clear demarcation
• May be accompanied by ulceration and/or atrophy of the involved skin
• Typically affects specific body areas with clear demarcation
• May be accompanied by ulceration and/or atrophy of the involved skin
• Vascular telangiectasia (spider veins)
• Dilated, tortuous superficial veins
• Body asymmetry in the form of hemihypoplasia
• Typically affects specific body areas with clear demarcation
• May be accompanied by ulceration and/or atrophy of the involved skin
## Establishing the Diagnosis
While there are no universally accepted clinical diagnostic criteria, the authors suggest that an affected individual should have all three of the following:
Congenital, net-like pattern of red-to-purplish cutaneous erythema that is obvious at rest
Erythema that does not mostly or completely resolve with warming or any other acute intervention
No other features of syndromes in which CMTC or CMTC-like lesions are present (See
Note: These proposed clinical diagnostic criteria have not been validated.
A molecular diagnosis of isolated and classic CMTC can be established in a proband with suggestive cutaneous findings if a mosaic heterozygous pathogenic (or likely pathogenic) variant in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Because the few reported individuals with a molecular diagnosis have a
Experience suggests that sequence analysis of DNA derived from affected skin or subcutaneous tissue has a higher detection rate than that of peripheral blood-derived DNA, where the variant is often absent.
Because CMTC is a focal disorder, pathogenic variants may only be detectable in affected tissues.
Failure to detect a
Sensitivity to detect low-level mosaicism of a
Molecular Genetic Testing Used in Isolated and Classic Cutis Marmorata Telangiectatica Congenita
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Most identified
Next-generation sequencing of affected tissues has failed to detect
• Congenital, net-like pattern of red-to-purplish cutaneous erythema that is obvious at rest
• Erythema that does not mostly or completely resolve with warming or any other acute intervention
• No other features of syndromes in which CMTC or CMTC-like lesions are present (See
• Experience suggests that sequence analysis of DNA derived from affected skin or subcutaneous tissue has a higher detection rate than that of peripheral blood-derived DNA, where the variant is often absent.
• Because CMTC is a focal disorder, pathogenic variants may only be detectable in affected tissues.
• Failure to detect a
• Sensitivity to detect low-level mosaicism of a
## Clinical Diagnosis
While there are no universally accepted clinical diagnostic criteria, the authors suggest that an affected individual should have all three of the following:
Congenital, net-like pattern of red-to-purplish cutaneous erythema that is obvious at rest
Erythema that does not mostly or completely resolve with warming or any other acute intervention
No other features of syndromes in which CMTC or CMTC-like lesions are present (See
Note: These proposed clinical diagnostic criteria have not been validated.
• Congenital, net-like pattern of red-to-purplish cutaneous erythema that is obvious at rest
• Erythema that does not mostly or completely resolve with warming or any other acute intervention
• No other features of syndromes in which CMTC or CMTC-like lesions are present (See
## Molecular Diagnosis
A molecular diagnosis of isolated and classic CMTC can be established in a proband with suggestive cutaneous findings if a mosaic heterozygous pathogenic (or likely pathogenic) variant in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Because the few reported individuals with a molecular diagnosis have a
Experience suggests that sequence analysis of DNA derived from affected skin or subcutaneous tissue has a higher detection rate than that of peripheral blood-derived DNA, where the variant is often absent.
Because CMTC is a focal disorder, pathogenic variants may only be detectable in affected tissues.
Failure to detect a
Sensitivity to detect low-level mosaicism of a
Molecular Genetic Testing Used in Isolated and Classic Cutis Marmorata Telangiectatica Congenita
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Most identified
Next-generation sequencing of affected tissues has failed to detect
• Experience suggests that sequence analysis of DNA derived from affected skin or subcutaneous tissue has a higher detection rate than that of peripheral blood-derived DNA, where the variant is often absent.
• Because CMTC is a focal disorder, pathogenic variants may only be detectable in affected tissues.
• Failure to detect a
• Sensitivity to detect low-level mosaicism of a
## Clinical Characteristics
To date, nearly 500 individuals with all clinical subtypes of cutis marmorata telangiectatica congenita (CMTC), including isolated and classic CMTC, have been published (reviewed in
While individuals with the physical finding of CMTC may have a spectrum of features (see
Note: Care should be taken by the clinician to distinguish whether there is hemihypoplasia on one side versus hemihyperplasia on the other side, as the presence of hemihyperplasia indicates that a different diagnosis should be sought.
The most common location for the lesions is the legs.
Some authors report the presence of linear depressions, usually over the limb joints, in individuals with CMTC [
Lesions localized to the face are found in only 7.1% of affected individuals.
Generalized CMTC is found in one quarter of people with any type of CMTC (isolated, classic, syndromic, or plus; see
Capillary malformations
Discrete, superficial, often tortuous varicose veins. Such veins in an affected limb may be fragile.
Nevus anemicus. It is unknown whether this is a distinct lesion or the result of a "steal syndrome" [
Some skin lesions may evolve into a nevus vascularis mixtus, with CMTC-like and nevus anemicus features [
Disappearance of CMTC entirely is rare but has been reported to occur, particularly with long-term follow up [
A congenital lesion appearing as ulcerated retiform purpura that evolved within days and took the appearance of typical CMTC by three months has been reported, suggesting that this could be one way in which CMTC lesions develop [
Patient 3 of
About 13% (9 of 69) of children with classic CMTC were found to have a clinically significant leg length discrepancy of 2 cm or greater [
Some leg length discrepancies resolve or stabilize in the first two years of life, and growth trajectories are not linear, requiring ongoing monitoring; differences in the range of 1 cm to 6.8 cm have been reported.
An affected limb may also display weakness or be unusually susceptible to cold compared to an unaffected limb.
Self-esteem issues can be a major problem for affected individuals and may be addressed proactively through resiliency training and bibliotherapy with books such as
Giving children age-appropriate language to describe their condition can help with curious peers.
Children should be coached on strategies like smiling broadly until they get a smile in return and age-appropriate one-liners to manage staring.
No clinically relevant genotype-phenotype correlations for isolated and classic CMTC have been identified.
Clinically, the authors classify the physical finding of CMTC into the following groups:
Previous terms used to refer to isolated and classic CMTC:
Congenital phlebectasia or congenital generalized phlebectasia
Naevus vascularis reticularis
Congenital livedo reticularis
Isolated and classic CMTC are rare conditions, with fewer than 500 individuals reported in the literature. Unfortunately, individuals with any type of CMTC (see
• Note: Care should be taken by the clinician to distinguish whether there is hemihypoplasia on one side versus hemihyperplasia on the other side, as the presence of hemihyperplasia indicates that a different diagnosis should be sought.
•
• The most common location for the lesions is the legs.
• Some authors report the presence of linear depressions, usually over the limb joints, in individuals with CMTC [
• Lesions localized to the face are found in only 7.1% of affected individuals.
• Generalized CMTC is found in one quarter of people with any type of CMTC (isolated, classic, syndromic, or plus; see
• The most common location for the lesions is the legs.
• Some authors report the presence of linear depressions, usually over the limb joints, in individuals with CMTC [
• Lesions localized to the face are found in only 7.1% of affected individuals.
• Generalized CMTC is found in one quarter of people with any type of CMTC (isolated, classic, syndromic, or plus; see
• Capillary malformations
• Discrete, superficial, often tortuous varicose veins. Such veins in an affected limb may be fragile.
• Nevus anemicus. It is unknown whether this is a distinct lesion or the result of a "steal syndrome" [
• Capillary malformations
• Discrete, superficial, often tortuous varicose veins. Such veins in an affected limb may be fragile.
• Nevus anemicus. It is unknown whether this is a distinct lesion or the result of a "steal syndrome" [
•
• Some skin lesions may evolve into a nevus vascularis mixtus, with CMTC-like and nevus anemicus features [
• Disappearance of CMTC entirely is rare but has been reported to occur, particularly with long-term follow up [
• A congenital lesion appearing as ulcerated retiform purpura that evolved within days and took the appearance of typical CMTC by three months has been reported, suggesting that this could be one way in which CMTC lesions develop [
• Patient 3 of
• Some skin lesions may evolve into a nevus vascularis mixtus, with CMTC-like and nevus anemicus features [
• Disappearance of CMTC entirely is rare but has been reported to occur, particularly with long-term follow up [
• A congenital lesion appearing as ulcerated retiform purpura that evolved within days and took the appearance of typical CMTC by three months has been reported, suggesting that this could be one way in which CMTC lesions develop [
• Patient 3 of
• The most common location for the lesions is the legs.
• Some authors report the presence of linear depressions, usually over the limb joints, in individuals with CMTC [
• Lesions localized to the face are found in only 7.1% of affected individuals.
• Generalized CMTC is found in one quarter of people with any type of CMTC (isolated, classic, syndromic, or plus; see
• Capillary malformations
• Discrete, superficial, often tortuous varicose veins. Such veins in an affected limb may be fragile.
• Nevus anemicus. It is unknown whether this is a distinct lesion or the result of a "steal syndrome" [
• Some skin lesions may evolve into a nevus vascularis mixtus, with CMTC-like and nevus anemicus features [
• Disappearance of CMTC entirely is rare but has been reported to occur, particularly with long-term follow up [
• A congenital lesion appearing as ulcerated retiform purpura that evolved within days and took the appearance of typical CMTC by three months has been reported, suggesting that this could be one way in which CMTC lesions develop [
• Patient 3 of
• About 13% (9 of 69) of children with classic CMTC were found to have a clinically significant leg length discrepancy of 2 cm or greater [
• Some leg length discrepancies resolve or stabilize in the first two years of life, and growth trajectories are not linear, requiring ongoing monitoring; differences in the range of 1 cm to 6.8 cm have been reported.
• An affected limb may also display weakness or be unusually susceptible to cold compared to an unaffected limb.
• Self-esteem issues can be a major problem for affected individuals and may be addressed proactively through resiliency training and bibliotherapy with books such as
• Giving children age-appropriate language to describe their condition can help with curious peers.
• Children should be coached on strategies like smiling broadly until they get a smile in return and age-appropriate one-liners to manage staring.
• Congenital phlebectasia or congenital generalized phlebectasia
• Naevus vascularis reticularis
• Congenital livedo reticularis
## Clinical Description
To date, nearly 500 individuals with all clinical subtypes of cutis marmorata telangiectatica congenita (CMTC), including isolated and classic CMTC, have been published (reviewed in
While individuals with the physical finding of CMTC may have a spectrum of features (see
Note: Care should be taken by the clinician to distinguish whether there is hemihypoplasia on one side versus hemihyperplasia on the other side, as the presence of hemihyperplasia indicates that a different diagnosis should be sought.
The most common location for the lesions is the legs.
Some authors report the presence of linear depressions, usually over the limb joints, in individuals with CMTC [
Lesions localized to the face are found in only 7.1% of affected individuals.
Generalized CMTC is found in one quarter of people with any type of CMTC (isolated, classic, syndromic, or plus; see
Capillary malformations
Discrete, superficial, often tortuous varicose veins. Such veins in an affected limb may be fragile.
Nevus anemicus. It is unknown whether this is a distinct lesion or the result of a "steal syndrome" [
Some skin lesions may evolve into a nevus vascularis mixtus, with CMTC-like and nevus anemicus features [
Disappearance of CMTC entirely is rare but has been reported to occur, particularly with long-term follow up [
A congenital lesion appearing as ulcerated retiform purpura that evolved within days and took the appearance of typical CMTC by three months has been reported, suggesting that this could be one way in which CMTC lesions develop [
Patient 3 of
About 13% (9 of 69) of children with classic CMTC were found to have a clinically significant leg length discrepancy of 2 cm or greater [
Some leg length discrepancies resolve or stabilize in the first two years of life, and growth trajectories are not linear, requiring ongoing monitoring; differences in the range of 1 cm to 6.8 cm have been reported.
An affected limb may also display weakness or be unusually susceptible to cold compared to an unaffected limb.
Self-esteem issues can be a major problem for affected individuals and may be addressed proactively through resiliency training and bibliotherapy with books such as
Giving children age-appropriate language to describe their condition can help with curious peers.
Children should be coached on strategies like smiling broadly until they get a smile in return and age-appropriate one-liners to manage staring.
• Note: Care should be taken by the clinician to distinguish whether there is hemihypoplasia on one side versus hemihyperplasia on the other side, as the presence of hemihyperplasia indicates that a different diagnosis should be sought.
•
• The most common location for the lesions is the legs.
• Some authors report the presence of linear depressions, usually over the limb joints, in individuals with CMTC [
• Lesions localized to the face are found in only 7.1% of affected individuals.
• Generalized CMTC is found in one quarter of people with any type of CMTC (isolated, classic, syndromic, or plus; see
• The most common location for the lesions is the legs.
• Some authors report the presence of linear depressions, usually over the limb joints, in individuals with CMTC [
• Lesions localized to the face are found in only 7.1% of affected individuals.
• Generalized CMTC is found in one quarter of people with any type of CMTC (isolated, classic, syndromic, or plus; see
• Capillary malformations
• Discrete, superficial, often tortuous varicose veins. Such veins in an affected limb may be fragile.
• Nevus anemicus. It is unknown whether this is a distinct lesion or the result of a "steal syndrome" [
• Capillary malformations
• Discrete, superficial, often tortuous varicose veins. Such veins in an affected limb may be fragile.
• Nevus anemicus. It is unknown whether this is a distinct lesion or the result of a "steal syndrome" [
•
• Some skin lesions may evolve into a nevus vascularis mixtus, with CMTC-like and nevus anemicus features [
• Disappearance of CMTC entirely is rare but has been reported to occur, particularly with long-term follow up [
• A congenital lesion appearing as ulcerated retiform purpura that evolved within days and took the appearance of typical CMTC by three months has been reported, suggesting that this could be one way in which CMTC lesions develop [
• Patient 3 of
• Some skin lesions may evolve into a nevus vascularis mixtus, with CMTC-like and nevus anemicus features [
• Disappearance of CMTC entirely is rare but has been reported to occur, particularly with long-term follow up [
• A congenital lesion appearing as ulcerated retiform purpura that evolved within days and took the appearance of typical CMTC by three months has been reported, suggesting that this could be one way in which CMTC lesions develop [
• Patient 3 of
• The most common location for the lesions is the legs.
• Some authors report the presence of linear depressions, usually over the limb joints, in individuals with CMTC [
• Lesions localized to the face are found in only 7.1% of affected individuals.
• Generalized CMTC is found in one quarter of people with any type of CMTC (isolated, classic, syndromic, or plus; see
• Capillary malformations
• Discrete, superficial, often tortuous varicose veins. Such veins in an affected limb may be fragile.
• Nevus anemicus. It is unknown whether this is a distinct lesion or the result of a "steal syndrome" [
• Some skin lesions may evolve into a nevus vascularis mixtus, with CMTC-like and nevus anemicus features [
• Disappearance of CMTC entirely is rare but has been reported to occur, particularly with long-term follow up [
• A congenital lesion appearing as ulcerated retiform purpura that evolved within days and took the appearance of typical CMTC by three months has been reported, suggesting that this could be one way in which CMTC lesions develop [
• Patient 3 of
• About 13% (9 of 69) of children with classic CMTC were found to have a clinically significant leg length discrepancy of 2 cm or greater [
• Some leg length discrepancies resolve or stabilize in the first two years of life, and growth trajectories are not linear, requiring ongoing monitoring; differences in the range of 1 cm to 6.8 cm have been reported.
• An affected limb may also display weakness or be unusually susceptible to cold compared to an unaffected limb.
• Self-esteem issues can be a major problem for affected individuals and may be addressed proactively through resiliency training and bibliotherapy with books such as
• Giving children age-appropriate language to describe their condition can help with curious peers.
• Children should be coached on strategies like smiling broadly until they get a smile in return and age-appropriate one-liners to manage staring.
## Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations for isolated and classic CMTC have been identified.
## Nomenclature
Clinically, the authors classify the physical finding of CMTC into the following groups:
Previous terms used to refer to isolated and classic CMTC:
Congenital phlebectasia or congenital generalized phlebectasia
Naevus vascularis reticularis
Congenital livedo reticularis
• Congenital phlebectasia or congenital generalized phlebectasia
• Naevus vascularis reticularis
• Congenital livedo reticularis
## Prevalence
Isolated and classic CMTC are rare conditions, with fewer than 500 individuals reported in the literature. Unfortunately, individuals with any type of CMTC (see
## Genetically Related (Allelic) Disorders
Other phenotypes associated with pathogenic variants in
Allelic Disorders
## Differential Diagnosis
Isolated and classic cutis marmorata telangiectatica congenita (CMTC) are congenital conditions; similar skin lesions occurring later in life are referred to as livedo reticularis or livedo racemosa (see
The primary differential diagnosis for congenital isolated CMTC is physiologic cutis marmorata (CM). CM is a normal physiologic finding that is apparent at rest in a minority of newborns. CM consists of a homogeneous, fine, lacy, or reticular capillary change that worsens (or becomes apparent) with cold or emotion, completely (or nearly completely) resolves with warming, and usually fades by age four to six months. No ulcerations or skin atrophy are present. In contrast, while CMTC lesions often show changes with warming or strong emotion, the lesions do not rapidly resolve, regardless of the intervention. If complete or near-complete resolution occurs acutely with any intervention, the individual has physiologic CM, not CMTC.
Syndromes of Known Genetic Cause in Which CMTC or CMTC-Like Lesions Are Present
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth restriction, MOI = mode of inheritance; XL = X-linked
Cutis marmorata that is much more prominent than expected and is persistent may be seen in neonatal lupus (or any primary antiphospholipid antibody syndrome).
Hypoplasia of an affected limb may be seen in "inverse Klippel-Trenaunay" in association with geographic capillary malformations, and in diffuse capillary malformation with undergrowth [
Genuine diffuse phlebectasia (Bockenheimer disease)
Similar to classic CMTC, glaucoma (which is often congenital) is the most common finding. The latest reported age for onset of glaucoma is nine years.
Other ocular findings are also similar to what may be described in individuals with classic CMTC and may consist of retinal abnormalities (perfusion defects and vascular abnormalities), which were recognized on specific imaging in eight of nine cases [
Developmental delays and seizures were found to be the most commonly reported neurologic manifestations in CMTC of any type, along with a wide variety of other findings including skull shape changes, brain arteriovenous malformation, intellectual disability, hydrocephalus, corpus callosum agenesis, brain ischemia, microcephaly, and hearing impairment – some of which may be incidental associations.
Transient ischemic attacks and cerebral vascular malformations were described in association with a homozygous truncating variant in
Livedo reticularis (LR) is net-like and uniform. Some authors divide it into four subcategories: physiologic LR (synonymous with CM); primary LR (usually as a result of embolism, thrombosis, or occlusion of arterioles as seen with multiple cholesterol emboli, vasculitis, and other disorders); idiopathic LR; and amantadine-induced LR.
Livedo racemosa presents with a less uniform, broken net-like appearance and irregular mottling, usually
• Cutis marmorata that is much more prominent than expected and is persistent may be seen in neonatal lupus (or any primary antiphospholipid antibody syndrome).
• Hypoplasia of an affected limb may be seen in "inverse Klippel-Trenaunay" in association with geographic capillary malformations, and in diffuse capillary malformation with undergrowth [
• Genuine diffuse phlebectasia (Bockenheimer disease)
• Similar to classic CMTC, glaucoma (which is often congenital) is the most common finding. The latest reported age for onset of glaucoma is nine years.
• Other ocular findings are also similar to what may be described in individuals with classic CMTC and may consist of retinal abnormalities (perfusion defects and vascular abnormalities), which were recognized on specific imaging in eight of nine cases [
• Similar to classic CMTC, glaucoma (which is often congenital) is the most common finding. The latest reported age for onset of glaucoma is nine years.
• Other ocular findings are also similar to what may be described in individuals with classic CMTC and may consist of retinal abnormalities (perfusion defects and vascular abnormalities), which were recognized on specific imaging in eight of nine cases [
•
• Developmental delays and seizures were found to be the most commonly reported neurologic manifestations in CMTC of any type, along with a wide variety of other findings including skull shape changes, brain arteriovenous malformation, intellectual disability, hydrocephalus, corpus callosum agenesis, brain ischemia, microcephaly, and hearing impairment – some of which may be incidental associations.
• Transient ischemic attacks and cerebral vascular malformations were described in association with a homozygous truncating variant in
• Developmental delays and seizures were found to be the most commonly reported neurologic manifestations in CMTC of any type, along with a wide variety of other findings including skull shape changes, brain arteriovenous malformation, intellectual disability, hydrocephalus, corpus callosum agenesis, brain ischemia, microcephaly, and hearing impairment – some of which may be incidental associations.
• Transient ischemic attacks and cerebral vascular malformations were described in association with a homozygous truncating variant in
• Similar to classic CMTC, glaucoma (which is often congenital) is the most common finding. The latest reported age for onset of glaucoma is nine years.
• Other ocular findings are also similar to what may be described in individuals with classic CMTC and may consist of retinal abnormalities (perfusion defects and vascular abnormalities), which were recognized on specific imaging in eight of nine cases [
• Developmental delays and seizures were found to be the most commonly reported neurologic manifestations in CMTC of any type, along with a wide variety of other findings including skull shape changes, brain arteriovenous malformation, intellectual disability, hydrocephalus, corpus callosum agenesis, brain ischemia, microcephaly, and hearing impairment – some of which may be incidental associations.
• Transient ischemic attacks and cerebral vascular malformations were described in association with a homozygous truncating variant in
• Livedo reticularis (LR) is net-like and uniform. Some authors divide it into four subcategories: physiologic LR (synonymous with CM); primary LR (usually as a result of embolism, thrombosis, or occlusion of arterioles as seen with multiple cholesterol emboli, vasculitis, and other disorders); idiopathic LR; and amantadine-induced LR.
• Livedo racemosa presents with a less uniform, broken net-like appearance and irregular mottling, usually
## Management
No clinical practice guidelines for cutis marmorata telangiectatica congenita (CMTC) have been published.
To establish the extent of disease and needs in an individual diagnosed with isolated and classic CMTC, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Isolated and Classic Cutis Marmorata Telangiectatica Congenita
Community or
Social work involvement for parental support.
MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)nurse
Treatment of Manifestations in Individuals with Isolated and Classic Cutis Marmorata Telangiectatica Congenita
Anecdotally, some children worsen w/this therapy.
Laser therapy is typically not needed; usually done for cosmetic reasons.
Bibliotherapy to normalize differences;
Resilience training;
Training in strategies for dealing w/staring or unwanted attention;
Preparing parents to deal w/potential child abuse allegations.
The efficacy of this treatment has not been clearly demonstrated [
Recommended Surveillance for Individuals with Isolated and Classic Cutis Marmorata Telangiectatica Congenita
Avoid blood draws or IV placement in affected limbs because of potential vein fragility.
Cold exposure of affected limbs may be painful for some people with CMTC.
See
Search
• Community or
• Social work involvement for parental support.
• Anecdotally, some children worsen w/this therapy.
• Laser therapy is typically not needed; usually done for cosmetic reasons.
• Bibliotherapy to normalize differences;
• Resilience training;
• Training in strategies for dealing w/staring or unwanted attention;
• Preparing parents to deal w/potential child abuse allegations.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with isolated and classic CMTC, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Isolated and Classic Cutis Marmorata Telangiectatica Congenita
Community or
Social work involvement for parental support.
MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)nurse
• Community or
• Social work involvement for parental support.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Isolated and Classic Cutis Marmorata Telangiectatica Congenita
Anecdotally, some children worsen w/this therapy.
Laser therapy is typically not needed; usually done for cosmetic reasons.
Bibliotherapy to normalize differences;
Resilience training;
Training in strategies for dealing w/staring or unwanted attention;
Preparing parents to deal w/potential child abuse allegations.
The efficacy of this treatment has not been clearly demonstrated [
• Anecdotally, some children worsen w/this therapy.
• Laser therapy is typically not needed; usually done for cosmetic reasons.
• Bibliotherapy to normalize differences;
• Resilience training;
• Training in strategies for dealing w/staring or unwanted attention;
• Preparing parents to deal w/potential child abuse allegations.
## Surveillance
Recommended Surveillance for Individuals with Isolated and Classic Cutis Marmorata Telangiectatica Congenita
## Agents/Circumstances to Avoid
Avoid blood draws or IV placement in affected limbs because of potential vein fragility.
Cold exposure of affected limbs may be painful for some people with CMTC.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Isolated and classic cutis marmorata telangiectatica congenita (CMTC) are typically not inherited. Most affected individuals represent simplex cases (i.e., a single affected family member).
Vertical transmission of a
Parents of children with somatic mosaicism for a pathogenic variant in
Only very rarely has a parent of a child with a clinical diagnosis of isolated or classic CMTC had any significant, distinctive manifestations of the disorder. Four families in which inheritance of isolated or classic CMTC appeared to follow an autosomal dominant inheritance pattern have been described [
The risk to sibs of a proband with somatic mosaicism for a pathogenic variant in
Note: This is a relatively new area for clinical genetics as only a small (albeit growing) number of disorders are known to be caused by mosaic pathogenic variants. Counseling for sib recurrence risk in CMTC should emphasize that, while no pregnancy is at zero risk, all evidence suggests that the risk for recurrence is very low (<1%).
Sib recurrence in families with a clinical diagnosis of isolated or classic CMTC has been described but is very rare. Isolated CMTC was reported in two sisters, one of whom also had scleroderma [
All individuals with a molecular diagnosis of isolated or classic CMTC have had somatic mosaicism for a pathogenic variant in
The risk to offspring of a proband with a clinical diagnosis of isolated or classic CMTC is presumed to be low but slightly greater than that of the general population (vertical transmission has been observed in only four families to date).
The optimal time for determination of genetic risk is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
Because vertical transmission of a mosaic
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Parents of children with somatic mosaicism for a pathogenic variant in
• Only very rarely has a parent of a child with a clinical diagnosis of isolated or classic CMTC had any significant, distinctive manifestations of the disorder. Four families in which inheritance of isolated or classic CMTC appeared to follow an autosomal dominant inheritance pattern have been described [
• The risk to sibs of a proband with somatic mosaicism for a pathogenic variant in
• Note: This is a relatively new area for clinical genetics as only a small (albeit growing) number of disorders are known to be caused by mosaic pathogenic variants. Counseling for sib recurrence risk in CMTC should emphasize that, while no pregnancy is at zero risk, all evidence suggests that the risk for recurrence is very low (<1%).
• Sib recurrence in families with a clinical diagnosis of isolated or classic CMTC has been described but is very rare. Isolated CMTC was reported in two sisters, one of whom also had scleroderma [
• All individuals with a molecular diagnosis of isolated or classic CMTC have had somatic mosaicism for a pathogenic variant in
• The risk to offspring of a proband with a clinical diagnosis of isolated or classic CMTC is presumed to be low but slightly greater than that of the general population (vertical transmission has been observed in only four families to date).
• The optimal time for determination of genetic risk is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
## Mode of Inheritance
Isolated and classic cutis marmorata telangiectatica congenita (CMTC) are typically not inherited. Most affected individuals represent simplex cases (i.e., a single affected family member).
Vertical transmission of a
## Risk to Family Members
Parents of children with somatic mosaicism for a pathogenic variant in
Only very rarely has a parent of a child with a clinical diagnosis of isolated or classic CMTC had any significant, distinctive manifestations of the disorder. Four families in which inheritance of isolated or classic CMTC appeared to follow an autosomal dominant inheritance pattern have been described [
The risk to sibs of a proband with somatic mosaicism for a pathogenic variant in
Note: This is a relatively new area for clinical genetics as only a small (albeit growing) number of disorders are known to be caused by mosaic pathogenic variants. Counseling for sib recurrence risk in CMTC should emphasize that, while no pregnancy is at zero risk, all evidence suggests that the risk for recurrence is very low (<1%).
Sib recurrence in families with a clinical diagnosis of isolated or classic CMTC has been described but is very rare. Isolated CMTC was reported in two sisters, one of whom also had scleroderma [
All individuals with a molecular diagnosis of isolated or classic CMTC have had somatic mosaicism for a pathogenic variant in
The risk to offspring of a proband with a clinical diagnosis of isolated or classic CMTC is presumed to be low but slightly greater than that of the general population (vertical transmission has been observed in only four families to date).
• Parents of children with somatic mosaicism for a pathogenic variant in
• Only very rarely has a parent of a child with a clinical diagnosis of isolated or classic CMTC had any significant, distinctive manifestations of the disorder. Four families in which inheritance of isolated or classic CMTC appeared to follow an autosomal dominant inheritance pattern have been described [
• The risk to sibs of a proband with somatic mosaicism for a pathogenic variant in
• Note: This is a relatively new area for clinical genetics as only a small (albeit growing) number of disorders are known to be caused by mosaic pathogenic variants. Counseling for sib recurrence risk in CMTC should emphasize that, while no pregnancy is at zero risk, all evidence suggests that the risk for recurrence is very low (<1%).
• Sib recurrence in families with a clinical diagnosis of isolated or classic CMTC has been described but is very rare. Isolated CMTC was reported in two sisters, one of whom also had scleroderma [
• All individuals with a molecular diagnosis of isolated or classic CMTC have had somatic mosaicism for a pathogenic variant in
• The risk to offspring of a proband with a clinical diagnosis of isolated or classic CMTC is presumed to be low but slightly greater than that of the general population (vertical transmission has been observed in only four families to date).
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
• The optimal time for determination of genetic risk is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
## Prenatal Testing and Preimplantation Genetic Testing
Because vertical transmission of a mosaic
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
3715 Wesley Chapel Road
Zanesville OH 43701
Kapelweg 154B
Netherlands
•
•
• 3715 Wesley Chapel Road
• Zanesville OH 43701
•
•
•
• Kapelweg 154B
• Netherlands
•
## Molecular Genetics
Isolated and Classic Cutis Marmorata Telangiectatica Congenita: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Isolated and Classic Cutis Marmorata Telangiectatica Congenita (
Isolated and classic cutis marmorata telangiectatica congenita (CMTC) affects capillaries and venules. Pathologically, vessels are abundant and show tortuous dilatation. Capillary lakes, venous dilatation, and stenoses are also seen, and vessels may have an irregular intima and elastic lamina [
Mosaic activating pathogenic variants in
Research studies to elucidate the genetic architecture of CMTC currently are being conducted by Dr Beth Drolet at the University of Wisconsin, Dr Pierre Vabres at the Université de Bourgogne, and Dr Miikka Vikkula at the Institut de Duve, Université catholique de Louvain.
Note: No prenatal exposure or teratogen has been identified to cause isolated or classic CMTC. When four affected infants (3 with classic CMTC and 1 with isolated CMTC) who all lived less than 20 km from each other were diagnosed over an 18-month period in Australia, no teratogens meeting modified Bradford Hill epidemiologic criteria for causal association could be identified [
Notable
Variants listed in the table have been provided by the authors.
Pathogenic activating variants in
## Molecular Pathogenesis
Isolated and classic cutis marmorata telangiectatica congenita (CMTC) affects capillaries and venules. Pathologically, vessels are abundant and show tortuous dilatation. Capillary lakes, venous dilatation, and stenoses are also seen, and vessels may have an irregular intima and elastic lamina [
Mosaic activating pathogenic variants in
Research studies to elucidate the genetic architecture of CMTC currently are being conducted by Dr Beth Drolet at the University of Wisconsin, Dr Pierre Vabres at the Université de Bourgogne, and Dr Miikka Vikkula at the Institut de Duve, Université catholique de Louvain.
Note: No prenatal exposure or teratogen has been identified to cause isolated or classic CMTC. When four affected infants (3 with classic CMTC and 1 with isolated CMTC) who all lived less than 20 km from each other were diagnosed over an 18-month period in Australia, no teratogens meeting modified Bradford Hill epidemiologic criteria for causal association could be identified [
Notable
Variants listed in the table have been provided by the authors.
## Cancer and Benign Tumors
Pathogenic activating variants in
## Chapter Notes
Dr Tamburro is a dermatologist who has attended CMTC patient conferences for years to provide expertise to the CMTC community.
Dr Traboulsi is a pediatric ophthalmologist and clinical geneticist who cares for multiple patients with CMTC and is a team member with Dr Tamburro in the Cleveland Clinic Vascular Anomalies Clinic.
Dr Patel is a medical geneticist who has attended several CMTC patient conferences to provide expertise. He researches Adams-Oliver syndrome and sees patients with CMTC.
We thank the many patients and parents who have taught us over the years and the CMTC Alliance and CMTC-OVM organizations for their dedication to people with this condition.
9 June 2022 (ma) Review posted live
19 July 2021 (mp) Original submission
• 9 June 2022 (ma) Review posted live
• 19 July 2021 (mp) Original submission
## Author Notes
Dr Tamburro is a dermatologist who has attended CMTC patient conferences for years to provide expertise to the CMTC community.
Dr Traboulsi is a pediatric ophthalmologist and clinical geneticist who cares for multiple patients with CMTC and is a team member with Dr Tamburro in the Cleveland Clinic Vascular Anomalies Clinic.
Dr Patel is a medical geneticist who has attended several CMTC patient conferences to provide expertise. He researches Adams-Oliver syndrome and sees patients with CMTC.
## Acknowledgments
We thank the many patients and parents who have taught us over the years and the CMTC Alliance and CMTC-OVM organizations for their dedication to people with this condition.
## Revision History
9 June 2022 (ma) Review posted live
19 July 2021 (mp) Original submission
• 9 June 2022 (ma) Review posted live
• 19 July 2021 (mp) Original submission
## References
## Literature Cited
Cutis marmorata telangiectatica congenita lesions and skin ulceration in an individual age nine years
|
[] |
9/6/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
cmtx
|
cmtx
|
[
"CMTX1",
"Gap junction beta-1 protein",
"GJB1",
"GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes"
] |
Charles K Abrams
|
Summary Less commonly, initial manifestations in some affected individuals are stroke-like episodes (acute fulminant episodes of reversible CNS dysfunction). The diagnosis of CMT1X is established in a male by identification of a hemizygous CMT1X is inherited in an X-linked manner. Affected males transmit the
|
## Diagnosis
Occasionally fixed CNS abnormalities
Acute, self-limited episodes of transient neurologic dysfunction, especially weakness and dysarthria
Forearm NCVs are typically in the "intermediate" range of 30-40 m/sec for males; in females NCVs from 30-60 m/sec are seen [
Median nerve conductions are more severely affected than those of the ulnar nerve [
Note: NCV can vary from nerve to nerve in a single individual [
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of CMT1X is broad and overlaps with other forms of CMT, individuals with the findings of peripheral neuropathy described in
Sequence analysis of
An inherited neuropathy
For an introduction to multigene panels click
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Note, disease-associated variants in the upstream regulatory region, 5'UTR, non-coding exons, and 3'UTR are frequently associated with disease; therefore, sequence analysis should include these regions [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Occasionally fixed CNS abnormalities
• Acute, self-limited episodes of transient neurologic dysfunction, especially weakness and dysarthria
• Occasionally fixed CNS abnormalities
• Acute, self-limited episodes of transient neurologic dysfunction, especially weakness and dysarthria
• Occasionally fixed CNS abnormalities
• Acute, self-limited episodes of transient neurologic dysfunction, especially weakness and dysarthria
• Forearm NCVs are typically in the "intermediate" range of 30-40 m/sec for males; in females NCVs from 30-60 m/sec are seen [
• Median nerve conductions are more severely affected than those of the ulnar nerve [
• Note: NCV can vary from nerve to nerve in a single individual [
## Suggestive Findings
Occasionally fixed CNS abnormalities
Acute, self-limited episodes of transient neurologic dysfunction, especially weakness and dysarthria
Forearm NCVs are typically in the "intermediate" range of 30-40 m/sec for males; in females NCVs from 30-60 m/sec are seen [
Median nerve conductions are more severely affected than those of the ulnar nerve [
Note: NCV can vary from nerve to nerve in a single individual [
• Occasionally fixed CNS abnormalities
• Acute, self-limited episodes of transient neurologic dysfunction, especially weakness and dysarthria
• Occasionally fixed CNS abnormalities
• Acute, self-limited episodes of transient neurologic dysfunction, especially weakness and dysarthria
• Occasionally fixed CNS abnormalities
• Acute, self-limited episodes of transient neurologic dysfunction, especially weakness and dysarthria
• Forearm NCVs are typically in the "intermediate" range of 30-40 m/sec for males; in females NCVs from 30-60 m/sec are seen [
• Median nerve conductions are more severely affected than those of the ulnar nerve [
• Note: NCV can vary from nerve to nerve in a single individual [
## Establishing the Diagnosis
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of CMT1X is broad and overlaps with other forms of CMT, individuals with the findings of peripheral neuropathy described in
Sequence analysis of
An inherited neuropathy
For an introduction to multigene panels click
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Note, disease-associated variants in the upstream regulatory region, 5'UTR, non-coding exons, and 3'UTR are frequently associated with disease; therefore, sequence analysis should include these regions [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Option 1
Sequence analysis of
An inherited neuropathy
For an introduction to multigene panels click
## Option 2
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Note, disease-associated variants in the upstream regulatory region, 5'UTR, non-coding exons, and 3'UTR are frequently associated with disease; therefore, sequence analysis should include these regions [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
Although both men and women are affected, manifestations tend to be less severe in women because of X-chromosome inactivation, as a result of which some women may remain asymptomatic [
Signs and symptoms are those of progressive peripheral motor and sensory neuropathy including sensory loss, weakness and atrophy of the distal muscles of the upper and lower extremities, and loss of deep tendon reflexes. The typical affected adult has bilateral foot drop, symmetric atrophy of muscles below the knee (stork leg appearance),
Mild-to-moderate sensory deficits of position, vibration, and pain/temperature commonly occur in the feet.
MRI changes, seen on both diffusion-weighted and T
Extensor plantar responses [
Hyperreflexia and/or spasticity [
Ataxia with upper motor neuron signs in a large kindred (SCA-X1) [
Vocal cord paresis with dysphonia and dysphagia (reported in 4/8 affected members of a single family) [
Hearing loss (occasionally reported) [
MRI evidence of fixed pathology in CNS myelin [
Reduced cerebellar blood flow on SPECT analysis [
Most affected individuals show abnormalities in visual, brain stem auditory, and/or somatosensory evoked responses (reviewed in
Most
Abnormal motor evoked potentials [
Electron microscopy reveals widened collars of adaxonal Schwann cell cytoplasm and separation of axons from their surrounding myelin sheaths [
Nerve biopsies rarely show nerve hypertrophy or generalized onion bulb formation, findings considered to be typical for demyelinating CMT(e.g., CMT type 1A caused by a duplication of a ~1-MB region of chromosome 17 that includes
Note that the widespread availability of molecular genetic testing has rendered nerve biopsy unnecessary for diagnosis unless genetic testing is unrevealing.
The six variants that have been reported in multiple unrelated individuals with stroke-like episodes and which may confer a higher risk for this phenotype are included in
From a severity standpoint, most pathogenic variants cause a similar phenotype [
The term XL-CMTIn-
See
The overall prevalence of hereditary neuropathies is estimated at 30:100,000 population. More than half of these cases are CMT type 1 (15 to 20:100,000).
CMT1X represents at least 10%-20% of those with the CMT neuropathy (see
• Extensor plantar responses [
• Hyperreflexia and/or spasticity [
• Ataxia with upper motor neuron signs in a large kindred (SCA-X1) [
• Vocal cord paresis with dysphonia and dysphagia (reported in 4/8 affected members of a single family) [
• Hearing loss (occasionally reported) [
• MRI evidence of fixed pathology in CNS myelin [
• Reduced cerebellar blood flow on SPECT analysis [
• Most affected individuals show abnormalities in visual, brain stem auditory, and/or somatosensory evoked responses (reviewed in
• Most
• Abnormal motor evoked potentials [
## Clinical Description
Although both men and women are affected, manifestations tend to be less severe in women because of X-chromosome inactivation, as a result of which some women may remain asymptomatic [
Signs and symptoms are those of progressive peripheral motor and sensory neuropathy including sensory loss, weakness and atrophy of the distal muscles of the upper and lower extremities, and loss of deep tendon reflexes. The typical affected adult has bilateral foot drop, symmetric atrophy of muscles below the knee (stork leg appearance),
Mild-to-moderate sensory deficits of position, vibration, and pain/temperature commonly occur in the feet.
MRI changes, seen on both diffusion-weighted and T
Extensor plantar responses [
Hyperreflexia and/or spasticity [
Ataxia with upper motor neuron signs in a large kindred (SCA-X1) [
Vocal cord paresis with dysphonia and dysphagia (reported in 4/8 affected members of a single family) [
Hearing loss (occasionally reported) [
MRI evidence of fixed pathology in CNS myelin [
Reduced cerebellar blood flow on SPECT analysis [
Most affected individuals show abnormalities in visual, brain stem auditory, and/or somatosensory evoked responses (reviewed in
Most
Abnormal motor evoked potentials [
Electron microscopy reveals widened collars of adaxonal Schwann cell cytoplasm and separation of axons from their surrounding myelin sheaths [
Nerve biopsies rarely show nerve hypertrophy or generalized onion bulb formation, findings considered to be typical for demyelinating CMT(e.g., CMT type 1A caused by a duplication of a ~1-MB region of chromosome 17 that includes
Note that the widespread availability of molecular genetic testing has rendered nerve biopsy unnecessary for diagnosis unless genetic testing is unrevealing.
• Extensor plantar responses [
• Hyperreflexia and/or spasticity [
• Ataxia with upper motor neuron signs in a large kindred (SCA-X1) [
• Vocal cord paresis with dysphonia and dysphagia (reported in 4/8 affected members of a single family) [
• Hearing loss (occasionally reported) [
• MRI evidence of fixed pathology in CNS myelin [
• Reduced cerebellar blood flow on SPECT analysis [
• Most affected individuals show abnormalities in visual, brain stem auditory, and/or somatosensory evoked responses (reviewed in
• Most
• Abnormal motor evoked potentials [
## Genotype-Phenotype Correlations
The six variants that have been reported in multiple unrelated individuals with stroke-like episodes and which may confer a higher risk for this phenotype are included in
From a severity standpoint, most pathogenic variants cause a similar phenotype [
## Nomenclature
The term XL-CMTIn-
See
## Prevalence
The overall prevalence of hereditary neuropathies is estimated at 30:100,000 population. More than half of these cases are CMT type 1 (15 to 20:100,000).
CMT1X represents at least 10%-20% of those with the CMT neuropathy (see
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Metabolic encephalopathy or ischemia due to complications of diabetes mellitus, kidney disease, or liver disease
Neurosarcoidosis [
Lupus and other collagen vascular diseases
Vasculitis
• Metabolic encephalopathy or ischemia due to complications of diabetes mellitus, kidney disease, or liver disease
• Neurosarcoidosis [
• Lupus and other collagen vascular diseases
• Vasculitis
## Management
Individuals with
To establish the extent of disease and needs in an individual diagnosed with CMT1X , the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with CMT1X
To determine extent of weakness & atrophy,
To evaluate for pain
To evaluate for less common fixed manifestations (e.g., spasticity, hyperreflexia, ataxia)
To determine if affected person &/or any family member has had episodes of acute transient neurologic dysfunction
Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Feet for evidence of
Mobility, activities of daily living, & need for adaptive devices
Need for handicapped parking
OT = occupational therapy; PT = physical therapy
Treatment is symptomatic.
Special shoes, including those with good ankle support, may be needed.
Ankle/foot orthoses (AFO) are often required to correct foot drop and aid walking. Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.
Orthopedic surgery may be required to correct severe
Forearm crutches or canes may be required for gait stability. Use of a wheelchair may occasionally be required.
Exercise is encouraged within the individual's capability, as many affected individuals remain physically active.
Treatment is supportive, as these are self-limited. See
Recommended Surveillance for Individuals with CMT1X
Screening neurologic exam focused on motor system & cerebellar function
Eval for pain
PT (gross motor skills) & ADL
OT (fine motor skills) & ADL
ADL = activities of daily living; OT = occupational therapy; PT = physical therapy
Obesity is to be avoided because it makes walking more difficult.
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
Affected individuals should be informed of the small possibility of stroke-like episodes, which appears to be higher in younger individuals with a family history or in individuals who have a variant previously associated with such events (see
Examination of at-risk relatives is recommended since individuals with few manifestations may go unrecognized. Even individuals with few manifestations may benefit from use of orthotics.
It may be appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual when the apparent risk for stroke-like episodes may be higher (family history or a variant previously associated with such episodes; see
See
Search
• To determine extent of weakness & atrophy,
• To evaluate for pain
• To evaluate for less common fixed manifestations (e.g., spasticity, hyperreflexia, ataxia)
• To determine if affected person &/or any family member has had episodes of acute transient neurologic dysfunction
• Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Feet for evidence of
• Mobility, activities of daily living, & need for adaptive devices
• Need for handicapped parking
• Screening neurologic exam focused on motor system & cerebellar function
• Eval for pain
• PT (gross motor skills) & ADL
• OT (fine motor skills) & ADL
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CMT1X , the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with CMT1X
To determine extent of weakness & atrophy,
To evaluate for pain
To evaluate for less common fixed manifestations (e.g., spasticity, hyperreflexia, ataxia)
To determine if affected person &/or any family member has had episodes of acute transient neurologic dysfunction
Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Feet for evidence of
Mobility, activities of daily living, & need for adaptive devices
Need for handicapped parking
OT = occupational therapy; PT = physical therapy
• To determine extent of weakness & atrophy,
• To evaluate for pain
• To evaluate for less common fixed manifestations (e.g., spasticity, hyperreflexia, ataxia)
• To determine if affected person &/or any family member has had episodes of acute transient neurologic dysfunction
• Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Feet for evidence of
• Mobility, activities of daily living, & need for adaptive devices
• Need for handicapped parking
## Treatment of Manifestations
Treatment is symptomatic.
Special shoes, including those with good ankle support, may be needed.
Ankle/foot orthoses (AFO) are often required to correct foot drop and aid walking. Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.
Orthopedic surgery may be required to correct severe
Forearm crutches or canes may be required for gait stability. Use of a wheelchair may occasionally be required.
Exercise is encouraged within the individual's capability, as many affected individuals remain physically active.
Treatment is supportive, as these are self-limited. See
## Neuropathy
Special shoes, including those with good ankle support, may be needed.
Ankle/foot orthoses (AFO) are often required to correct foot drop and aid walking. Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.
Orthopedic surgery may be required to correct severe
Forearm crutches or canes may be required for gait stability. Use of a wheelchair may occasionally be required.
Exercise is encouraged within the individual's capability, as many affected individuals remain physically active.
## Stroke-Like Episodes
Treatment is supportive, as these are self-limited. See
## Surveillance
Recommended Surveillance for Individuals with CMT1X
Screening neurologic exam focused on motor system & cerebellar function
Eval for pain
PT (gross motor skills) & ADL
OT (fine motor skills) & ADL
ADL = activities of daily living; OT = occupational therapy; PT = physical therapy
• Screening neurologic exam focused on motor system & cerebellar function
• Eval for pain
• PT (gross motor skills) & ADL
• OT (fine motor skills) & ADL
## Agents/Circumstances to Avoid
Obesity is to be avoided because it makes walking more difficult.
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
Affected individuals should be informed of the small possibility of stroke-like episodes, which appears to be higher in younger individuals with a family history or in individuals who have a variant previously associated with such events (see
## Evaluation of Relatives at Risk
Examination of at-risk relatives is recommended since individuals with few manifestations may go unrecognized. Even individuals with few manifestations may benefit from use of orthotics.
It may be appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual when the apparent risk for stroke-like episodes may be higher (family history or a variant previously associated with such episodes; see
See
## Therapies Under Investigation
Search
## Genetic Counseling
The father of an affected male will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a
A female proband may have inherited the
Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
If the mother of the proband has a
If the proband represents a simplex case and if the
If the mother of the proband has a
If the father of the proband has a
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
Note: Molecular genetic testing may be able to identify the family member in whom a
Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the
Note: (1) Females who are heterozygous for this X-linked disorder may have no clinical findings of peripheral neuropathy (but an abnormal EMG/NCV); or, more often, have mild-to-moderate signs and symptoms that may progress (see
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adult males who are affected (i.e., hemizygous) or females who are known to be heterozygous or who are at increased risk of being heterozygotes.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a
• A female proband may have inherited the
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
• If the mother of the proband has a
• If the proband represents a simplex case and if the
• If the mother of the proband has a
• If the father of the proband has a
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adult males who are affected (i.e., hemizygous) or females who are known to be heterozygous or who are at increased risk of being heterozygotes.
## Mode of Inheritance
## Risk to Family Members
The father of an affected male will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a
A female proband may have inherited the
Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
If the mother of the proband has a
If the proband represents a simplex case and if the
If the mother of the proband has a
If the father of the proband has a
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
Note: Molecular genetic testing may be able to identify the family member in whom a
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a
• A female proband may have inherited the
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
• If the mother of the proband has a
• If the proband represents a simplex case and if the
• If the mother of the proband has a
• If the father of the proband has a
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
## Heterozygote Detection
Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the
Note: (1) Females who are heterozygous for this X-linked disorder may have no clinical findings of peripheral neuropathy (but an abnormal EMG/NCV); or, more often, have mild-to-moderate signs and symptoms that may progress (see
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adult males who are affected (i.e., hemizygous) or females who are known to be heterozygous or who are at increased risk of being heterozygotes.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adult males who are affected (i.e., hemizygous) or females who are known to be heterozygous or who are at increased risk of being heterozygotes.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
France
Department of Molecular Genetics
University of Antwerp
Antwerp Antwerpen B-2610
Belgium
Institute of Translational and Clinical Research
University of Newcastle upon Tyne
International Centre for Life
Newcastle upon Tyne NE1 3BZ
United Kingdom
France
United Kingdom
•
• France
•
•
•
•
•
•
• Department of Molecular Genetics
• University of Antwerp
• Antwerp Antwerpen B-2610
• Belgium
•
•
•
•
•
•
•
• Institute of Translational and Clinical Research
• University of Newcastle upon Tyne
• International Centre for Life
• Newcastle upon Tyne NE1 3BZ
• United Kingdom
•
•
• France
•
•
•
•
•
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• United Kingdom
•
•
•
## Molecular Genetics
GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes (
Almost all disease-associated variants are predicted to be loss-of-function variants. Some cause Cx32 to traffic inappropriately, thus leading to a failure to form gap junction plaques [
Gap junction-independent mechanisms may also play a role. At least one disease-associated
Notable
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
## Chapter Notes
Charles K Abrams directs a laboratory at the University of Illinois College of Medicine at Chicago (UIC) studying the role of connexins including connexin 32 in the central and peripheral nervous system. A major area of focus is understanding how pathogenic variants in
Dr Abrams acts as a paid consultant for Atheneum Partners, Sarepta Therapeutics, and Stealth Biotherapeutics. Dr Abrams' work on CMT1X is supported by grants from the MDA, CMTA, and NIH.
Charles K Abrams, MD, PhD (2020-present)Thomas D Bird, MD; Seattle VA Medical Center (1998-2020)
25 April 2024 (tb) Revision: add new findings from
20 February 2020 (bp) Comprehensive update posted live
15 April 2010 (me) Comprehensive update posted live
26 June 2007 (me) Comprehensive update posted live
15 April 2005 (me) Comprehensive update posted live
10 April 2003 (me) Comprehensive update posted live
25 August 2000 (me) Comprehensive update posted live
18 June 1998 (pb) Review posted live
April 1996 (tb) Original submission
• 25 April 2024 (tb) Revision: add new findings from
• 20 February 2020 (bp) Comprehensive update posted live
• 15 April 2010 (me) Comprehensive update posted live
• 26 June 2007 (me) Comprehensive update posted live
• 15 April 2005 (me) Comprehensive update posted live
• 10 April 2003 (me) Comprehensive update posted live
• 25 August 2000 (me) Comprehensive update posted live
• 18 June 1998 (pb) Review posted live
• April 1996 (tb) Original submission
## Author Notes
Charles K Abrams directs a laboratory at the University of Illinois College of Medicine at Chicago (UIC) studying the role of connexins including connexin 32 in the central and peripheral nervous system. A major area of focus is understanding how pathogenic variants in
## Acknowledgments
Dr Abrams acts as a paid consultant for Atheneum Partners, Sarepta Therapeutics, and Stealth Biotherapeutics. Dr Abrams' work on CMT1X is supported by grants from the MDA, CMTA, and NIH.
## Author History
Charles K Abrams, MD, PhD (2020-present)Thomas D Bird, MD; Seattle VA Medical Center (1998-2020)
## Revision History
25 April 2024 (tb) Revision: add new findings from
20 February 2020 (bp) Comprehensive update posted live
15 April 2010 (me) Comprehensive update posted live
26 June 2007 (me) Comprehensive update posted live
15 April 2005 (me) Comprehensive update posted live
10 April 2003 (me) Comprehensive update posted live
25 August 2000 (me) Comprehensive update posted live
18 June 1998 (pb) Review posted live
April 1996 (tb) Original submission
• 25 April 2024 (tb) Revision: add new findings from
• 20 February 2020 (bp) Comprehensive update posted live
• 15 April 2010 (me) Comprehensive update posted live
• 26 June 2007 (me) Comprehensive update posted live
• 15 April 2005 (me) Comprehensive update posted live
• 10 April 2003 (me) Comprehensive update posted live
• 25 August 2000 (me) Comprehensive update posted live
• 18 June 1998 (pb) Review posted live
• April 1996 (tb) Original submission
## References
Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
## Published Guidelines / Consensus Statements
Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
## Literature Cited
|
[] |
18/6/1998
|
20/2/2020
|
25/4/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
cmtx5
|
cmtx5
|
[
"CMTX5",
"Rosenberg-Chutorian Syndrome",
"CMTX5",
"Rosenberg-Chutorian Syndrome",
"CMT X5",
"Ribose-phosphate pyrophosphokinase 1",
"PRPS1",
"Charcot-Marie-Tooth Neuropathy X Type 5"
] |
Charcot-Marie-Tooth Neuropathy X Type 5 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Jong-Won Kim, Hee-Jin Kim
|
Summary X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5), part of the spectrum of Diagnosis is based on clinical findings, family history consistent with X-linked inheritance, and identification of a pathogenic variant in CMTX5 is inherited in an X-linked manner. Carrier women have a 50% chance of transmitting the
|
## Diagnosis
X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5), part of the spectrum of
Motor nerve conduction velocities (NCVs) of affected males reveal delayed distal latencies and decreased amplitudes with relatively normal velocities (median motor NCV ≥38 m/s), consistent with an axonal neuropathy.
Compound motor/sensory action potentials are not induced.
Needle electromyography (EMG) reveals polyphasic potentials with a prolonged duration and reduced recruitment pattern.
Pure tone audiograms demonstrate bilateral profound sensorineural hearing loss.
Auditory brain stem response waveforms may not be obtained.
Temporal bone computed tomography reveals no abnormal findings.
Fundoscopic examination shows bilateral optic disc pallor, indicating optic atrophy.
Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100.
Electroretinogram is normal.
PRS enzyme activity in three individuals with CMTX5 was decreased compared to controls [
Note: Because it is difficult to assay PRS1 enzyme activity separately from that of the other two isoforms (PRS2 and PRS3), decrease in PRS enzyme activity is assumed to reflect decreased activity of PRS1, not PRS2 or PRS3.
Molecular Genetic Testing Used in CMTX5
See
See
The ability of the test method used to detect a pathogenic variant that is present in the indicated gene
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Two families reported to date [
Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.
Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
No deletions or duplications of
Note: (1) Carriers are heterozygotes for this X-linked disorder and are not known to be at risk of developing clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the pathogenic variant in an affected male relative or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis and then, if no pathogenic variant is identified, by deletion/duplication analysis.
• Motor nerve conduction velocities (NCVs) of affected males reveal delayed distal latencies and decreased amplitudes with relatively normal velocities (median motor NCV ≥38 m/s), consistent with an axonal neuropathy.
• Compound motor/sensory action potentials are not induced.
• Needle electromyography (EMG) reveals polyphasic potentials with a prolonged duration and reduced recruitment pattern.
• Pure tone audiograms demonstrate bilateral profound sensorineural hearing loss.
• Auditory brain stem response waveforms may not be obtained.
• Temporal bone computed tomography reveals no abnormal findings.
• Fundoscopic examination shows bilateral optic disc pallor, indicating optic atrophy.
• Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100.
• Electroretinogram is normal.
## Clinical Diagnosis
X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5), part of the spectrum of
Motor nerve conduction velocities (NCVs) of affected males reveal delayed distal latencies and decreased amplitudes with relatively normal velocities (median motor NCV ≥38 m/s), consistent with an axonal neuropathy.
Compound motor/sensory action potentials are not induced.
Needle electromyography (EMG) reveals polyphasic potentials with a prolonged duration and reduced recruitment pattern.
Pure tone audiograms demonstrate bilateral profound sensorineural hearing loss.
Auditory brain stem response waveforms may not be obtained.
Temporal bone computed tomography reveals no abnormal findings.
Fundoscopic examination shows bilateral optic disc pallor, indicating optic atrophy.
Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100.
Electroretinogram is normal.
• Motor nerve conduction velocities (NCVs) of affected males reveal delayed distal latencies and decreased amplitudes with relatively normal velocities (median motor NCV ≥38 m/s), consistent with an axonal neuropathy.
• Compound motor/sensory action potentials are not induced.
• Needle electromyography (EMG) reveals polyphasic potentials with a prolonged duration and reduced recruitment pattern.
• Pure tone audiograms demonstrate bilateral profound sensorineural hearing loss.
• Auditory brain stem response waveforms may not be obtained.
• Temporal bone computed tomography reveals no abnormal findings.
• Fundoscopic examination shows bilateral optic disc pallor, indicating optic atrophy.
• Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100.
• Electroretinogram is normal.
## Testing
PRS enzyme activity in three individuals with CMTX5 was decreased compared to controls [
Note: Because it is difficult to assay PRS1 enzyme activity separately from that of the other two isoforms (PRS2 and PRS3), decrease in PRS enzyme activity is assumed to reflect decreased activity of PRS1, not PRS2 or PRS3.
Molecular Genetic Testing Used in CMTX5
See
See
The ability of the test method used to detect a pathogenic variant that is present in the indicated gene
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Two families reported to date [
Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.
Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
No deletions or duplications of
## Molecular Genetic Testing
Molecular Genetic Testing Used in CMTX5
See
See
The ability of the test method used to detect a pathogenic variant that is present in the indicated gene
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Two families reported to date [
Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.
Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
No deletions or duplications of
## Testing Strategy
Note: (1) Carriers are heterozygotes for this X-linked disorder and are not known to be at risk of developing clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the pathogenic variant in an affected male relative or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis and then, if no pathogenic variant is identified, by deletion/duplication analysis.
## Clinical Characteristics
The symptom triad of CMTX5 is peripheral neuropathy, sensorineural hearing loss, and optic neuropathy.
The age at onset of symptoms of peripheral neuropathy ranges from five to 12 years. The initial manifestation is often foot drop or gait disturbance. Deep tendon reflexes are usually absent. Motor signs predominate, but impairment of sensory function may accompany motor dysfunction or develop during disease progression. Lower extremities are affected earlier and more severely than upper extremities.
Typically, boys with CMTX5 have early-onset (prelingual) sensorineural hearing loss.
The age at onset of visual impairment ranged from seven to 20 years.
Affected individuals have normal intellect.
Both peripheral neuropathy and optic neuropathy progress with time. With advancing disease, affected individuals may become dependent on crutches or a wheelchair. There is no evidence that life span is shortened in individuals with CMTX5 [
Across the four disease phenotypes included as
Penetrance is complete for CMTX5.
Prevalence has not been estimated. Two families with CMTX5 have been identified worldwide [
CMTX5 appears to be very rare; however, it may be underdiagnosed as a result of under-recognition by physicians.
## Clinical Description
The symptom triad of CMTX5 is peripheral neuropathy, sensorineural hearing loss, and optic neuropathy.
The age at onset of symptoms of peripheral neuropathy ranges from five to 12 years. The initial manifestation is often foot drop or gait disturbance. Deep tendon reflexes are usually absent. Motor signs predominate, but impairment of sensory function may accompany motor dysfunction or develop during disease progression. Lower extremities are affected earlier and more severely than upper extremities.
Typically, boys with CMTX5 have early-onset (prelingual) sensorineural hearing loss.
The age at onset of visual impairment ranged from seven to 20 years.
Affected individuals have normal intellect.
Both peripheral neuropathy and optic neuropathy progress with time. With advancing disease, affected individuals may become dependent on crutches or a wheelchair. There is no evidence that life span is shortened in individuals with CMTX5 [
## Genotype-Phenotype Correlations
Across the four disease phenotypes included as
## Penetrance
Penetrance is complete for CMTX5.
## Prevalence
Prevalence has not been estimated. Two families with CMTX5 have been identified worldwide [
CMTX5 appears to be very rare; however, it may be underdiagnosed as a result of under-recognition by physicians.
## Genetically Related (Allelic) Disorders
The spectrum of
Major Clinical Findings in
± = variably present ; ID = intellectual disability; SNHL = sensorineural hearing loss
Associated with hyperuricemia, hyperuricosuria
## Differential Diagnosis
See
## Management
To establish the extent of disease and needs in an individual diagnosed with CMTX5, the following evaluations are recommended:
Neurologic examination
Pure tone audiograms, auditory brain stem response test
Evaluation of visual acuity, fundoscopic examination
Consultation with a clinical geneticist and/or genetic counselor
Daily heel cord stretching exercises are desirable to prevent Achilles’ tendon shortening from peripheral neuropathy, which can occur in individuals with CMTX5.
Individuals should be evaluated regularly by a team comprising otologists, ophthalmologists, neurologists, physiatrists, and physical and occupational therapists to determine neurologic status and functional disability. While profound hearing loss begins during infancy, optic neuropathy and peripheral neuropathy in CMTX5 vary in age of onset of manifestations and progression. Thus, regular ophthalmologic and neurologic exams are warranted to monitor symptom development and progression.
Obesity makes walking more difficult.
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
It is appropriate to evaluate at-risk males at birth with detailed audiometry to assure early diagnosis and treatment of hearing loss.
See
Dietary
An open-label clinical trial of SAM in two Australian brothers (ages 14 and 13 in 2010) with Arts syndrome is continuing [J Christodoulou et al, unpublished data; approved by the ethics and drug committees, Children's Hospital at Westmead, Sydney, Australia]. Oral SAM supplementation is presently set at 30 mg/kg/day. The boys appear to have had significant benefit from this therapy based on decreased number of hospitalizations and stabilization of nocturnal BIPAP requirements; however, slight deterioration in their vision has been noted.
Mildly affected carrier females from families with Arts syndrome may also benefit from SAM supplementation in their diet, although this remains to be tested. Whether treatment with SAM supplementation would benefit individuals with allelic disorders (
Search
• Neurologic examination
• Pure tone audiograms, auditory brain stem response test
• Evaluation of visual acuity, fundoscopic examination
• Consultation with a clinical geneticist and/or genetic counselor
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CMTX5, the following evaluations are recommended:
Neurologic examination
Pure tone audiograms, auditory brain stem response test
Evaluation of visual acuity, fundoscopic examination
Consultation with a clinical geneticist and/or genetic counselor
• Neurologic examination
• Pure tone audiograms, auditory brain stem response test
• Evaluation of visual acuity, fundoscopic examination
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
## Prevention of Secondary Complications
Daily heel cord stretching exercises are desirable to prevent Achilles’ tendon shortening from peripheral neuropathy, which can occur in individuals with CMTX5.
## Surveillance
Individuals should be evaluated regularly by a team comprising otologists, ophthalmologists, neurologists, physiatrists, and physical and occupational therapists to determine neurologic status and functional disability. While profound hearing loss begins during infancy, optic neuropathy and peripheral neuropathy in CMTX5 vary in age of onset of manifestations and progression. Thus, regular ophthalmologic and neurologic exams are warranted to monitor symptom development and progression.
## Agents/Circumstances to Avoid
Obesity makes walking more difficult.
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association
## Evaluation of Relatives at Risk
It is appropriate to evaluate at-risk males at birth with detailed audiometry to assure early diagnosis and treatment of hearing loss.
See
## Therapies Under Investigation
Dietary
An open-label clinical trial of SAM in two Australian brothers (ages 14 and 13 in 2010) with Arts syndrome is continuing [J Christodoulou et al, unpublished data; approved by the ethics and drug committees, Children's Hospital at Westmead, Sydney, Australia]. Oral SAM supplementation is presently set at 30 mg/kg/day. The boys appear to have had significant benefit from this therapy based on decreased number of hospitalizations and stabilization of nocturnal BIPAP requirements; however, slight deterioration in their vision has been noted.
Mildly affected carrier females from families with Arts syndrome may also benefit from SAM supplementation in their diet, although this remains to be tested. Whether treatment with SAM supplementation would benefit individuals with allelic disorders (
Search
## Genetic Counseling
CMTX5 is inherited in an X-linked manner.
In a family with more than one affected individual, the mother of an affected male is likely to be an obligate carrier:
A mother who is a carrier may have a
The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
When an affected male is the only affected individual in the family; several possibilities regarding his mother's carrier status need to be considered:
He has a
His mother has a
His mother has a pathogenic variant that she inherited from a maternal female ancestor.
The risk to the sibs of a proband depends on the genetic status of the parents:
If the mother has a pathogenic variant, the chance of transmitting the
If the pathogenic variant cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
No instances of germline mosaicism have been reported, but it remains a possibility.
Carrier testing is possible if the pathogenic variant has been identified in the family.
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
• In a family with more than one affected individual, the mother of an affected male is likely to be an obligate carrier:
• A mother who is a carrier may have a
• The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
• A mother who is a carrier may have a
• The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
• When an affected male is the only affected individual in the family; several possibilities regarding his mother's carrier status need to be considered:
• He has a
• His mother has a
• His mother has a pathogenic variant that she inherited from a maternal female ancestor.
• He has a
• His mother has a
• His mother has a pathogenic variant that she inherited from a maternal female ancestor.
• A mother who is a carrier may have a
• The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
• He has a
• His mother has a
• His mother has a pathogenic variant that she inherited from a maternal female ancestor.
• The risk to the sibs of a proband depends on the genetic status of the parents:
• If the mother has a pathogenic variant, the chance of transmitting the
• If the pathogenic variant cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
• If the mother has a pathogenic variant, the chance of transmitting the
• If the pathogenic variant cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
• No instances of germline mosaicism have been reported, but it remains a possibility.
• If the mother has a pathogenic variant, the chance of transmitting the
• If the pathogenic variant cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
CMTX5 is inherited in an X-linked manner.
## Risk to Family Members
In a family with more than one affected individual, the mother of an affected male is likely to be an obligate carrier:
A mother who is a carrier may have a
The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
When an affected male is the only affected individual in the family; several possibilities regarding his mother's carrier status need to be considered:
He has a
His mother has a
His mother has a pathogenic variant that she inherited from a maternal female ancestor.
The risk to the sibs of a proband depends on the genetic status of the parents:
If the mother has a pathogenic variant, the chance of transmitting the
If the pathogenic variant cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
No instances of germline mosaicism have been reported, but it remains a possibility.
• In a family with more than one affected individual, the mother of an affected male is likely to be an obligate carrier:
• A mother who is a carrier may have a
• The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
• A mother who is a carrier may have a
• The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
• When an affected male is the only affected individual in the family; several possibilities regarding his mother's carrier status need to be considered:
• He has a
• His mother has a
• His mother has a pathogenic variant that she inherited from a maternal female ancestor.
• He has a
• His mother has a
• His mother has a pathogenic variant that she inherited from a maternal female ancestor.
• A mother who is a carrier may have a
• The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
• He has a
• His mother has a
• His mother has a pathogenic variant that she inherited from a maternal female ancestor.
• The risk to the sibs of a proband depends on the genetic status of the parents:
• If the mother has a pathogenic variant, the chance of transmitting the
• If the pathogenic variant cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
• If the mother has a pathogenic variant, the chance of transmitting the
• If the pathogenic variant cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
• No instances of germline mosaicism have been reported, but it remains a possibility.
• If the mother has a pathogenic variant, the chance of transmitting the
• If the pathogenic variant cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
## Carrier Detection
Carrier testing is possible if the pathogenic variant has been identified in the family.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
## Resources
France
Concord Hospital
Building 51
Concord New South Wales 2139
Australia
Department of Molecular Genetics
University of Antwerp
Antwerp Antwerpen B-2610
Belgium
Institute of Translational and Clinical Research
University of Newcastle upon Tyne
International Centre for Life
Newcastle upon Tyne NE1 3BZ
United Kingdom
1 Rue de l'International
BP59
Evry cedex 91002
France
Netherlands
United Kingdom
•
• France
•
•
•
•
• Concord Hospital
• Building 51
• Concord New South Wales 2139
• Australia
•
•
• Department of Molecular Genetics
• University of Antwerp
• Antwerp Antwerpen B-2610
• Belgium
•
•
•
•
•
• Institute of Translational and Clinical Research
• University of Newcastle upon Tyne
• International Centre for Life
• Newcastle upon Tyne NE1 3BZ
• United Kingdom
•
•
• 1 Rue de l'International
• BP59
• Evry cedex 91002
• France
•
•
• Netherlands
•
•
•
•
• United Kingdom
•
•
•
## Molecular Genetics
Charcot-Marie-Tooth Neuropathy X Type 5: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Charcot-Marie-Tooth Neuropathy X Type 5 (
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Observed with an allele frequency of 1.1% (2/185) in control chromosomes of Korean descent [
## Chapter Notes
8 June 2023 (ma) Chapter retired: covered in
6 June 2013 (me) Comprehensive update posted live
18 January 2011 (cd) Revision: additions to therapies under investigation
23 September 2010 (cd) Revision: prenatal testing available clinically
10 June 2010 (cd) Revision: edits to agents and circumstances to avoid
26 August 2008 (cg) Review posted live
3 June 2008 (jwk) Original submission
• 8 June 2023 (ma) Chapter retired: covered in
• 6 June 2013 (me) Comprehensive update posted live
• 18 January 2011 (cd) Revision: additions to therapies under investigation
• 23 September 2010 (cd) Revision: prenatal testing available clinically
• 10 June 2010 (cd) Revision: edits to agents and circumstances to avoid
• 26 August 2008 (cg) Review posted live
• 3 June 2008 (jwk) Original submission
## Revision History
8 June 2023 (ma) Chapter retired: covered in
6 June 2013 (me) Comprehensive update posted live
18 January 2011 (cd) Revision: additions to therapies under investigation
23 September 2010 (cd) Revision: prenatal testing available clinically
10 June 2010 (cd) Revision: edits to agents and circumstances to avoid
26 August 2008 (cg) Review posted live
3 June 2008 (jwk) Original submission
• 8 June 2023 (ma) Chapter retired: covered in
• 6 June 2013 (me) Comprehensive update posted live
• 18 January 2011 (cd) Revision: additions to therapies under investigation
• 23 September 2010 (cd) Revision: prenatal testing available clinically
• 10 June 2010 (cd) Revision: edits to agents and circumstances to avoid
• 26 August 2008 (cg) Review posted live
• 3 June 2008 (jwk) Original submission
## References
## Literature Cited
|
[
"MA Becker. Phosphoribosylpyrophosphate synthetase and the regulation of phosphoribosylpyrophosphate production in human cells.. Prog Nucleic Acid Res Mol Biol 2001;69:115-48",
"FS Cowchock, SW Duckett, LJ Streletz, LJ Graziani, LG Jackson. X-linked motor-sensory neuropathy type-II with deafness and mental retardation: a new disorder.. Am J Med Genet 1985;20:307-15",
"AP de Brouwer, KL Williams, JA Duley, AB van Kuilenburg, SB Nabuurs, M Egmont-Petersen, D Lugtenberg, L Zoetekouw, MJ Banning, M Roeffen, BC Hamel, L Weaving, RA Ouvrier, JA Donald, RA Wevers, J Christodoulou, H van Bokhoven. Arts syndrome is caused by loss-of-function mutations in PRPS1.. Am J Hum Genet 2007;81:507-18",
"N Glick. Dramatic reduction in self-injury in Lesch-Nyhan disease following S-adenosylmethionine administration.. J Inherit Metab Dis. 2006;29:687",
"IG Huttner, ML Kennerson, SW Reddel, D Radovanovic, GA Nicholson. Proof of genetic heterogeneity in X-linked Charcot-Marie-Tooth disease.. Neurology 2006;67:2016-21",
"VV Ionasescu, J Trofatter, JL Haines, AM Summers, R Ionasescu, C Searby. Heterogeneity in X-linked recessive Charcot-Marie-Tooth neuropathy.. Am J Hum Genet 1991;48:1075-83",
"VV Ionasescu, J Trofatter, JL Haines, AM Summers, R Ionasescu, C Searby. X-linked recessive Charcot-Marie-Tooth neuropathy: clinical and genetic study.. Muscle Nerve 1992;15:368-73",
"ML Kennerson, EM Yiu, DT Chuang, A Kidambi, SC Tso, C Ly, R Chaudhry, AP Drew, G Rance, MB Delatycki, S Züchner, MM Ryan, GA Nicholson. A new locus for X-linked dominant Charcot-Marie-Tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene.. Hum Mol Genet. 2013;22:1404-16",
"HJ Kim, SH Hong, CS Ki, BJ Kim, JS Shim, SH Cho, JH Park, JW Kim. A novel locus for X-linked recessive CMT with deafness and optic neuropathy maps to Xq21.32-q24.. Neurology 2005;64:1964-7",
"HJ Kim, KM Sohn, ME Shy, KM Krajewski, M Hwang, JH Park, SY Jang, HH Won, BO Choi, SH Hong, BJ Kim, YL Suh, CS Ki, SY Lee, SH Kim, JW Kim. Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy with hearing loss and optic neuropathy (cmtx5).. Am J Hum Genet 2007;81:552-8",
"X Liu, D Han, J Li, B Han, X Ouyang, J Cheng, X Li, Z Jin, Y Wang, M Bitner-Glindzicz, X Kong, H Xu, A Kantardzhieva, RD Eavey, CE Seidman, JG Seidman, LL Du, ZY Chen, P Dai, M Teng, D Yan, H Yuan. Loss-of-function mutations in the PRPS1 gene cause a type of nonsyndromic X-linked sensorineural deafness, DFN2.. Am J Hum Genet. 2010;86:65-71",
"JM Priest, KH Fischbeck, N Nouri, BJ Keats. A locus for axonal motor-sensory neuropathy with deafness and mental retardation maps to Xq24-q26.. Genomics 1995;29:409-12",
"C Rinaldi, C Grunseich, IF Sevrioukova, A Schindler, I Horkayne-Szakaly, C Lamperti, G Landouré, ML Kennerson, BG Burnett, C Bönnemann, LG Biesecker, D Ghezzi, M Zeviani, KH Fischbeck. Cowchock syndrome is associated with a mutation in apoptosis-inducing factor.. Am J Hum Genet. 2012;91:1095-102",
"RN Rosenberg, A Chutorian. Familial opticoacoustic nerve degeneration and polyneuropathy.. Neurology 1967;17:827-32",
"RJ Torres, FA Mateos, JG Puig, MA Becker. Determination of phosphoribosylpyrophosphate synthetase activity in human cells by a non-isotopic, one step method.. Clin Chim Acta 1996;245:105-12"
] |
26/8/2008
|
6/6/2013
|
18/1/2011
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cockayne
|
cockayne
|
[
"Cockayne Syndrome Type II",
"Cockayne Syndrome Type I",
"Cockayne Syndrome Type III",
"Cerebrooculofacioskeletal (COFS) Syndrome",
"DNA excision repair protein ERCC-6",
"DNA excision repair protein ERCC-8",
"ERCC6",
"ERCC8",
"Cockayne Syndrome"
] |
Cockayne Syndrome
|
Vincent Laugel
|
Summary Cockayne syndrome (referred to as CS in this CS type I is characterized by normal prenatal growth with the onset of growth and developmental abnormalities in the first two years. By the time the disease has become fully manifest, height, weight, and head circumference are far below the fifth percentile. Progressive impairment of vision, hearing, and central and peripheral nervous system function leads to severe disability; death typically occurs in the first or second decade. CS type II is characterized by growth failure at birth, with little or no postnatal neurologic development. Congenital cataracts or other structural anomalies of the eye may be present. Affected children have early postnatal contractures of the spine (kyphosis, scoliosis) and joints. Death usually occurs by age five years. CS type III is a phenotype in which major clinical features associated with CS only become apparent after age two years; growth and/or cognition exceeds the expectations for CS type I. COFS syndrome is characterized by very severe prenatal developmental anomalies (arthrogryposis and microphthalmia). The diagnosis of Cockayne syndrome is established in a proband with biallelic pathogenic variants in Cockayne syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the CS-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.
|
CS type I
CS type II
CS type III
Cerebrooculofacioskeletal (COFS) syndrome
For synonyms and outdated names see
• CS type I
• CS type II
• CS type III
• Cerebrooculofacioskeletal (COFS) syndrome
## Diagnosis
Formal clinical diagnostic criteria originally proposed for Cockayne syndrome (CS) type I [
Cockayne syndrome is characterized by growth failure and multisystemic involvement, with a variable age of onset and rate of progression. Due to the progressive nature of CS, the clinical diagnosis becomes more certain as additional clinical manifestations gradually evolve over time.
To facilitate clinical recognition and follow up, the phenotypic spectrum of CS can be divided into different clinical presentations. Note, however, that among all individuals with CS there is a continuous spectrum of clinical severities and that intermediate phenotypes may arise.
Cockayne syndrome
Postnatal growth failure (height and weight <5th centile by age 2 years)
Progressive microcephaly and neurologic dysfunction manifested as early developmental delay in most individuals, followed by progressive behavioral and intellectual deterioration in all individuals. Brain MRI reveals white matter dysmyelination and cerebral and cerebellar atrophy [
Note: White matter dysmyelination is usually present at disease onset. Cerebral and cerebellar atrophy appear during the course of the disease and worsen over time. Intracranial calcifications may be absent in some individuals, especially during the early stages, but when present typically become more prominent with time.
Cutaneous photosensitivity
Demyelinating peripheral neuropathy diagnosed by nerve conduction testing
Pigmentary retinopathy and/or cataracts
Sensorineural hearing loss
Dental anomalies including dental caries, enamel hypoplasia, and anomalies of tooth number, size, and shape
A characteristic physical appearance of "cachectic dwarfism" with sunken eyes
In an older child when both major criteria are present and at least three minor criteria are present;
In an infant or toddler when both major criteria are present, especially if there is increased cutaneous photosensitivity.
In infants with growth failure at birth and little postnatal increase in height, weight, or head circumference;
When there is little or no postnatal neurologic development;
When congenital cataracts are present.
In children or teenagers with short stature, mild neurologic impairment, and progressive ataxia;
Especially but not exclusively when there is cutaneous photosensitivity.
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic and neuroimaging findings suggest the diagnosis of Cockayne syndrome, molecular genetic testing approaches include use of a
For an introduction to multigene panels click
When the diagnosis of Cockayne syndrome is not considered because an individual has atypical phenotypic features,
Note: If exome sequencing is not diagnostic, an
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cockayne Syndrome
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Assays of DNA repair are performed on skin fibroblasts. The most consistent findings in CS fibroblasts are marked sensitivity to UV radiation and deficient recovery of RNA synthesis following UV damage (i.e., impaired repair of actively transcribed genes, or "transcription-coupled repair") [
• Postnatal growth failure (height and weight <5th centile by age 2 years)
• Progressive microcephaly and neurologic dysfunction manifested as early developmental delay in most individuals, followed by progressive behavioral and intellectual deterioration in all individuals. Brain MRI reveals white matter dysmyelination and cerebral and cerebellar atrophy [
• Note: White matter dysmyelination is usually present at disease onset. Cerebral and cerebellar atrophy appear during the course of the disease and worsen over time. Intracranial calcifications may be absent in some individuals, especially during the early stages, but when present typically become more prominent with time.
• Cutaneous photosensitivity
• Demyelinating peripheral neuropathy diagnosed by nerve conduction testing
• Pigmentary retinopathy and/or cataracts
• Sensorineural hearing loss
• Dental anomalies including dental caries, enamel hypoplasia, and anomalies of tooth number, size, and shape
• A characteristic physical appearance of "cachectic dwarfism" with sunken eyes
• In an older child when both major criteria are present and at least three minor criteria are present;
• In an infant or toddler when both major criteria are present, especially if there is increased cutaneous photosensitivity.
• In infants with growth failure at birth and little postnatal increase in height, weight, or head circumference;
• When there is little or no postnatal neurologic development;
• When congenital cataracts are present.
• In children or teenagers with short stature, mild neurologic impairment, and progressive ataxia;
• Especially but not exclusively when there is cutaneous photosensitivity.
## Suggestive Findings
Cockayne syndrome
Postnatal growth failure (height and weight <5th centile by age 2 years)
Progressive microcephaly and neurologic dysfunction manifested as early developmental delay in most individuals, followed by progressive behavioral and intellectual deterioration in all individuals. Brain MRI reveals white matter dysmyelination and cerebral and cerebellar atrophy [
Note: White matter dysmyelination is usually present at disease onset. Cerebral and cerebellar atrophy appear during the course of the disease and worsen over time. Intracranial calcifications may be absent in some individuals, especially during the early stages, but when present typically become more prominent with time.
Cutaneous photosensitivity
Demyelinating peripheral neuropathy diagnosed by nerve conduction testing
Pigmentary retinopathy and/or cataracts
Sensorineural hearing loss
Dental anomalies including dental caries, enamel hypoplasia, and anomalies of tooth number, size, and shape
A characteristic physical appearance of "cachectic dwarfism" with sunken eyes
In an older child when both major criteria are present and at least three minor criteria are present;
In an infant or toddler when both major criteria are present, especially if there is increased cutaneous photosensitivity.
In infants with growth failure at birth and little postnatal increase in height, weight, or head circumference;
When there is little or no postnatal neurologic development;
When congenital cataracts are present.
In children or teenagers with short stature, mild neurologic impairment, and progressive ataxia;
Especially but not exclusively when there is cutaneous photosensitivity.
• Postnatal growth failure (height and weight <5th centile by age 2 years)
• Progressive microcephaly and neurologic dysfunction manifested as early developmental delay in most individuals, followed by progressive behavioral and intellectual deterioration in all individuals. Brain MRI reveals white matter dysmyelination and cerebral and cerebellar atrophy [
• Note: White matter dysmyelination is usually present at disease onset. Cerebral and cerebellar atrophy appear during the course of the disease and worsen over time. Intracranial calcifications may be absent in some individuals, especially during the early stages, but when present typically become more prominent with time.
• Cutaneous photosensitivity
• Demyelinating peripheral neuropathy diagnosed by nerve conduction testing
• Pigmentary retinopathy and/or cataracts
• Sensorineural hearing loss
• Dental anomalies including dental caries, enamel hypoplasia, and anomalies of tooth number, size, and shape
• A characteristic physical appearance of "cachectic dwarfism" with sunken eyes
• In an older child when both major criteria are present and at least three minor criteria are present;
• In an infant or toddler when both major criteria are present, especially if there is increased cutaneous photosensitivity.
• In infants with growth failure at birth and little postnatal increase in height, weight, or head circumference;
• When there is little or no postnatal neurologic development;
• When congenital cataracts are present.
• In children or teenagers with short stature, mild neurologic impairment, and progressive ataxia;
• Especially but not exclusively when there is cutaneous photosensitivity.
## Establishing the Diagnosis
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic and neuroimaging findings suggest the diagnosis of Cockayne syndrome, molecular genetic testing approaches include use of a
For an introduction to multigene panels click
When the diagnosis of Cockayne syndrome is not considered because an individual has atypical phenotypic features,
Note: If exome sequencing is not diagnostic, an
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cockayne Syndrome
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Assays of DNA repair are performed on skin fibroblasts. The most consistent findings in CS fibroblasts are marked sensitivity to UV radiation and deficient recovery of RNA synthesis following UV damage (i.e., impaired repair of actively transcribed genes, or "transcription-coupled repair") [
## Option 1
When the phenotypic and neuroimaging findings suggest the diagnosis of Cockayne syndrome, molecular genetic testing approaches include use of a
For an introduction to multigene panels click
## Option 2
When the diagnosis of Cockayne syndrome is not considered because an individual has atypical phenotypic features,
Note: If exome sequencing is not diagnostic, an
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Cockayne Syndrome
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Assays of DNA repair are performed on skin fibroblasts. The most consistent findings in CS fibroblasts are marked sensitivity to UV radiation and deficient recovery of RNA synthesis following UV damage (i.e., impaired repair of actively transcribed genes, or "transcription-coupled repair") [
## Clinical Characteristics
Cockayne syndrome is characterized by growth failure, microcephaly, neurodevelopmental delays, cutaneous photosensitivity, sensorial impairment, and dental anomalies [
Before the molecular genetics of Cockayne syndrome was understood, it was thought to have a single, discrete phenotype: classic Cockayne syndrome. Importantly, it is now recognized that Cockayne syndrome spans a continuous phenotypic spectrum without clear thresholds and includes the following but somewhat arbitrary subtypes [
CS type I, the "classic" form
CS type II, a more severe form with symptoms present at birth (overlapping with cerebrooculofacioskeletal syndrome [COFS])
CS type III, a milder form
Cerebrooculofacioskeletal (COFS) syndrome, the most severe end of the phenotypic spectrum of CS, with findings identifiable during fetal life
To date, hundreds of individuals have been identified with Cockayne syndrome and biallelic pathogenic variants in
Cockayne Syndrome: Comparison of Phenotypes by Select Features
COFS = cerebrooculofacioskeletal syndrome; CS = Cockayne syndrome
Based on
Death typically occurs in the first or second decade. The mean age of death is 16 years, although survival into the third decade has been reported [
Children with severe CS have evidence of growth failure at birth, with little or no postnatal neurologic development. Congenital cataracts or other structural anomalies of the eye are present in 30% of individuals. Affected individuals may have some contractures of the spine (kyphosis, scoliosis) and joints in neonatal or early postnatal life. Affected children typically die by age five years [
DNA sequencing has confirmed the diagnosis of CS type III in some individuals who have clinical features associated with CS but whose growth and/or cognition exceeds the expectations for CS type I [
COFS syndrome is the most severe subtype of the CS spectrum and can be identified during fetal life. Similar to individuals with CS type II, individuals with COFS syndrome present with severe prenatal growth failure, severe developmental delay / intellectual disability from birth, axial hypotonia, peripheral hypertonia, and neonatal feeding difficulties. COFS syndrome is additionally defined by the presence of arthrogryposis and usually the combination of extreme congenital microcephaly and congenital cataracts [
COFS syndrome can be recognized during prenatal surveillance and is responsible for cases of spontaneous fetal deaths.
In all forms of Cockayne syndrome, a characteristic "tigroid" pattern of demyelination in the subcortical white matter of the brain and multifocal calcium deposition, with relative preservation of neurons and without senile plaques, amyloid, ubiquitin, or tau deposition, has been observed together with arteriosclerosis [
To date no clear genotype-phenotype correlations for
For individuals with pathogenic variants in
The term "cerebrooculofacioskeletal (COFS) syndrome" and its former synonym, Pena-Shokeir syndrome type II, have been used to refer to a heterogeneous group of disorders characterized by congenital neurogenic arthrogryposis (multiple joint contractures), microcephaly, microphthalmia, and cataracts. The original cases of COFS syndrome, described by
The minimum incidence of CS has been estimated at 2.7 in 1 million births in Western Europe; the disease is probably underdiagnosed [
• CS type I, the "classic" form
• CS type II, a more severe form with symptoms present at birth (overlapping with cerebrooculofacioskeletal syndrome [COFS])
• CS type III, a milder form
• Cerebrooculofacioskeletal (COFS) syndrome, the most severe end of the phenotypic spectrum of CS, with findings identifiable during fetal life
## Clinical Description
Cockayne syndrome is characterized by growth failure, microcephaly, neurodevelopmental delays, cutaneous photosensitivity, sensorial impairment, and dental anomalies [
Before the molecular genetics of Cockayne syndrome was understood, it was thought to have a single, discrete phenotype: classic Cockayne syndrome. Importantly, it is now recognized that Cockayne syndrome spans a continuous phenotypic spectrum without clear thresholds and includes the following but somewhat arbitrary subtypes [
CS type I, the "classic" form
CS type II, a more severe form with symptoms present at birth (overlapping with cerebrooculofacioskeletal syndrome [COFS])
CS type III, a milder form
Cerebrooculofacioskeletal (COFS) syndrome, the most severe end of the phenotypic spectrum of CS, with findings identifiable during fetal life
To date, hundreds of individuals have been identified with Cockayne syndrome and biallelic pathogenic variants in
Cockayne Syndrome: Comparison of Phenotypes by Select Features
COFS = cerebrooculofacioskeletal syndrome; CS = Cockayne syndrome
Based on
Death typically occurs in the first or second decade. The mean age of death is 16 years, although survival into the third decade has been reported [
Children with severe CS have evidence of growth failure at birth, with little or no postnatal neurologic development. Congenital cataracts or other structural anomalies of the eye are present in 30% of individuals. Affected individuals may have some contractures of the spine (kyphosis, scoliosis) and joints in neonatal or early postnatal life. Affected children typically die by age five years [
DNA sequencing has confirmed the diagnosis of CS type III in some individuals who have clinical features associated with CS but whose growth and/or cognition exceeds the expectations for CS type I [
COFS syndrome is the most severe subtype of the CS spectrum and can be identified during fetal life. Similar to individuals with CS type II, individuals with COFS syndrome present with severe prenatal growth failure, severe developmental delay / intellectual disability from birth, axial hypotonia, peripheral hypertonia, and neonatal feeding difficulties. COFS syndrome is additionally defined by the presence of arthrogryposis and usually the combination of extreme congenital microcephaly and congenital cataracts [
COFS syndrome can be recognized during prenatal surveillance and is responsible for cases of spontaneous fetal deaths.
In all forms of Cockayne syndrome, a characteristic "tigroid" pattern of demyelination in the subcortical white matter of the brain and multifocal calcium deposition, with relative preservation of neurons and without senile plaques, amyloid, ubiquitin, or tau deposition, has been observed together with arteriosclerosis [
• CS type I, the "classic" form
• CS type II, a more severe form with symptoms present at birth (overlapping with cerebrooculofacioskeletal syndrome [COFS])
• CS type III, a milder form
• Cerebrooculofacioskeletal (COFS) syndrome, the most severe end of the phenotypic spectrum of CS, with findings identifiable during fetal life
## CS Type I
Death typically occurs in the first or second decade. The mean age of death is 16 years, although survival into the third decade has been reported [
## CS Type II
Children with severe CS have evidence of growth failure at birth, with little or no postnatal neurologic development. Congenital cataracts or other structural anomalies of the eye are present in 30% of individuals. Affected individuals may have some contractures of the spine (kyphosis, scoliosis) and joints in neonatal or early postnatal life. Affected children typically die by age five years [
## CS Type III
DNA sequencing has confirmed the diagnosis of CS type III in some individuals who have clinical features associated with CS but whose growth and/or cognition exceeds the expectations for CS type I [
## COFS Syndrome
COFS syndrome is the most severe subtype of the CS spectrum and can be identified during fetal life. Similar to individuals with CS type II, individuals with COFS syndrome present with severe prenatal growth failure, severe developmental delay / intellectual disability from birth, axial hypotonia, peripheral hypertonia, and neonatal feeding difficulties. COFS syndrome is additionally defined by the presence of arthrogryposis and usually the combination of extreme congenital microcephaly and congenital cataracts [
COFS syndrome can be recognized during prenatal surveillance and is responsible for cases of spontaneous fetal deaths.
## Neuropathology
In all forms of Cockayne syndrome, a characteristic "tigroid" pattern of demyelination in the subcortical white matter of the brain and multifocal calcium deposition, with relative preservation of neurons and without senile plaques, amyloid, ubiquitin, or tau deposition, has been observed together with arteriosclerosis [
## Genotype-Phenotype Correlations
To date no clear genotype-phenotype correlations for
For individuals with pathogenic variants in
## Nomenclature
The term "cerebrooculofacioskeletal (COFS) syndrome" and its former synonym, Pena-Shokeir syndrome type II, have been used to refer to a heterogeneous group of disorders characterized by congenital neurogenic arthrogryposis (multiple joint contractures), microcephaly, microphthalmia, and cataracts. The original cases of COFS syndrome, described by
## Prevalence
The minimum incidence of CS has been estimated at 2.7 in 1 million births in Western Europe; the disease is probably underdiagnosed [
## Genetically Related (Allelic) Disorders
Other phenotypes associated with germline pathogenic variants in
Allelic Disorders
## Differential Diagnosis
The differential diagnosis of Cockayne syndrome (CS) depends on the presenting features of the individual. Abnormalities that suggest alternative diagnoses include congenital anomalies of the face, limbs, heart, or viscera; recurrent infections (other than otitis media or respiratory infections); metabolic or neurologic crises; hematologic abnormality (e.g., anemia, leukopenia); and cancer of any kind.
Disorders to Consider in the Differential Diagnosis of Cockayne Syndrome
AD = autosomal dominant; AR = autosomal recessive; COFS = cerebrooculofacioskeletal syndrome; CS = Cockayne syndrome; Mat = maternal; MOI = mode of inheritance; XL = X-linked
Most leukodystrophies are not associated with growth restriction, with the exception of the severe or "connatal" form of Pelizaeus-Merzbacher disease, in which children may have short stature and poor weight gain.
Genetic testing confirms clinical diagnosis in approximately 60% of affected individuals. Hypomethylation of the imprinted control region 1 (ICR1) at 11p15.5 causes Silver-Russell syndrome (SRS) in 35%-50% of individuals, and maternal uniparental disomy causes SRS in 7%-10% of individuals. Accurate assessment of SRS recurrence requires identification of the causative genetic mechanism in the proband.
Other disorders and acquired conditions include the following:
Profound growth restriction is seen in Dubowitz syndrome (OMIM
Calcifications on brain imaging can be associated with congenital infections (e.g., rubella or toxoplasmosis) and disorders of calcium and phosphate metabolism. These conditions are distinguished from CS by the absence of white matter abnormalities and the distinctive physical appearance observed in individuals with CS.
Growth restriction can also be seen in chromosome disorders and endocrine, metabolic, or gastrointestinal disorders, including malnutrition.
• Profound growth restriction is seen in Dubowitz syndrome (OMIM
• Calcifications on brain imaging can be associated with congenital infections (e.g., rubella or toxoplasmosis) and disorders of calcium and phosphate metabolism. These conditions are distinguished from CS by the absence of white matter abnormalities and the distinctive physical appearance observed in individuals with CS.
• Growth restriction can also be seen in chromosome disorders and endocrine, metabolic, or gastrointestinal disorders, including malnutrition.
## Management
No clinical practice guidelines for Cockayne syndrome (CS) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.
To establish the extent of disease and needs in an individual diagnosed with CS, the evaluations summarized in
Cockayne Syndrome: Recommended Evaluations Following Initial Diagnosis
Measure & plot growth on appropriate growth charts.
Appropriately assess feeding & nutritional status according to specific curves.
To incl motor, adaptive, cognitive & speech-language eval
Eval for early intervention / special education
Brain MRI
Neurologic eval incl assessment of muscle tone
Community or
Social work involvement for parental support
Home nursing referral
CS = Cockayne syndrome; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for CS. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Cockayne Syndrome: Treatment of Manifestations
Feeding support
Gastrostomy tube placement as needed. Note: Avoid rapid ↑ in volume of feeds.
PT to prevent joint contractures
Home safety assessments to prevent falls
Standard treatment(s) per ophthalmologist
Use of sunglasses for lens & retina protection
Hearing aids may be helpful per otolaryngologist.
Cochlear implants may be used.
PT = physical therapy
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine if any changes are needed.
Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Cockayne Syndrome: Recommended Surveillance
Excessive sun exposure should be avoided.
Use of metronidazole should be avoided in any circumstance (risk of severe hepatitis) [
Extra vigilance is needed for opioid and sedative use due to exaggerated response to these types of medications [
Growth hormone (GH) levels in individuals with CS may be elevated or decreased [
See
No individuals with classic or severe CS (types I or II) have been known to reproduce. A successful (but very difficult) pregnancy has been reported in a young woman with mild CS (type III) [
In pregnant women with CS, the limited size of the pelvis and abdomen is the major obstacle to the growth of the fetus and the major threat to pregnancy outcome. Prevention of premature labor and cesarean section under spinal anesthesia are usually needed [
Search
• Measure & plot growth on appropriate growth charts.
• Appropriately assess feeding & nutritional status according to specific curves.
• To incl motor, adaptive, cognitive & speech-language eval
• Eval for early intervention / special education
• Brain MRI
• Neurologic eval incl assessment of muscle tone
• Community or
• Social work involvement for parental support
• Home nursing referral
• Feeding support
• Gastrostomy tube placement as needed. Note: Avoid rapid ↑ in volume of feeds.
• PT to prevent joint contractures
• Home safety assessments to prevent falls
• Standard treatment(s) per ophthalmologist
• Use of sunglasses for lens & retina protection
• Hearing aids may be helpful per otolaryngologist.
• Cochlear implants may be used.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CS, the evaluations summarized in
Cockayne Syndrome: Recommended Evaluations Following Initial Diagnosis
Measure & plot growth on appropriate growth charts.
Appropriately assess feeding & nutritional status according to specific curves.
To incl motor, adaptive, cognitive & speech-language eval
Eval for early intervention / special education
Brain MRI
Neurologic eval incl assessment of muscle tone
Community or
Social work involvement for parental support
Home nursing referral
CS = Cockayne syndrome; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Measure & plot growth on appropriate growth charts.
• Appropriately assess feeding & nutritional status according to specific curves.
• To incl motor, adaptive, cognitive & speech-language eval
• Eval for early intervention / special education
• Brain MRI
• Neurologic eval incl assessment of muscle tone
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for CS. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Cockayne Syndrome: Treatment of Manifestations
Feeding support
Gastrostomy tube placement as needed. Note: Avoid rapid ↑ in volume of feeds.
PT to prevent joint contractures
Home safety assessments to prevent falls
Standard treatment(s) per ophthalmologist
Use of sunglasses for lens & retina protection
Hearing aids may be helpful per otolaryngologist.
Cochlear implants may be used.
PT = physical therapy
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine if any changes are needed.
Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications.
• Feeding support
• Gastrostomy tube placement as needed. Note: Avoid rapid ↑ in volume of feeds.
• PT to prevent joint contractures
• Home safety assessments to prevent falls
• Standard treatment(s) per ophthalmologist
• Use of sunglasses for lens & retina protection
• Hearing aids may be helpful per otolaryngologist.
• Cochlear implants may be used.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine if any changes are needed.
Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Cockayne Syndrome: Recommended Surveillance
## Agents/Circumstances to Avoid
Excessive sun exposure should be avoided.
Use of metronidazole should be avoided in any circumstance (risk of severe hepatitis) [
Extra vigilance is needed for opioid and sedative use due to exaggerated response to these types of medications [
Growth hormone (GH) levels in individuals with CS may be elevated or decreased [
## Evaluation of Relatives at Risk
See
## Pregnancy Management
No individuals with classic or severe CS (types I or II) have been known to reproduce. A successful (but very difficult) pregnancy has been reported in a young woman with mild CS (type III) [
In pregnant women with CS, the limited size of the pelvis and abdomen is the major obstacle to the growth of the fetus and the major threat to pregnancy outcome. Prevention of premature labor and cesarean section under spinal anesthesia are usually needed [
## Therapies Under Investigation
Search
## Genetic Counseling
Cockayne syndrome (CS) is inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygous for an
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CS-related pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a CS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Affected sibs will most likely be recognizable as affected within the first few years of life.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Individuals with CS types I or II are not known to reproduce.
The offspring of an individual with CS type III are obligate heterozygotes (carriers) for a pathogenic variant in
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of individuals known to be heterozygous for a CS-related pathogenic variant, particularly if both partners are of the same ancestral background.
Once the CS-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for an
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CS-related pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a CS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Affected sibs will most likely be recognizable as affected within the first few years of life.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Individuals with CS types I or II are not known to reproduce.
• The offspring of an individual with CS type III are obligate heterozygotes (carriers) for a pathogenic variant in
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals known to be heterozygous for a CS-related pathogenic variant, particularly if both partners are of the same ancestral background.
## Mode of Inheritance
Cockayne syndrome (CS) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for an
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CS-related pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a CS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Affected sibs will most likely be recognizable as affected within the first few years of life.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Individuals with CS types I or II are not known to reproduce.
The offspring of an individual with CS type III are obligate heterozygotes (carriers) for a pathogenic variant in
• The parents of an affected child are presumed to be heterozygous for an
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CS-related pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a CS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Affected sibs will most likely be recognizable as affected within the first few years of life.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Individuals with CS types I or II are not known to reproduce.
• The offspring of an individual with CS type III are obligate heterozygotes (carriers) for a pathogenic variant in
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of individuals known to be heterozygous for a CS-related pathogenic variant, particularly if both partners are of the same ancestral background.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals known to be heterozygous for a CS-related pathogenic variant, particularly if both partners are of the same ancestral background.
## Prenatal Testing and Preimplantation Genetic Testing
Once the CS-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
Netherlands
France
•
• United Kingdom
•
•
• Netherlands
•
•
•
•
• France
•
•
•
•
•
•
•
•
•
•
•
•
•
## Molecular Genetics
Cockayne Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Cockayne Syndrome (
The proteins encoded by
A deficiency of TC-NER is sufficient to explain the cutaneous photosensitivity of individuals with CS. It is unlikely, however, to explain the growth failure and neurodegeneration that typify CS. In contrast to CS, most individuals with
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the author.
Genes from
## Molecular Pathogenesis
The proteins encoded by
A deficiency of TC-NER is sufficient to explain the cutaneous photosensitivity of individuals with CS. It is unlikely, however, to explain the growth failure and neurodegeneration that typify CS. In contrast to CS, most individuals with
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the author.
Genes from
## Chapter Notes
Vincent Laugel (
Dr Laugel is also interested in hearing from clinicians treating families affected by DNA repair and transcription disorders in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
Contact Dr Laugel to inquire about review of
The author wishes to thank "Amy and friends" and "Les P'tits Bouts" family support groups for continuous support.
Vincent Laugel, MD, PhD (2012-present)Martha A Nance, MD; Park Nicollet Clinic (2000-2006) Edward G Neilan, MD, PhD; Children's Hospital Boston (2006-2012)
29 August 2024 (gm) Comprehensive update posted live
29 August 2019 (ha) Comprehensive update posted live
14 June 2012 (me) Comprehensive update posted live
7 March 2006 (me) Comprehensive update posted live
31 July 2003 (me) Comprehensive update posted live
28 December 2000 (me) Review posted live
June 2000 (mn) Original submission
• 29 August 2024 (gm) Comprehensive update posted live
• 29 August 2019 (ha) Comprehensive update posted live
• 14 June 2012 (me) Comprehensive update posted live
• 7 March 2006 (me) Comprehensive update posted live
• 31 July 2003 (me) Comprehensive update posted live
• 28 December 2000 (me) Review posted live
• June 2000 (mn) Original submission
## Author Notes
Vincent Laugel (
Dr Laugel is also interested in hearing from clinicians treating families affected by DNA repair and transcription disorders in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
Contact Dr Laugel to inquire about review of
## Acknowledgements
The author wishes to thank "Amy and friends" and "Les P'tits Bouts" family support groups for continuous support.
## Author History
Vincent Laugel, MD, PhD (2012-present)Martha A Nance, MD; Park Nicollet Clinic (2000-2006) Edward G Neilan, MD, PhD; Children's Hospital Boston (2006-2012)
## Revision History
29 August 2024 (gm) Comprehensive update posted live
29 August 2019 (ha) Comprehensive update posted live
14 June 2012 (me) Comprehensive update posted live
7 March 2006 (me) Comprehensive update posted live
31 July 2003 (me) Comprehensive update posted live
28 December 2000 (me) Review posted live
June 2000 (mn) Original submission
• 29 August 2024 (gm) Comprehensive update posted live
• 29 August 2019 (ha) Comprehensive update posted live
• 14 June 2012 (me) Comprehensive update posted live
• 7 March 2006 (me) Comprehensive update posted live
• 31 July 2003 (me) Comprehensive update posted live
• 28 December 2000 (me) Review posted live
• June 2000 (mn) Original submission
## References
## Literature Cited
|
[] |
28/12/2000
|
29/8/2024
|
24/9/2003
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
coffin-siris
|
coffin-siris
|
[
"Fifth Digit Syndrome",
"Fifth Digit Syndrome",
"AT-rich interactive domain-containing protein 1A",
"AT-rich interactive domain-containing protein 1B",
"AT-rich interactive domain-containing protein 2",
"BRD4-interacting chromatin-remodeling complex-associated protein",
"SWI/SNF complex subunit SMARCC2",
"SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4",
"SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1",
"SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1",
"SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1",
"Transcription factor SOX-11",
"Transcription factor SOX-4",
"Zinc finger protein ubi-d4",
"ARID1A",
"ARID1B",
"ARID2",
"BICRA",
"DPF2",
"SMARCA4",
"SMARCB1",
"SMARCC2",
"SMARCD1",
"SMARCE1",
"SOX11",
"SOX4",
"Coffin-Siris Syndrome"
] |
Coffin-Siris Syndrome
|
Samantha Schrier Vergano, Gijs Santen, Dagmar Wieczorek, Naomichi Matsumoto
|
Summary Classically, Coffin-Siris syndrome (CSS) was characterized by specific dysmorphic features (coarse facies, sparse scalp hair, thick eyebrows with long lashes, wide nasal bridge with broad nasal tip, anteverted nares with thick ala nasi, wide mouth with thick, everted vermilion of the upper and lower lips, and hypertrichosis), the absence or underdevelopment of the fifth digit finger/toe or nail, learning and developmental differences, and various organ system-related anomalies. As genetic technology has evolved, more individuals with subtle physical exam findings are being diagnosed with CSS. The vast majority of affected individuals have developmental delay / intellectual disability, typically in the moderate-to-severe range, although those with mild cognitive impairment or even normal intelligence have more rarely been described. Most affected individuals have feeding difficulties (with ~25%-50% requiring a feeding tube in childhood, some of whom then outgrow it), hypotonia, and frequent infections. About half of affected individuals have epilepsy. Other findings may include skeletal features (joint laxity, scoliosis), hearing impairment (both conductive and sensorineural), eye issues (ptosis, strabismus), congenital heart defects, genitourinary malformations, and behavioral issues (including hyperactivity and/or aggressiveness). The diagnosis of CSS is established in a proband with suggestive findings and a heterozygous pathogenic variant in one of the following 14 known genes identified by molecular genetic testing: CSS is inherited in an autosomal dominant manner; however, most affected individuals have the disorder as the result of a
|
## Diagnosis
No consensus clinical diagnostic criteria for Coffin-Siris syndrome (CCS) have been published.
CSS
Facial features (see
Coarse facies
Sparse scalp hair, particularly in the temporal regions, especially in infancy
Thick eyebrows
Long eyelashes
Wide nasal bridge with broad nasal tip
Anteverted nares with thick ala nasi
A wide mouth with thick, everted vermilion of the upper and lower lips suggestive of coarseness
Fifth digit nail / distal phalanx hypoplasia/aplasia (
Hirsutism/hypertrichosis. Hair growth in atypical areas (e.g., the back) or excessive hair growth on the arms or face
Central hypotonia
Developmental delay (DD) or intellectual disability (ID) of variable degree, most typically in the moderate-to-severe range
The diagnosis of CSS
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic findings suggest the diagnosis of CSS, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
When the diagnosis of CCS has not been considered because an individual has atypical phenotypic features, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Coffin-Siris Syndrome
NA = not applicable
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Mosaic pathogenic variants have been noted for
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Small deletions of chromosome 6q25.3 that include
Only seven individuals with pathogenic variants in this gene have been reported [
Fewer than ten affected individuals have been identified with pathogenic variants in this gene [
Individuals initially ascertained with CSS when younger have been found to have pathogenic variants in
Only two affected individuals with a CCS phenotype have been reported to have pathogenic variants in this gene [
Reevaluation of an individual initially thought to have CSS concluded that findings were more consistent with Nicolaides-Baraitser syndrome [
Evidence indicates that pathogenic variants in
Approximately 80 individuals have been identified to date, and
Only four individuals with a CSS phenotype have been reported to have pathogenic variants in this gene [
Approximately 40% of individuals with CSS do not have a pathogenic variant in one of the known genes [
• Facial features (see
• Coarse facies
• Sparse scalp hair, particularly in the temporal regions, especially in infancy
• Thick eyebrows
• Long eyelashes
• Wide nasal bridge with broad nasal tip
• Anteverted nares with thick ala nasi
• A wide mouth with thick, everted vermilion of the upper and lower lips suggestive of coarseness
• Coarse facies
• Sparse scalp hair, particularly in the temporal regions, especially in infancy
• Thick eyebrows
• Long eyelashes
• Wide nasal bridge with broad nasal tip
• Anteverted nares with thick ala nasi
• A wide mouth with thick, everted vermilion of the upper and lower lips suggestive of coarseness
• Fifth digit nail / distal phalanx hypoplasia/aplasia (
• Hirsutism/hypertrichosis. Hair growth in atypical areas (e.g., the back) or excessive hair growth on the arms or face
• Central hypotonia
• Developmental delay (DD) or intellectual disability (ID) of variable degree, most typically in the moderate-to-severe range
• Coarse facies
• Sparse scalp hair, particularly in the temporal regions, especially in infancy
• Thick eyebrows
• Long eyelashes
• Wide nasal bridge with broad nasal tip
• Anteverted nares with thick ala nasi
• A wide mouth with thick, everted vermilion of the upper and lower lips suggestive of coarseness
## Suggestive Findings
CSS
Facial features (see
Coarse facies
Sparse scalp hair, particularly in the temporal regions, especially in infancy
Thick eyebrows
Long eyelashes
Wide nasal bridge with broad nasal tip
Anteverted nares with thick ala nasi
A wide mouth with thick, everted vermilion of the upper and lower lips suggestive of coarseness
Fifth digit nail / distal phalanx hypoplasia/aplasia (
Hirsutism/hypertrichosis. Hair growth in atypical areas (e.g., the back) or excessive hair growth on the arms or face
Central hypotonia
Developmental delay (DD) or intellectual disability (ID) of variable degree, most typically in the moderate-to-severe range
• Facial features (see
• Coarse facies
• Sparse scalp hair, particularly in the temporal regions, especially in infancy
• Thick eyebrows
• Long eyelashes
• Wide nasal bridge with broad nasal tip
• Anteverted nares with thick ala nasi
• A wide mouth with thick, everted vermilion of the upper and lower lips suggestive of coarseness
• Coarse facies
• Sparse scalp hair, particularly in the temporal regions, especially in infancy
• Thick eyebrows
• Long eyelashes
• Wide nasal bridge with broad nasal tip
• Anteverted nares with thick ala nasi
• A wide mouth with thick, everted vermilion of the upper and lower lips suggestive of coarseness
• Fifth digit nail / distal phalanx hypoplasia/aplasia (
• Hirsutism/hypertrichosis. Hair growth in atypical areas (e.g., the back) or excessive hair growth on the arms or face
• Central hypotonia
• Developmental delay (DD) or intellectual disability (ID) of variable degree, most typically in the moderate-to-severe range
• Coarse facies
• Sparse scalp hair, particularly in the temporal regions, especially in infancy
• Thick eyebrows
• Long eyelashes
• Wide nasal bridge with broad nasal tip
• Anteverted nares with thick ala nasi
• A wide mouth with thick, everted vermilion of the upper and lower lips suggestive of coarseness
## Establishing the Diagnosis
The diagnosis of CSS
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic findings suggest the diagnosis of CSS, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
When the diagnosis of CCS has not been considered because an individual has atypical phenotypic features, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Coffin-Siris Syndrome
NA = not applicable
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Mosaic pathogenic variants have been noted for
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Small deletions of chromosome 6q25.3 that include
Only seven individuals with pathogenic variants in this gene have been reported [
Fewer than ten affected individuals have been identified with pathogenic variants in this gene [
Individuals initially ascertained with CSS when younger have been found to have pathogenic variants in
Only two affected individuals with a CCS phenotype have been reported to have pathogenic variants in this gene [
Reevaluation of an individual initially thought to have CSS concluded that findings were more consistent with Nicolaides-Baraitser syndrome [
Evidence indicates that pathogenic variants in
Approximately 80 individuals have been identified to date, and
Only four individuals with a CSS phenotype have been reported to have pathogenic variants in this gene [
Approximately 40% of individuals with CSS do not have a pathogenic variant in one of the known genes [
## Option 1
When the phenotypic findings suggest the diagnosis of CSS, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
## Option 2
When the diagnosis of CCS has not been considered because an individual has atypical phenotypic features, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Coffin-Siris Syndrome
NA = not applicable
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Mosaic pathogenic variants have been noted for
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Small deletions of chromosome 6q25.3 that include
Only seven individuals with pathogenic variants in this gene have been reported [
Fewer than ten affected individuals have been identified with pathogenic variants in this gene [
Individuals initially ascertained with CSS when younger have been found to have pathogenic variants in
Only two affected individuals with a CCS phenotype have been reported to have pathogenic variants in this gene [
Reevaluation of an individual initially thought to have CSS concluded that findings were more consistent with Nicolaides-Baraitser syndrome [
Evidence indicates that pathogenic variants in
Approximately 80 individuals have been identified to date, and
Only four individuals with a CSS phenotype have been reported to have pathogenic variants in this gene [
Approximately 40% of individuals with CSS do not have a pathogenic variant in one of the known genes [
## Clinical Characteristics
The clinical manifestations of Coffin-Siris syndrome have expanded over the years as greater phenotypic variability has been recognized. Classically, the syndrome was first identified by the absence or underdevelopment of the fifth digit finger/toe or nail. Additional "classic" features have included sparse scalp hair, hypertrichosis, learning and developmental differences, and various organ system-related anomalies. As genetic technology has evolved, more individuals with subtle physical exam findings are being diagnosed with CSS.
To date, at least 550 individuals have been identified with a diagnosis of Coffin-Siris syndrome, including those enrolled in the Coffin-Siris syndrome / BAF complex registry [
Select Features of Coffin-Siris Syndrome
Typically, individuals with a clinical diagnosis of CSS have either aplasia or hypoplasia of the distal phalanx or absence of the nail, classically involving the fifth finger, but other digits may also be affected. Toes can also be affected, where the finding tends to involve multiple digits.
While formal studies of IQ have not yet been conducted, those who have been tested range from mild to severe depending on the gene (i.e., individuals with
On average, children with CSS learn to sit at 12 months, walk at 30 months, and speak their first words at 24 months.
Expressive language is more severely affected than receptive language, with no speech in about 12% of individuals (median age: 10 years). A review of language acquisition in registry-enrolled individuals reported by
26% of individuals had normal speech development (words by 18 months)
<1% had mild development delay (speech by 19-21 months)
13% had moderate speech delay (speech by 22-25 months)
60% had severe speech delay (speech after 25 months)
In a study of 35 adult individuals with CSS, only one presented with absence of ID [
Hypotonia is usually noted in infancy and is typically persistent, although some affected individuals experience improvement with age and therapies.
Infant feeding difficulties may be due to an oral aversion or difficulty feeding in the absence of any evident intestinal malformations. Approximately 25%-50% of reported individuals used a feeding tube, some of whom grew out of it [
Other skeletal findings can include the following:
Hypertrichosis (95%) may appear in areas unexpected for an individual's ancestry (i.e., back, shoulders).
A low anterior hairline is common (75%).
Sparse scalp hair (60%), particularly involving the temporal region. Hair may appear at an appropriate age but may be very thin.
Hernias (10%)
Bone age typically lags about two to three years behind chronologic age.
Primary and secondary dentition is delayed in about 40% of affected individuals.
Pathogenic variants in
An individual with a 4.2-Mb deletion that included (among 14 genes)
Multiple studies have reported the same single individual who has CSS,
It is unknown whether life span in CSS is abnormal. One reported individual is alive at age 69 years [
Phenotype correlations by gene have been seen in individuals with pathogenic variants in
No clinically relevant genotype-phenotype correlations have been identified for
More than 530 individuals with molecularly confirmed CSS have been reported (per the CSS registry). Rough estimates suggest a possible frequency of one in 100,000 births based on known cases, indicating that the diagnosis is still rare. True prevalence is likely higher.
In addition, the identification of a pathogenic variant in
• On average, children with CSS learn to sit at 12 months, walk at 30 months, and speak their first words at 24 months.
• Expressive language is more severely affected than receptive language, with no speech in about 12% of individuals (median age: 10 years). A review of language acquisition in registry-enrolled individuals reported by
• 26% of individuals had normal speech development (words by 18 months)
• <1% had mild development delay (speech by 19-21 months)
• 13% had moderate speech delay (speech by 22-25 months)
• 60% had severe speech delay (speech after 25 months)
• 26% of individuals had normal speech development (words by 18 months)
• <1% had mild development delay (speech by 19-21 months)
• 13% had moderate speech delay (speech by 22-25 months)
• 60% had severe speech delay (speech after 25 months)
• In a study of 35 adult individuals with CSS, only one presented with absence of ID [
• 26% of individuals had normal speech development (words by 18 months)
• <1% had mild development delay (speech by 19-21 months)
• 13% had moderate speech delay (speech by 22-25 months)
• 60% had severe speech delay (speech after 25 months)
• Hypotonia is usually noted in infancy and is typically persistent, although some affected individuals experience improvement with age and therapies.
• Infant feeding difficulties may be due to an oral aversion or difficulty feeding in the absence of any evident intestinal malformations. Approximately 25%-50% of reported individuals used a feeding tube, some of whom grew out of it [
• Hypertrichosis (95%) may appear in areas unexpected for an individual's ancestry (i.e., back, shoulders).
• A low anterior hairline is common (75%).
• Sparse scalp hair (60%), particularly involving the temporal region. Hair may appear at an appropriate age but may be very thin.
• Hernias (10%)
• Bone age typically lags about two to three years behind chronologic age.
• Primary and secondary dentition is delayed in about 40% of affected individuals.
• Pathogenic variants in
• An individual with a 4.2-Mb deletion that included (among 14 genes)
• Multiple studies have reported the same single individual who has CSS,
## Clinical Description
The clinical manifestations of Coffin-Siris syndrome have expanded over the years as greater phenotypic variability has been recognized. Classically, the syndrome was first identified by the absence or underdevelopment of the fifth digit finger/toe or nail. Additional "classic" features have included sparse scalp hair, hypertrichosis, learning and developmental differences, and various organ system-related anomalies. As genetic technology has evolved, more individuals with subtle physical exam findings are being diagnosed with CSS.
To date, at least 550 individuals have been identified with a diagnosis of Coffin-Siris syndrome, including those enrolled in the Coffin-Siris syndrome / BAF complex registry [
Select Features of Coffin-Siris Syndrome
Typically, individuals with a clinical diagnosis of CSS have either aplasia or hypoplasia of the distal phalanx or absence of the nail, classically involving the fifth finger, but other digits may also be affected. Toes can also be affected, where the finding tends to involve multiple digits.
While formal studies of IQ have not yet been conducted, those who have been tested range from mild to severe depending on the gene (i.e., individuals with
On average, children with CSS learn to sit at 12 months, walk at 30 months, and speak their first words at 24 months.
Expressive language is more severely affected than receptive language, with no speech in about 12% of individuals (median age: 10 years). A review of language acquisition in registry-enrolled individuals reported by
26% of individuals had normal speech development (words by 18 months)
<1% had mild development delay (speech by 19-21 months)
13% had moderate speech delay (speech by 22-25 months)
60% had severe speech delay (speech after 25 months)
In a study of 35 adult individuals with CSS, only one presented with absence of ID [
Hypotonia is usually noted in infancy and is typically persistent, although some affected individuals experience improvement with age and therapies.
Infant feeding difficulties may be due to an oral aversion or difficulty feeding in the absence of any evident intestinal malformations. Approximately 25%-50% of reported individuals used a feeding tube, some of whom grew out of it [
Other skeletal findings can include the following:
Hypertrichosis (95%) may appear in areas unexpected for an individual's ancestry (i.e., back, shoulders).
A low anterior hairline is common (75%).
Sparse scalp hair (60%), particularly involving the temporal region. Hair may appear at an appropriate age but may be very thin.
Hernias (10%)
Bone age typically lags about two to three years behind chronologic age.
Primary and secondary dentition is delayed in about 40% of affected individuals.
Pathogenic variants in
An individual with a 4.2-Mb deletion that included (among 14 genes)
Multiple studies have reported the same single individual who has CSS,
It is unknown whether life span in CSS is abnormal. One reported individual is alive at age 69 years [
• On average, children with CSS learn to sit at 12 months, walk at 30 months, and speak their first words at 24 months.
• Expressive language is more severely affected than receptive language, with no speech in about 12% of individuals (median age: 10 years). A review of language acquisition in registry-enrolled individuals reported by
• 26% of individuals had normal speech development (words by 18 months)
• <1% had mild development delay (speech by 19-21 months)
• 13% had moderate speech delay (speech by 22-25 months)
• 60% had severe speech delay (speech after 25 months)
• 26% of individuals had normal speech development (words by 18 months)
• <1% had mild development delay (speech by 19-21 months)
• 13% had moderate speech delay (speech by 22-25 months)
• 60% had severe speech delay (speech after 25 months)
• In a study of 35 adult individuals with CSS, only one presented with absence of ID [
• 26% of individuals had normal speech development (words by 18 months)
• <1% had mild development delay (speech by 19-21 months)
• 13% had moderate speech delay (speech by 22-25 months)
• 60% had severe speech delay (speech after 25 months)
• Hypotonia is usually noted in infancy and is typically persistent, although some affected individuals experience improvement with age and therapies.
• Infant feeding difficulties may be due to an oral aversion or difficulty feeding in the absence of any evident intestinal malformations. Approximately 25%-50% of reported individuals used a feeding tube, some of whom grew out of it [
• Hypertrichosis (95%) may appear in areas unexpected for an individual's ancestry (i.e., back, shoulders).
• A low anterior hairline is common (75%).
• Sparse scalp hair (60%), particularly involving the temporal region. Hair may appear at an appropriate age but may be very thin.
• Hernias (10%)
• Bone age typically lags about two to three years behind chronologic age.
• Primary and secondary dentition is delayed in about 40% of affected individuals.
• Pathogenic variants in
• An individual with a 4.2-Mb deletion that included (among 14 genes)
• Multiple studies have reported the same single individual who has CSS,
## Phenotype Correlations by Gene
Phenotype correlations by gene have been seen in individuals with pathogenic variants in
## Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations have been identified for
## Prevalence
More than 530 individuals with molecularly confirmed CSS have been reported (per the CSS registry). Rough estimates suggest a possible frequency of one in 100,000 births based on known cases, indicating that the diagnosis is still rare. True prevalence is likely higher.
In addition, the identification of a pathogenic variant in
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Phenotypes in addition to classic Coffin-Siris syndrome (CSS) have been associated with germline pathogenic variants in
Allelic Disorders
Typically characterized by males w/severe ID, epilepsy, hypogonadism, hypometabolism, marked obesity, swelling of subcutaneous tissue of face, narrow palpebral fissure, & large but not deformed ears
Females demonstrate some phenotypic overlap w/CSS;
Characterized by sparse scalp hair, prominence of interphalangeal joints & distal phalanges due to ↓ subcutaneous fat, characteristic coarse facial features, microcephaly, seizures, & DD/ID. Nearly 1/3 never develop speech.
Facial features in NCBRS can be similar to those of CSS. Digital findings are helpful in differentiating the disorders: persons w/NCBRS uniquely have prominent interphalangeal joints & do not have hypoplasia of 5th digits.
CSS = Coffin-Siris syndrome; DD = developmental delay; ID = intellectual disability
• Typically characterized by males w/severe ID, epilepsy, hypogonadism, hypometabolism, marked obesity, swelling of subcutaneous tissue of face, narrow palpebral fissure, & large but not deformed ears
• Females demonstrate some phenotypic overlap w/CSS;
• Characterized by sparse scalp hair, prominence of interphalangeal joints & distal phalanges due to ↓ subcutaneous fat, characteristic coarse facial features, microcephaly, seizures, & DD/ID. Nearly 1/3 never develop speech.
• Facial features in NCBRS can be similar to those of CSS. Digital findings are helpful in differentiating the disorders: persons w/NCBRS uniquely have prominent interphalangeal joints & do not have hypoplasia of 5th digits.
## Differential Diagnosis
Genes of interest in the differential diagnosis of Coffin-Siris syndrome (CSS) are listed in
Genes of Interest in the Differential Diagnosis of Coffin-Siris Syndrome
AD = autosomal dominant; ALP = alkaline phosphatase; AR = autosomal recessive; CSS = Coffin-Siris syndrome; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
## Management
Several publications have recommended various medical surveillance guidelines for individuals with Coffin-Siris syndrome (CSS) [
To establish the extent of disease and needs in an individual diagnosed with CSS, the evaluations summarized in
Coffin-Siris Syndrome: Recommended Evaluations Following Initial Diagnosis
To incl brain MRI if clinically indicated
Consider EEG if seizures are a concern.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Assessment for signs & symptoms of knee subluxation, joint laxity, & scoliosis
To incl eval of aspiration risk, oral aversion, & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; AFP = alpha-fetoprotein; ADL = activities of daily living; ASD = autism spectrum disorder; CSS = Coffin-Siris syndrome; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
There is no cure for CSS. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Coffin-Siris Syndrome: Treatment of Manifestations
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Coffin-Siris Syndrome: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitoring of those w/seizures &/or tics as clinically indicated
Assessment for new manifestations such as seizures & tics
ADHD = attention-deficit/hyperactivity disorder; AFP = alpha-fetoprotein; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
Because of the rarity of tumors in CSS, the utility of tumor surveillance is unclear. There have been several reports of individuals with
See
Search
• To incl brain MRI if clinically indicated
• Consider EEG if seizures are a concern.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Assessment for signs & symptoms of knee subluxation, joint laxity, & scoliosis
• To incl eval of aspiration risk, oral aversion, & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support
• Home nursing referral
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitoring of those w/seizures &/or tics as clinically indicated
• Assessment for new manifestations such as seizures & tics
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CSS, the evaluations summarized in
Coffin-Siris Syndrome: Recommended Evaluations Following Initial Diagnosis
To incl brain MRI if clinically indicated
Consider EEG if seizures are a concern.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Assessment for signs & symptoms of knee subluxation, joint laxity, & scoliosis
To incl eval of aspiration risk, oral aversion, & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; AFP = alpha-fetoprotein; ADL = activities of daily living; ASD = autism spectrum disorder; CSS = Coffin-Siris syndrome; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• To incl brain MRI if clinically indicated
• Consider EEG if seizures are a concern.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Assessment for signs & symptoms of knee subluxation, joint laxity, & scoliosis
• To incl eval of aspiration risk, oral aversion, & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for CSS. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Coffin-Siris Syndrome: Treatment of Manifestations
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Neurobehavioral/Psychiatric Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Coffin-Siris Syndrome: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitoring of those w/seizures &/or tics as clinically indicated
Assessment for new manifestations such as seizures & tics
ADHD = attention-deficit/hyperactivity disorder; AFP = alpha-fetoprotein; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
Because of the rarity of tumors in CSS, the utility of tumor surveillance is unclear. There have been several reports of individuals with
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitoring of those w/seizures &/or tics as clinically indicated
• Assessment for new manifestations such as seizures & tics
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Coffin-Siris syndrome (CSS) is an autosomal dominant disorder typically caused by a
Most individuals diagnosed with CSShave the disorder as the result of a
Rarely, an individual diagnosed with CSS has an affected parent.
Transmission of a
Several inherited
If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
* A parent with somatic and gonadal mosaicism for a CSS-causing pathogenic variant may be mildly/minimally affected [
Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotype. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (if a molecular diagnosis has been established in the proband).
In the rare circumstance that a parent of the proband is affected and/or is known to have a CSS-causing pathogenic variant, the risk to the sibs is 50%.
If the proband has a known CSS-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental gonadal mosaicism.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to couples who have had an affected child.
Once the Coffin-Siris syndrome-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal t and preimplantation genetic esting. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals diagnosed with CSShave the disorder as the result of a
• Rarely, an individual diagnosed with CSS has an affected parent.
• Transmission of a
• Several inherited
• Transmission of a
• Several inherited
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• * A parent with somatic and gonadal mosaicism for a CSS-causing pathogenic variant may be mildly/minimally affected [
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• * A parent with somatic and gonadal mosaicism for a CSS-causing pathogenic variant may be mildly/minimally affected [
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotype. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (if a molecular diagnosis has been established in the proband).
• Transmission of a
• Several inherited
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• * A parent with somatic and gonadal mosaicism for a CSS-causing pathogenic variant may be mildly/minimally affected [
• In the rare circumstance that a parent of the proband is affected and/or is known to have a CSS-causing pathogenic variant, the risk to the sibs is 50%.
• If the proband has a known CSS-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental gonadal mosaicism.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to couples who have had an affected child.
## Mode of Inheritance
Coffin-Siris syndrome (CSS) is an autosomal dominant disorder typically caused by a
## Risk to Family Members
Most individuals diagnosed with CSShave the disorder as the result of a
Rarely, an individual diagnosed with CSS has an affected parent.
Transmission of a
Several inherited
If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
* A parent with somatic and gonadal mosaicism for a CSS-causing pathogenic variant may be mildly/minimally affected [
Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotype. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (if a molecular diagnosis has been established in the proband).
In the rare circumstance that a parent of the proband is affected and/or is known to have a CSS-causing pathogenic variant, the risk to the sibs is 50%.
If the proband has a known CSS-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental gonadal mosaicism.
• Most individuals diagnosed with CSShave the disorder as the result of a
• Rarely, an individual diagnosed with CSS has an affected parent.
• Transmission of a
• Several inherited
• Transmission of a
• Several inherited
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• * A parent with somatic and gonadal mosaicism for a CSS-causing pathogenic variant may be mildly/minimally affected [
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• * A parent with somatic and gonadal mosaicism for a CSS-causing pathogenic variant may be mildly/minimally affected [
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotype. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (if a molecular diagnosis has been established in the proband).
• Transmission of a
• Several inherited
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• * A parent with somatic and gonadal mosaicism for a CSS-causing pathogenic variant may be mildly/minimally affected [
• In the rare circumstance that a parent of the proband is affected and/or is known to have a CSS-causing pathogenic variant, the risk to the sibs is 50%.
• If the proband has a known CSS-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental gonadal mosaicism.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to couples who have had an affected child.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to couples who have had an affected child.
## Prenatal Testing and Preimplantation Genetic Testing
Once the Coffin-Siris syndrome-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal t and preimplantation genetic esting. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Sanford Research
•
•
•
•
•
•
•
•
•
•
•
•
• Sanford Research
•
## Molecular Genetics
Coffin-Siris Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Coffin-Siris Syndrome (
Many of the genes identified to be causative of the Coffin-Siris syndrome (CSS) phenotype to date encode human homologs of proteins first identified in yeast and
Coffin-Siris Syndrome: Mechanism of Disease Causation
Genes from
Coffin-Siris Syndrome: Gene-Specific Laboratory Considerations
Genes from
Coffin-Siris Syndrome: Pathogenic Variants Referenced in This
DD = developmental delay
Variants listed in the table have been provided by the authors.
Genes from
## Molecular Pathogenesis
Many of the genes identified to be causative of the Coffin-Siris syndrome (CSS) phenotype to date encode human homologs of proteins first identified in yeast and
Coffin-Siris Syndrome: Mechanism of Disease Causation
Genes from
Coffin-Siris Syndrome: Gene-Specific Laboratory Considerations
Genes from
Coffin-Siris Syndrome: Pathogenic Variants Referenced in This
DD = developmental delay
Variants listed in the table have been provided by the authors.
Genes from
## Chapter Notes
All of the authors of this chapter study the clinical features and molecular basis of Coffin-Siris syndrome (CSS).
Dr Samantha Schrier Vergano at Seattle Children's Hospital is actively involved in clinical research regarding individuals with CSS and runs the CSS clinical registry. She would be happy to communicate with persons who have any questions regarding the diagnosis of CSS or other considerations. Email
Dr Dagmar Wieczorek at the Institute of Human Genetics has long-standing experience in the identification of new genes and signaling pathways related to neurodevelopmental disorders (NDD), autism, and syndromal entities (especially craniofacial malformations). She has more than ten years' experience in the use of next-generation sequencing for the detection of causative genetic variations. She hosts large patient cohorts for the study of NDD. In 2025, she will start as one PI in a natural history study on
Dr Schrier Vergano would like to acknowledge Ashley Vasko, BS, and Catherine Nguyen, MS, who assisted with the 2021 revision of this chapter.
Matthew A Deardorff, MD, PhD; University of Southern California (2013-2025)Naomichi Matsumoto, MD, PhD (2013-present)Gijs Santen, MD, PhD (2013-present)Samantha Schrier Vergano, MD (2013-present)Dagmar Wieczorek, MD (2013-present)Bernd Wollnik, MD; University of Cologne (2013-2025)
15 May 2025 (ma) Comprehensive update posted live
12 May 2016 (ha) Comprehensive update posted live
4 April 2013 (me) Review posted live
19 July 2012 (md) Original submission
• 15 May 2025 (ma) Comprehensive update posted live
• 12 May 2016 (ha) Comprehensive update posted live
• 4 April 2013 (me) Review posted live
• 19 July 2012 (md) Original submission
## Author Notes
All of the authors of this chapter study the clinical features and molecular basis of Coffin-Siris syndrome (CSS).
Dr Samantha Schrier Vergano at Seattle Children's Hospital is actively involved in clinical research regarding individuals with CSS and runs the CSS clinical registry. She would be happy to communicate with persons who have any questions regarding the diagnosis of CSS or other considerations. Email
Dr Dagmar Wieczorek at the Institute of Human Genetics has long-standing experience in the identification of new genes and signaling pathways related to neurodevelopmental disorders (NDD), autism, and syndromal entities (especially craniofacial malformations). She has more than ten years' experience in the use of next-generation sequencing for the detection of causative genetic variations. She hosts large patient cohorts for the study of NDD. In 2025, she will start as one PI in a natural history study on
## Acknowledgments
Dr Schrier Vergano would like to acknowledge Ashley Vasko, BS, and Catherine Nguyen, MS, who assisted with the 2021 revision of this chapter.
## Author History
Matthew A Deardorff, MD, PhD; University of Southern California (2013-2025)Naomichi Matsumoto, MD, PhD (2013-present)Gijs Santen, MD, PhD (2013-present)Samantha Schrier Vergano, MD (2013-present)Dagmar Wieczorek, MD (2013-present)Bernd Wollnik, MD; University of Cologne (2013-2025)
## Revision History
15 May 2025 (ma) Comprehensive update posted live
12 May 2016 (ha) Comprehensive update posted live
4 April 2013 (me) Review posted live
19 July 2012 (md) Original submission
• 15 May 2025 (ma) Comprehensive update posted live
• 12 May 2016 (ha) Comprehensive update posted live
• 4 April 2013 (me) Review posted live
• 19 July 2012 (md) Original submission
## References
## Literature Cited
Coffin-Siris syndrome classic features
Facial features in a one-year-old girl (A), a young adult female (B), and a young adult male (C). Coarse facial features are evident in A but tend to become more apparent as individuals age; these may include thick lips, thick/full eyebrows, and a wide mouth.
Fifth digit hypoplasia of the nail (C) and the terminal phalanx (D)
Fifth toe nail (E) and phalanx (F) aplasia
Photos 1A-1C courtesy of Alison Graham for Positive Exposure and the Coffin-Sirus Syndrome Foundation, 2024.
|
[] |
4/4/2013
|
15/5/2025
|
12/8/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
cohen
|
cohen
|
[
"Intermembrane lipid transfer protein VPS13B",
"VPS13B",
"Cohen Syndrome"
] |
Cohen Syndrome
|
Heng Wang, Marni J Falk, Christine Wensel, Elias I Traboulsi
|
Summary Cohen syndrome is characterized by failure to thrive in infancy and childhood; truncal obesity in the teen years; early-onset hypotonia and developmental delays; microcephaly developing during the first year of life; moderate to profound psychomotor retardation; progressive retinochoroidal dystrophy and high myopia; neutropenia in many with recurrent infections and aphthous ulcers in some; a cheerful disposition; joint hypermobility; and characteristic facial features. The diagnosis of Cohen syndrome is based on clinical findings, but no consensus diagnostic criteria exist. Identification of biallelic pathogenic variants in Cohen syndrome is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Offspring of an individual with Cohen syndrome are obligate heterozygotes (carriers). Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants have been identified in an affected family member.
|
## Diagnosis
Cohen syndrome
Retinal dystrophy appearing by mid-childhood
Progressive high myopia
Acquired microcephaly
Non-progressive intellectual disability and global developmental delay
Hypotonia
Joint hypermobility
Typical Cohen syndrome facial gestalt: thick hair and eyebrows, long eyelashes, wave-shaped palpebral fissures, broad nasal tip, smooth or short philtrum, and hypotonic appearance
Short stature
Small or narrow hands and feet
Truncal obesity appearing in or after mid-childhood
Friendly disposition
Neutropenia
The diagnosis of Cohen syndrome
Retinal dystrophy and high myopia
Microcephaly
Developmental delay
Joint hypermobility
Typical Cohen syndrome facial gestalt
Truncal obesity with slender extremities
Overly sociable behavior
Neutropenia
For an introduction to multigene panels click
Molecular Genetic Testing Used in Cohen Syndrome
See
H Weng, personal observation
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Homozygous or compound heterozygous pathogenic variants are identified in approximately 70% of individuals with Cohen syndrome [
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
• Retinal dystrophy appearing by mid-childhood
• Progressive high myopia
• Acquired microcephaly
• Non-progressive intellectual disability and global developmental delay
• Hypotonia
• Joint hypermobility
• Typical Cohen syndrome facial gestalt: thick hair and eyebrows, long eyelashes, wave-shaped palpebral fissures, broad nasal tip, smooth or short philtrum, and hypotonic appearance
• Short stature
• Small or narrow hands and feet
• Truncal obesity appearing in or after mid-childhood
• Friendly disposition
• Neutropenia
• Retinal dystrophy and high myopia
• Microcephaly
• Developmental delay
• Joint hypermobility
• Typical Cohen syndrome facial gestalt
• Truncal obesity with slender extremities
• Overly sociable behavior
• Neutropenia
• For an introduction to multigene panels click
## Suggestive Findings
Cohen syndrome
Retinal dystrophy appearing by mid-childhood
Progressive high myopia
Acquired microcephaly
Non-progressive intellectual disability and global developmental delay
Hypotonia
Joint hypermobility
Typical Cohen syndrome facial gestalt: thick hair and eyebrows, long eyelashes, wave-shaped palpebral fissures, broad nasal tip, smooth or short philtrum, and hypotonic appearance
Short stature
Small or narrow hands and feet
Truncal obesity appearing in or after mid-childhood
Friendly disposition
Neutropenia
• Retinal dystrophy appearing by mid-childhood
• Progressive high myopia
• Acquired microcephaly
• Non-progressive intellectual disability and global developmental delay
• Hypotonia
• Joint hypermobility
• Typical Cohen syndrome facial gestalt: thick hair and eyebrows, long eyelashes, wave-shaped palpebral fissures, broad nasal tip, smooth or short philtrum, and hypotonic appearance
• Short stature
• Small or narrow hands and feet
• Truncal obesity appearing in or after mid-childhood
• Friendly disposition
• Neutropenia
## Establishing the Diagnosis
The diagnosis of Cohen syndrome
Retinal dystrophy and high myopia
Microcephaly
Developmental delay
Joint hypermobility
Typical Cohen syndrome facial gestalt
Truncal obesity with slender extremities
Overly sociable behavior
Neutropenia
For an introduction to multigene panels click
Molecular Genetic Testing Used in Cohen Syndrome
See
H Weng, personal observation
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Homozygous or compound heterozygous pathogenic variants are identified in approximately 70% of individuals with Cohen syndrome [
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
• Retinal dystrophy and high myopia
• Microcephaly
• Developmental delay
• Joint hypermobility
• Typical Cohen syndrome facial gestalt
• Truncal obesity with slender extremities
• Overly sociable behavior
• Neutropenia
• For an introduction to multigene panels click
## Clinical Characteristics
Phenotypic features of Cohen syndrome among the more than 200 affected individuals reported to date are variable and include progressive retinochoroidal dystrophy and myopia, acquired microcephaly, developmental delay, hypotonia, joint laxity, characteristic facial features, truncal obesity, cheerful disposition, and neutropenia.
Note: Certain statistics presented here are from National Cohen Syndrome Database (NCSD) in which approximately 50% of individuals are Old Order Amish; the diagnosis of Cohen syndrome has been confirmed by molecular genetic testing in the vast majority of individuals.
The progressive myopia and late-onset lens subluxation that occur in some individuals result from progressive laxity of zonules and progressive rounding up of the lens (spherophakia). Older individuals can have tremulousness of the iris (iridodonesis) because of lens subluxation and/or microspherophakia.
More than 70% of individuals in the NCSD fall often or trip easily, most likely because of constriction of peripheral visual fields secondary to retinal degeneration. Among ten individuals from nine families of Italian heritage with Cohen syndrome, 90% had retinal dystrophy and 80% had high myopia [
Other reported ophthalmic features include astigmatism, strabismus, microcornea, microphthalmia, sluggish pupillary reaction, iris atrophy and oval pupil, cataracts, optic atrophy, bull’s-eye maculopathy, coloboma of the retina or lids, congenital ptosis, and exophthalmos [
Timing of Achievement of Developmental Milestones in Cohen Syndrome
Systematic anthropometric and cephalometric analysis of 14 individuals confirmed microcephaly, short philtrum, forward-inclined upper incisors, and maxillary prognathia [
Among individuals in the NCSD, the prevalence of short stature is approximately 65% and delayed puberty 74%; clinical endocrinologic evaluations did not identify explanations for these findings. Adult height in six affected individuals from three families was at or below the 3
Growth hormone deficiency was reported in a girl who was clinically diagnosed with Cohen syndrome [
While cognitive ability varies, the majority of affected individuals fall into the moderate-to-profound range of intellectual disability [
More than 65% of affected individuals experience repeated oral mucosal ulcers and gingival infections, prophylactic granulocyte colony-stimulating factor (G-CSF) therapy has been commonly used in these individuals. The etiology of the neutropenia remains unclear. Bone marrow examination performed by the Finnish groups showed a normocellular or hypercellular marrow, with a left-shifted granulopoiesis in about half of those affected. No hematologic malignancies have been reported.
The frequency and severity of infections in individuals with Cohen syndrome appears to correlate poorly with ANC; individuals with frequent infections have an ANC in the same range as those without increased infections (500-1,200/mm
Other immune disturbances have been observed:
Magnetic resonance imaging (MRI) of 18 individuals with Cohen syndrome found normal gray and white matter signal intensity but a relatively enlarged corpus callosum compared to 26 controls [
Electromyography is reported to be normal [
No genotype-phenotype correlations have been identified.
About 200 individuals have been reported in the literature since the first description by
There is little doubt that Cohen syndrome is one of the more commonly underdiagnosed conditions. An early study by
Cohen syndrome is overrepresented in the Finnish population [
Cohen syndrome is overrepresented in the Amish population. Since the first report of Cohen syndrome in the Ohio Geauga Old Order Amish settlement in 2004 [
## Clinical Description
Phenotypic features of Cohen syndrome among the more than 200 affected individuals reported to date are variable and include progressive retinochoroidal dystrophy and myopia, acquired microcephaly, developmental delay, hypotonia, joint laxity, characteristic facial features, truncal obesity, cheerful disposition, and neutropenia.
Note: Certain statistics presented here are from National Cohen Syndrome Database (NCSD) in which approximately 50% of individuals are Old Order Amish; the diagnosis of Cohen syndrome has been confirmed by molecular genetic testing in the vast majority of individuals.
The progressive myopia and late-onset lens subluxation that occur in some individuals result from progressive laxity of zonules and progressive rounding up of the lens (spherophakia). Older individuals can have tremulousness of the iris (iridodonesis) because of lens subluxation and/or microspherophakia.
More than 70% of individuals in the NCSD fall often or trip easily, most likely because of constriction of peripheral visual fields secondary to retinal degeneration. Among ten individuals from nine families of Italian heritage with Cohen syndrome, 90% had retinal dystrophy and 80% had high myopia [
Other reported ophthalmic features include astigmatism, strabismus, microcornea, microphthalmia, sluggish pupillary reaction, iris atrophy and oval pupil, cataracts, optic atrophy, bull’s-eye maculopathy, coloboma of the retina or lids, congenital ptosis, and exophthalmos [
Timing of Achievement of Developmental Milestones in Cohen Syndrome
Systematic anthropometric and cephalometric analysis of 14 individuals confirmed microcephaly, short philtrum, forward-inclined upper incisors, and maxillary prognathia [
Among individuals in the NCSD, the prevalence of short stature is approximately 65% and delayed puberty 74%; clinical endocrinologic evaluations did not identify explanations for these findings. Adult height in six affected individuals from three families was at or below the 3
Growth hormone deficiency was reported in a girl who was clinically diagnosed with Cohen syndrome [
While cognitive ability varies, the majority of affected individuals fall into the moderate-to-profound range of intellectual disability [
More than 65% of affected individuals experience repeated oral mucosal ulcers and gingival infections, prophylactic granulocyte colony-stimulating factor (G-CSF) therapy has been commonly used in these individuals. The etiology of the neutropenia remains unclear. Bone marrow examination performed by the Finnish groups showed a normocellular or hypercellular marrow, with a left-shifted granulopoiesis in about half of those affected. No hematologic malignancies have been reported.
The frequency and severity of infections in individuals with Cohen syndrome appears to correlate poorly with ANC; individuals with frequent infections have an ANC in the same range as those without increased infections (500-1,200/mm
Other immune disturbances have been observed:
Magnetic resonance imaging (MRI) of 18 individuals with Cohen syndrome found normal gray and white matter signal intensity but a relatively enlarged corpus callosum compared to 26 controls [
Electromyography is reported to be normal [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Nomenclature
## Prevalence
About 200 individuals have been reported in the literature since the first description by
There is little doubt that Cohen syndrome is one of the more commonly underdiagnosed conditions. An early study by
Cohen syndrome is overrepresented in the Finnish population [
Cohen syndrome is overrepresented in the Amish population. Since the first report of Cohen syndrome in the Ohio Geauga Old Order Amish settlement in 2004 [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
There are several disorders for which the phenotype may overlap with Cohen syndrome, particularly in the first year(s) of life. Individuals with Cohen syndrome are often suspected of having the following disorders:
## Management
To establish the extent of disease and needs in an individual diagnosed with Cohen syndrome, the following evaluations are recommended:
Ophthalmologic evaluation to assess visual acuity, position and size of the lens, refractive error, and severity of the retinal dystrophy
Developmental assessment
Hematologic evaluation including a white blood cell count with differential to identify neutropenia
Consultation with a clinical geneticist and/or genetic counselor
Ophthalmologic issues are among the most concerning for families of individuals with Cohen syndrome registered in the National Cohen Syndrome Database. Management includes the following:
Spectacle correction of refractive errors
Low vision assessment with training as needed for the visually impaired
Psychosocial support for affected individuals and their families
Early intervention and physical, occupational, and speech therapy are appropriate to address gross developmental delay, hypotonia, joint hypermobility, and motor clumsiness.
If neutropenia is documented, consideration may be given to the use of granulocyte-colony stimulating factor (G-CSF). In a study reported by
Recurrent infections should be treated per standard therapy.
Annual ophthalmologic evaluation should assess visual acuity, refractive error, cataracts in older individuals, and/or retinal dystrophy.
Annual hematologic evaluation should include complete blood count and differential to assess neutropenia. More frequent monitoring may be needed for individuals with lower ANC or more frequent infections.
Growth and weight gain should be monitored.
Caution should be used regarding medications with the potential to decrease the neutrophil count.
See
Search
Anecdotal reports notwithstanding, pycnogenol, a standard French maritime pine bark extract effective in improving visual acuity in retinal vascular leakage conditions [
• Ophthalmologic evaluation to assess visual acuity, position and size of the lens, refractive error, and severity of the retinal dystrophy
• Developmental assessment
• Hematologic evaluation including a white blood cell count with differential to identify neutropenia
• Consultation with a clinical geneticist and/or genetic counselor
• Spectacle correction of refractive errors
• Low vision assessment with training as needed for the visually impaired
• Psychosocial support for affected individuals and their families
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Cohen syndrome, the following evaluations are recommended:
Ophthalmologic evaluation to assess visual acuity, position and size of the lens, refractive error, and severity of the retinal dystrophy
Developmental assessment
Hematologic evaluation including a white blood cell count with differential to identify neutropenia
Consultation with a clinical geneticist and/or genetic counselor
• Ophthalmologic evaluation to assess visual acuity, position and size of the lens, refractive error, and severity of the retinal dystrophy
• Developmental assessment
• Hematologic evaluation including a white blood cell count with differential to identify neutropenia
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Ophthalmologic issues are among the most concerning for families of individuals with Cohen syndrome registered in the National Cohen Syndrome Database. Management includes the following:
Spectacle correction of refractive errors
Low vision assessment with training as needed for the visually impaired
Psychosocial support for affected individuals and their families
Early intervention and physical, occupational, and speech therapy are appropriate to address gross developmental delay, hypotonia, joint hypermobility, and motor clumsiness.
If neutropenia is documented, consideration may be given to the use of granulocyte-colony stimulating factor (G-CSF). In a study reported by
Recurrent infections should be treated per standard therapy.
• Spectacle correction of refractive errors
• Low vision assessment with training as needed for the visually impaired
• Psychosocial support for affected individuals and their families
## Surveillance
Annual ophthalmologic evaluation should assess visual acuity, refractive error, cataracts in older individuals, and/or retinal dystrophy.
Annual hematologic evaluation should include complete blood count and differential to assess neutropenia. More frequent monitoring may be needed for individuals with lower ANC or more frequent infections.
Growth and weight gain should be monitored.
## Agents/Circumstances to Avoid
Caution should be used regarding medications with the potential to decrease the neutrophil count.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Other
Anecdotal reports notwithstanding, pycnogenol, a standard French maritime pine bark extract effective in improving visual acuity in retinal vascular leakage conditions [
## Genetic Counseling
Cohen syndrome is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier of a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier of a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Cohen syndrome is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier of a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier of a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
## Resources
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
## Molecular Genetics
Cohen Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Cohen Syndrome (
The common pathogenic variant described in the Finnish population is
Affected individuals of Amish descent have been found to be homozygous for both a pathogenic nonsense variant involving a 1-bp insertion (
There is no evidence for a major mutational hot spot in individuals with Cohen syndrome who are of non-Finnish, non-Amish ancestry [
Extensive allelic heterogeneity has now been described in a wide range of ethnic and geographically distributed populations, with more than 100 novel pathogenic variants throughout
Altered splicing or deletion/duplication of
Deletions in
The full-length splice form (
Selected
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Various
Wide expression of
As the Golgi complex is the place where glycosylation of newly synthesized proteins occurs, VPS13B deficiency could lead to glycosylation defects. Indeed,
• The common pathogenic variant described in the Finnish population is
• Affected individuals of Amish descent have been found to be homozygous for both a pathogenic nonsense variant involving a 1-bp insertion (
## References
## Literature Cited
## Chapter Notes
21 July 2016 (sw) Comprehensive update posted live
10 March 2011 (me) Comprehensive update posted live
24 October 2006 (cd) Revision: sequence analysis of the entire coding region clinically available
29 August 2006 (me) Review posted live
18 April 2006 (mjf) Original submission
• 21 July 2016 (sw) Comprehensive update posted live
• 10 March 2011 (me) Comprehensive update posted live
• 24 October 2006 (cd) Revision: sequence analysis of the entire coding region clinically available
• 29 August 2006 (me) Review posted live
• 18 April 2006 (mjf) Original submission
## Author Notes
## Revision History
21 July 2016 (sw) Comprehensive update posted live
10 March 2011 (me) Comprehensive update posted live
24 October 2006 (cd) Revision: sequence analysis of the entire coding region clinically available
29 August 2006 (me) Review posted live
18 April 2006 (mjf) Original submission
• 21 July 2016 (sw) Comprehensive update posted live
• 10 March 2011 (me) Comprehensive update posted live
• 24 October 2006 (cd) Revision: sequence analysis of the entire coding region clinically available
• 29 August 2006 (me) Review posted live
• 18 April 2006 (mjf) Original submission
|
[] |
29/8/2006
|
21/7/2016
|
24/10/2006
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
col4a1-dis
|
col4a1-dis
|
[
"Autosomal Dominant Familial Porencephaly",
"Autosomal Dominant Brain Small-Vessel Disease with Hemorrhage",
"Hereditary Angiopathy with Nephropathy, Aneurysms, and Muscle Cramps (HANAC) Syndrome",
"Tortuosity of Retinal Arteries",
"Nonsyndromic Autosomal Dominant Congenital Cataract",
"Collagen alpha-1(IV) chain",
"COL4A1",
"COL4A1-Related Disorders"
] |
Emmanuelle Plaisier, Pierre Ronco
|
Summary The spectrum of Diagnosis is based on clinical findings and molecular genetic testing of
|
Autosomal dominant familial porencephaly
Autosomal dominant brain small-vessel disease with hemorrhage
Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome
Tortuosity of retinal arteries
Nonsyndromic autosomal dominant congenital cataract
For other genetic causes of these phenotypes see
• Autosomal dominant familial porencephaly
• Autosomal dominant brain small-vessel disease with hemorrhage
• Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome
• Tortuosity of retinal arteries
• Nonsyndromic autosomal dominant congenital cataract
## Diagnosis
A
Porencephaly type 1 [
Brain small-vessel disease with or without ocular anomalies [
HANAC (
Tortuosity of retinal arteries [
Nonsyndromic autosomal dominant congenital cataract [
Neurologic
Infantile hemiplegia
Developmental delay
Migraines with or without aura
Seizures
Dementia
Intellectual disability
Intracerebral hemorrhage at any age including antenatal, neonatal, and recurrent episodes
Ischemic stroke
Typically on neuroimaging: features of brain small-vessel disease (
Ophthalmic
Transient visual loss caused by retinal hemorrhage
Cataract, glaucoma, microphthalmia/anophthalmia
Other systemic findings
Hematuria
Raynaud phenomenon
Supraventricular arrhythmia
Muscle cramps
The diagnosis of a
Molecular testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range pf techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Porencephaly type 1 [
• Brain small-vessel disease with or without ocular anomalies [
• HANAC (
• Tortuosity of retinal arteries [
• Nonsyndromic autosomal dominant congenital cataract [
• Neurologic
• Infantile hemiplegia
• Developmental delay
• Migraines with or without aura
• Seizures
• Dementia
• Intellectual disability
• Intracerebral hemorrhage at any age including antenatal, neonatal, and recurrent episodes
• Ischemic stroke
• Typically on neuroimaging: features of brain small-vessel disease (
• Infantile hemiplegia
• Developmental delay
• Migraines with or without aura
• Seizures
• Dementia
• Intellectual disability
• Intracerebral hemorrhage at any age including antenatal, neonatal, and recurrent episodes
• Ischemic stroke
• Typically on neuroimaging: features of brain small-vessel disease (
• Ophthalmic
• Transient visual loss caused by retinal hemorrhage
• Cataract, glaucoma, microphthalmia/anophthalmia
• Transient visual loss caused by retinal hemorrhage
• Cataract, glaucoma, microphthalmia/anophthalmia
• Other systemic findings
• Hematuria
• Raynaud phenomenon
• Supraventricular arrhythmia
• Muscle cramps
• Hematuria
• Raynaud phenomenon
• Supraventricular arrhythmia
• Muscle cramps
• Infantile hemiplegia
• Developmental delay
• Migraines with or without aura
• Seizures
• Dementia
• Intellectual disability
• Intracerebral hemorrhage at any age including antenatal, neonatal, and recurrent episodes
• Ischemic stroke
• Typically on neuroimaging: features of brain small-vessel disease (
• Transient visual loss caused by retinal hemorrhage
• Cataract, glaucoma, microphthalmia/anophthalmia
• Hematuria
• Raynaud phenomenon
• Supraventricular arrhythmia
• Muscle cramps
• For an introduction to multigene panels click
## Suggestive Findings
A
Porencephaly type 1 [
Brain small-vessel disease with or without ocular anomalies [
HANAC (
Tortuosity of retinal arteries [
Nonsyndromic autosomal dominant congenital cataract [
Neurologic
Infantile hemiplegia
Developmental delay
Migraines with or without aura
Seizures
Dementia
Intellectual disability
Intracerebral hemorrhage at any age including antenatal, neonatal, and recurrent episodes
Ischemic stroke
Typically on neuroimaging: features of brain small-vessel disease (
Ophthalmic
Transient visual loss caused by retinal hemorrhage
Cataract, glaucoma, microphthalmia/anophthalmia
Other systemic findings
Hematuria
Raynaud phenomenon
Supraventricular arrhythmia
Muscle cramps
• Porencephaly type 1 [
• Brain small-vessel disease with or without ocular anomalies [
• HANAC (
• Tortuosity of retinal arteries [
• Nonsyndromic autosomal dominant congenital cataract [
• Neurologic
• Infantile hemiplegia
• Developmental delay
• Migraines with or without aura
• Seizures
• Dementia
• Intellectual disability
• Intracerebral hemorrhage at any age including antenatal, neonatal, and recurrent episodes
• Ischemic stroke
• Typically on neuroimaging: features of brain small-vessel disease (
• Infantile hemiplegia
• Developmental delay
• Migraines with or without aura
• Seizures
• Dementia
• Intellectual disability
• Intracerebral hemorrhage at any age including antenatal, neonatal, and recurrent episodes
• Ischemic stroke
• Typically on neuroimaging: features of brain small-vessel disease (
• Ophthalmic
• Transient visual loss caused by retinal hemorrhage
• Cataract, glaucoma, microphthalmia/anophthalmia
• Transient visual loss caused by retinal hemorrhage
• Cataract, glaucoma, microphthalmia/anophthalmia
• Other systemic findings
• Hematuria
• Raynaud phenomenon
• Supraventricular arrhythmia
• Muscle cramps
• Hematuria
• Raynaud phenomenon
• Supraventricular arrhythmia
• Muscle cramps
• Infantile hemiplegia
• Developmental delay
• Migraines with or without aura
• Seizures
• Dementia
• Intellectual disability
• Intracerebral hemorrhage at any age including antenatal, neonatal, and recurrent episodes
• Ischemic stroke
• Typically on neuroimaging: features of brain small-vessel disease (
• Transient visual loss caused by retinal hemorrhage
• Cataract, glaucoma, microphthalmia/anophthalmia
• Hematuria
• Raynaud phenomenon
• Supraventricular arrhythmia
• Muscle cramps
## Establishing the Diagnosis
The diagnosis of a
Molecular testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range pf techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• For an introduction to multigene panels click
## Clinical Characteristics
Autosomal dominant familial porencephaly related to
The spectrum of neurologic clinical symptoms varies in degree of severity and age of onset, with wide intrafamilial heterogeneity. Typically, affected individuals may present with infantile hemiparesis, seizures, intellectual disability, dystonia, stroke, and migraine. First manifestations (including intracerebral hemorrhages) may occur in previously asymptomatic adults, and MRI brain anomalies can be clinically silent.
Congenital cataract is frequently observed in affected individuals. Retinal arteriolar tortuosity is more rarely associated with porencephaly [
Autosomal dominant brain small-vessel disease with hemorrhage differs from autosomal dominant familial porencephaly by the absence of porencephalic cavities, while brain imaging demonstrates characteristic brain small-vessel involvement, including diffuse periventricular leukoencephalopathy (
Neurologic manifestations are also heterogeneous within families, and vary from infantile hemiparesis with seizure to isolated migraine with aura to absence of clinical symptoms. Single or recurrent intracerebral hemorrhage may occur in non-hypertensive adults who are younger than age 50 years. Such hemorrhages can occur spontaneously, after trauma, or as a result of anticoagulant use; some are fatal. Antenatal intracerebral and intraventricular hemorrhage may be observed using fetal ultrasound examination. Mild cognitive impairment has also been reported in one family [
Concomitant eye anomalies including retinal arteriolar tortuosity, congenital cataract, and/or anterior segment anomalies of the Axenfeld-Rieger type may be observed [
More rarely, systemic symptoms including serum CK elevation with or without muscle cramps [
HANAC (
The small-vessel brain disease of HANAC is usually clinically asymptomatic [
Half of affected individuals have: cerebral small-vessel disease characterized by leukoencephalopathy affecting subcortical, periventricular, or pontine regions; dilated perivascular spaces; lacunar infarcts; and microbleeds. None have porencephaly. Only two of the 14 affected individuals have clinical cerebrovascular symptoms: a minor ischemic stroke and a mild post-traumatic intracerebral hemorrhage while on anticoagulants [
Single or multiple intracranial aneurysms, all located on the carotid siphon, have been observed in six individuals, with no rupture episode (
One family presented with isolated microscopic hematuria (i.e., without proteinuria or hypertension) and intermittent episodes of gross hematuria. Kidney biopsy was normal by light microscopy, but ultrastructural examination disclosed irregular and abnormal thickening of the basement membranes of the tubules, Bowman’s capsule, and interstitial capillaries. Small renal cysts were variably observed.
Three families had renal findings of bilateral cortical and medullary renal cysts without hematuria. Cysts were large, but the overall kidney size was normal (
In individuals with HANAC syndrome with hematuria, ultrastructural examination disclosed irregular and abnormal thickening of the basement membranes of the tubules, Bowman’s capsule, and interstitial capillaries [
In one individual with autosomal dominant porencephaly, focal disruption and a major increase in thickness of the basement membrane of skin capillaries were found [
The number of
However, all six
Penetrance of
Prevalence of
No data on the prevalence of
To date pathogenic variants have been reported in individuals of Dutch, Italian, French, German, American, Chinese, Spanish, and Japanese origin.
• Half of affected individuals have: cerebral small-vessel disease characterized by leukoencephalopathy affecting subcortical, periventricular, or pontine regions; dilated perivascular spaces; lacunar infarcts; and microbleeds. None have porencephaly. Only two of the 14 affected individuals have clinical cerebrovascular symptoms: a minor ischemic stroke and a mild post-traumatic intracerebral hemorrhage while on anticoagulants [
• Single or multiple intracranial aneurysms, all located on the carotid siphon, have been observed in six individuals, with no rupture episode (
• One family presented with isolated microscopic hematuria (i.e., without proteinuria or hypertension) and intermittent episodes of gross hematuria. Kidney biopsy was normal by light microscopy, but ultrastructural examination disclosed irregular and abnormal thickening of the basement membranes of the tubules, Bowman’s capsule, and interstitial capillaries. Small renal cysts were variably observed.
• Three families had renal findings of bilateral cortical and medullary renal cysts without hematuria. Cysts were large, but the overall kidney size was normal (
• In individuals with HANAC syndrome with hematuria, ultrastructural examination disclosed irregular and abnormal thickening of the basement membranes of the tubules, Bowman’s capsule, and interstitial capillaries [
• In one individual with autosomal dominant porencephaly, focal disruption and a major increase in thickness of the basement membrane of skin capillaries were found [
## Clinical Description
Autosomal dominant familial porencephaly related to
The spectrum of neurologic clinical symptoms varies in degree of severity and age of onset, with wide intrafamilial heterogeneity. Typically, affected individuals may present with infantile hemiparesis, seizures, intellectual disability, dystonia, stroke, and migraine. First manifestations (including intracerebral hemorrhages) may occur in previously asymptomatic adults, and MRI brain anomalies can be clinically silent.
Congenital cataract is frequently observed in affected individuals. Retinal arteriolar tortuosity is more rarely associated with porencephaly [
Autosomal dominant brain small-vessel disease with hemorrhage differs from autosomal dominant familial porencephaly by the absence of porencephalic cavities, while brain imaging demonstrates characteristic brain small-vessel involvement, including diffuse periventricular leukoencephalopathy (
Neurologic manifestations are also heterogeneous within families, and vary from infantile hemiparesis with seizure to isolated migraine with aura to absence of clinical symptoms. Single or recurrent intracerebral hemorrhage may occur in non-hypertensive adults who are younger than age 50 years. Such hemorrhages can occur spontaneously, after trauma, or as a result of anticoagulant use; some are fatal. Antenatal intracerebral and intraventricular hemorrhage may be observed using fetal ultrasound examination. Mild cognitive impairment has also been reported in one family [
Concomitant eye anomalies including retinal arteriolar tortuosity, congenital cataract, and/or anterior segment anomalies of the Axenfeld-Rieger type may be observed [
More rarely, systemic symptoms including serum CK elevation with or without muscle cramps [
HANAC (
The small-vessel brain disease of HANAC is usually clinically asymptomatic [
Half of affected individuals have: cerebral small-vessel disease characterized by leukoencephalopathy affecting subcortical, periventricular, or pontine regions; dilated perivascular spaces; lacunar infarcts; and microbleeds. None have porencephaly. Only two of the 14 affected individuals have clinical cerebrovascular symptoms: a minor ischemic stroke and a mild post-traumatic intracerebral hemorrhage while on anticoagulants [
Single or multiple intracranial aneurysms, all located on the carotid siphon, have been observed in six individuals, with no rupture episode (
One family presented with isolated microscopic hematuria (i.e., without proteinuria or hypertension) and intermittent episodes of gross hematuria. Kidney biopsy was normal by light microscopy, but ultrastructural examination disclosed irregular and abnormal thickening of the basement membranes of the tubules, Bowman’s capsule, and interstitial capillaries. Small renal cysts were variably observed.
Three families had renal findings of bilateral cortical and medullary renal cysts without hematuria. Cysts were large, but the overall kidney size was normal (
In individuals with HANAC syndrome with hematuria, ultrastructural examination disclosed irregular and abnormal thickening of the basement membranes of the tubules, Bowman’s capsule, and interstitial capillaries [
In one individual with autosomal dominant porencephaly, focal disruption and a major increase in thickness of the basement membrane of skin capillaries were found [
• Half of affected individuals have: cerebral small-vessel disease characterized by leukoencephalopathy affecting subcortical, periventricular, or pontine regions; dilated perivascular spaces; lacunar infarcts; and microbleeds. None have porencephaly. Only two of the 14 affected individuals have clinical cerebrovascular symptoms: a minor ischemic stroke and a mild post-traumatic intracerebral hemorrhage while on anticoagulants [
• Single or multiple intracranial aneurysms, all located on the carotid siphon, have been observed in six individuals, with no rupture episode (
• One family presented with isolated microscopic hematuria (i.e., without proteinuria or hypertension) and intermittent episodes of gross hematuria. Kidney biopsy was normal by light microscopy, but ultrastructural examination disclosed irregular and abnormal thickening of the basement membranes of the tubules, Bowman’s capsule, and interstitial capillaries. Small renal cysts were variably observed.
• Three families had renal findings of bilateral cortical and medullary renal cysts without hematuria. Cysts were large, but the overall kidney size was normal (
• In individuals with HANAC syndrome with hematuria, ultrastructural examination disclosed irregular and abnormal thickening of the basement membranes of the tubules, Bowman’s capsule, and interstitial capillaries [
• In one individual with autosomal dominant porencephaly, focal disruption and a major increase in thickness of the basement membrane of skin capillaries were found [
## Autosomal Dominant Familial Porencephaly
Autosomal dominant familial porencephaly related to
The spectrum of neurologic clinical symptoms varies in degree of severity and age of onset, with wide intrafamilial heterogeneity. Typically, affected individuals may present with infantile hemiparesis, seizures, intellectual disability, dystonia, stroke, and migraine. First manifestations (including intracerebral hemorrhages) may occur in previously asymptomatic adults, and MRI brain anomalies can be clinically silent.
Congenital cataract is frequently observed in affected individuals. Retinal arteriolar tortuosity is more rarely associated with porencephaly [
## Autosomal Dominant Brain Small-Vessel Disease with Hemorrhage
Autosomal dominant brain small-vessel disease with hemorrhage differs from autosomal dominant familial porencephaly by the absence of porencephalic cavities, while brain imaging demonstrates characteristic brain small-vessel involvement, including diffuse periventricular leukoencephalopathy (
Neurologic manifestations are also heterogeneous within families, and vary from infantile hemiparesis with seizure to isolated migraine with aura to absence of clinical symptoms. Single or recurrent intracerebral hemorrhage may occur in non-hypertensive adults who are younger than age 50 years. Such hemorrhages can occur spontaneously, after trauma, or as a result of anticoagulant use; some are fatal. Antenatal intracerebral and intraventricular hemorrhage may be observed using fetal ultrasound examination. Mild cognitive impairment has also been reported in one family [
Concomitant eye anomalies including retinal arteriolar tortuosity, congenital cataract, and/or anterior segment anomalies of the Axenfeld-Rieger type may be observed [
More rarely, systemic symptoms including serum CK elevation with or without muscle cramps [
## HANAC Syndrome
HANAC (
The small-vessel brain disease of HANAC is usually clinically asymptomatic [
Half of affected individuals have: cerebral small-vessel disease characterized by leukoencephalopathy affecting subcortical, periventricular, or pontine regions; dilated perivascular spaces; lacunar infarcts; and microbleeds. None have porencephaly. Only two of the 14 affected individuals have clinical cerebrovascular symptoms: a minor ischemic stroke and a mild post-traumatic intracerebral hemorrhage while on anticoagulants [
Single or multiple intracranial aneurysms, all located on the carotid siphon, have been observed in six individuals, with no rupture episode (
One family presented with isolated microscopic hematuria (i.e., without proteinuria or hypertension) and intermittent episodes of gross hematuria. Kidney biopsy was normal by light microscopy, but ultrastructural examination disclosed irregular and abnormal thickening of the basement membranes of the tubules, Bowman’s capsule, and interstitial capillaries. Small renal cysts were variably observed.
Three families had renal findings of bilateral cortical and medullary renal cysts without hematuria. Cysts were large, but the overall kidney size was normal (
• Half of affected individuals have: cerebral small-vessel disease characterized by leukoencephalopathy affecting subcortical, periventricular, or pontine regions; dilated perivascular spaces; lacunar infarcts; and microbleeds. None have porencephaly. Only two of the 14 affected individuals have clinical cerebrovascular symptoms: a minor ischemic stroke and a mild post-traumatic intracerebral hemorrhage while on anticoagulants [
• Single or multiple intracranial aneurysms, all located on the carotid siphon, have been observed in six individuals, with no rupture episode (
• One family presented with isolated microscopic hematuria (i.e., without proteinuria or hypertension) and intermittent episodes of gross hematuria. Kidney biopsy was normal by light microscopy, but ultrastructural examination disclosed irregular and abnormal thickening of the basement membranes of the tubules, Bowman’s capsule, and interstitial capillaries. Small renal cysts were variably observed.
• Three families had renal findings of bilateral cortical and medullary renal cysts without hematuria. Cysts were large, but the overall kidney size was normal (
## Additional Findings in
In individuals with HANAC syndrome with hematuria, ultrastructural examination disclosed irregular and abnormal thickening of the basement membranes of the tubules, Bowman’s capsule, and interstitial capillaries [
In one individual with autosomal dominant porencephaly, focal disruption and a major increase in thickness of the basement membrane of skin capillaries were found [
• In individuals with HANAC syndrome with hematuria, ultrastructural examination disclosed irregular and abnormal thickening of the basement membranes of the tubules, Bowman’s capsule, and interstitial capillaries [
• In one individual with autosomal dominant porencephaly, focal disruption and a major increase in thickness of the basement membrane of skin capillaries were found [
## Genotype-Phenotype Correlations
The number of
However, all six
## Penetrance
Penetrance of
## Prevalence
Prevalence of
No data on the prevalence of
To date pathogenic variants have been reported in individuals of Dutch, Italian, French, German, American, Chinese, Spanish, and Japanese origin.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
C terminus pathogenic variants in
## Management
To establish the extent of disease and needs in an individual diagnosed with
Brain MRI including T
Brain angiographic CT scan
Ophthalmologic examination including fundoscopic examination and slit-lamp examination
Kidney and liver ultrasound examination or CT
Measurement of serum CK concentration
Measurement of serum creatinine concentration and estimation of the glomerular filtration rate
Evaluation for the presence of hematuria
Electrocardiogram (EKG); echocardiography and ambulatory EKG monitoring in individuals presenting with palpitations
Consultation with a clinical geneticist and/or genetic counselor
Hypertensive individuals must be treated to reduce the global risk of stroke.
Supportive care including practical help, emotional support, and counseling are appropriate for affected individuals and their families.
No specific support exists for individuals with
Seizures are managed using standard protocols.
Cataract surgery may be required for individuals with severe lens opacities.
Glaucoma is initially treated with topical anti-glaucoma medication. Surgery is reserved for eyes that do not respond to medical therapy.
Symptomatic paroxysmal supraventricular arrhythmia should be treated with antiarrhythmic drugs (beta blockers).
Surgical or endovascular treatment should be discussed for asymptomatic intracranial aneurysms >10.0 mm in diameter.
Avoidance of anticoagulant exposure and activities that involve an increased risk for head trauma may decrease the risk for intracerebral hemorrhage.
See
The interval at which individuals with
Annual clinical evaluation is reasonable.
Regular brain imaging can be proposed, especially to evaluate the size of asymptomatic cerebral aneurysms.
The following should be avoided:
Smoking because it increases the global risk of stroke
Hypertension because it increases the risk of stroke
Sustained head pressure during birth or postnatal physical activities that may cause head trauma [
Anticoagulant use [
See
Cesarean delivery for pregnancies in which the fetus is at risk for a
Search
• Brain MRI including T
• Brain angiographic CT scan
• Ophthalmologic examination including fundoscopic examination and slit-lamp examination
• Kidney and liver ultrasound examination or CT
• Measurement of serum CK concentration
• Measurement of serum creatinine concentration and estimation of the glomerular filtration rate
• Evaluation for the presence of hematuria
• Electrocardiogram (EKG); echocardiography and ambulatory EKG monitoring in individuals presenting with palpitations
• Consultation with a clinical geneticist and/or genetic counselor
• Seizures are managed using standard protocols.
• Cataract surgery may be required for individuals with severe lens opacities.
• Glaucoma is initially treated with topical anti-glaucoma medication. Surgery is reserved for eyes that do not respond to medical therapy.
• Symptomatic paroxysmal supraventricular arrhythmia should be treated with antiarrhythmic drugs (beta blockers).
• Surgical or endovascular treatment should be discussed for asymptomatic intracranial aneurysms >10.0 mm in diameter.
• Smoking because it increases the global risk of stroke
• Hypertension because it increases the risk of stroke
• Sustained head pressure during birth or postnatal physical activities that may cause head trauma [
• Anticoagulant use [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Brain MRI including T
Brain angiographic CT scan
Ophthalmologic examination including fundoscopic examination and slit-lamp examination
Kidney and liver ultrasound examination or CT
Measurement of serum CK concentration
Measurement of serum creatinine concentration and estimation of the glomerular filtration rate
Evaluation for the presence of hematuria
Electrocardiogram (EKG); echocardiography and ambulatory EKG monitoring in individuals presenting with palpitations
Consultation with a clinical geneticist and/or genetic counselor
• Brain MRI including T
• Brain angiographic CT scan
• Ophthalmologic examination including fundoscopic examination and slit-lamp examination
• Kidney and liver ultrasound examination or CT
• Measurement of serum CK concentration
• Measurement of serum creatinine concentration and estimation of the glomerular filtration rate
• Evaluation for the presence of hematuria
• Electrocardiogram (EKG); echocardiography and ambulatory EKG monitoring in individuals presenting with palpitations
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Hypertensive individuals must be treated to reduce the global risk of stroke.
Supportive care including practical help, emotional support, and counseling are appropriate for affected individuals and their families.
No specific support exists for individuals with
Seizures are managed using standard protocols.
Cataract surgery may be required for individuals with severe lens opacities.
Glaucoma is initially treated with topical anti-glaucoma medication. Surgery is reserved for eyes that do not respond to medical therapy.
Symptomatic paroxysmal supraventricular arrhythmia should be treated with antiarrhythmic drugs (beta blockers).
Surgical or endovascular treatment should be discussed for asymptomatic intracranial aneurysms >10.0 mm in diameter.
• Seizures are managed using standard protocols.
• Cataract surgery may be required for individuals with severe lens opacities.
• Glaucoma is initially treated with topical anti-glaucoma medication. Surgery is reserved for eyes that do not respond to medical therapy.
• Symptomatic paroxysmal supraventricular arrhythmia should be treated with antiarrhythmic drugs (beta blockers).
• Surgical or endovascular treatment should be discussed for asymptomatic intracranial aneurysms >10.0 mm in diameter.
## Prevention of Primary Manifestations
Avoidance of anticoagulant exposure and activities that involve an increased risk for head trauma may decrease the risk for intracerebral hemorrhage.
## Prevention of Secondary Complications
See
## Surveillance
The interval at which individuals with
Annual clinical evaluation is reasonable.
Regular brain imaging can be proposed, especially to evaluate the size of asymptomatic cerebral aneurysms.
## Agents/Circumstances to Avoid
The following should be avoided:
Smoking because it increases the global risk of stroke
Hypertension because it increases the risk of stroke
Sustained head pressure during birth or postnatal physical activities that may cause head trauma [
Anticoagulant use [
• Smoking because it increases the global risk of stroke
• Hypertension because it increases the risk of stroke
• Sustained head pressure during birth or postnatal physical activities that may cause head trauma [
• Anticoagulant use [
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Cesarean delivery for pregnancies in which the fetus is at risk for a
## Therapies Under Investigation
Search
## Genetic Counseling
At least 50% of individuals diagnosed with a
A proband with a
Recommendations for the evaluation of parents of a proband with an apparent
If the
The family history of some individuals diagnosed with a
The risk to the sibs of the proband depends on the genetic status of the proband’s parents: if a parent of the proband is affected, the risk to the sibs is 50%.
Although penetrance of
The sibs of a proband with clinically unaffected parents are still at increased risk (for the disorder) because of the possibility of reduced penetrance in a parent.
If the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• At least 50% of individuals diagnosed with a
• A proband with a
• Recommendations for the evaluation of parents of a proband with an apparent
• If the
• The family history of some individuals diagnosed with a
• The risk to the sibs of the proband depends on the genetic status of the proband’s parents: if a parent of the proband is affected, the risk to the sibs is 50%.
• Although penetrance of
• The sibs of a proband with clinically unaffected parents are still at increased risk (for the disorder) because of the possibility of reduced penetrance in a parent.
• If the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
## Risk to Family Members
At least 50% of individuals diagnosed with a
A proband with a
Recommendations for the evaluation of parents of a proband with an apparent
If the
The family history of some individuals diagnosed with a
The risk to the sibs of the proband depends on the genetic status of the proband’s parents: if a parent of the proband is affected, the risk to the sibs is 50%.
Although penetrance of
The sibs of a proband with clinically unaffected parents are still at increased risk (for the disorder) because of the possibility of reduced penetrance in a parent.
If the
• At least 50% of individuals diagnosed with a
• A proband with a
• Recommendations for the evaluation of parents of a proband with an apparent
• If the
• The family history of some individuals diagnosed with a
• The risk to the sibs of the proband depends on the genetic status of the proband’s parents: if a parent of the proband is affected, the risk to the sibs is 50%.
• Although penetrance of
• The sibs of a proband with clinically unaffected parents are still at increased risk (for the disorder) because of the possibility of reduced penetrance in a parent.
• If the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
CHRU de Montpellier - Hôpital Arnaud de Villeneuve
371, Avenue du Doyen Gaston Giraud
France
Canada
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•
•
•
•
•
•
• CHRU de Montpellier - Hôpital Arnaud de Villeneuve
• 371, Avenue du Doyen Gaston Giraud
• France
•
•
• Canada
•
•
•
•
•
## Molecular Genetics
COL4A1-Related Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for COL4A1-Related Disorders (
Selected
Variants listed in the table have been provided by the authors.
## Chapter Notes
7 July 2016 (ha) Comprehensive update posted live
8 March 2011 (me) Comprehensive update posted live
25 June 2009 (et) Review posted live
27 February 2009 (ep) Original submission
• 7 July 2016 (ha) Comprehensive update posted live
• 8 March 2011 (me) Comprehensive update posted live
• 25 June 2009 (et) Review posted live
• 27 February 2009 (ep) Original submission
## Revision History
7 July 2016 (ha) Comprehensive update posted live
8 March 2011 (me) Comprehensive update posted live
25 June 2009 (et) Review posted live
27 February 2009 (ep) Original submission
• 7 July 2016 (ha) Comprehensive update posted live
• 8 March 2011 (me) Comprehensive update posted live
• 25 June 2009 (et) Review posted live
• 27 February 2009 (ep) Original submission
## References
## Literature Cited
Spectrum of brain imaging abnormalities in
A. Axial FLAIR showing right paraventricular porencephalic cyst and extensive white-matter abnormalities [
B. Axial FLAIR showing diffuse periventricular leukoencephalopathy and dilated perivascular space in the basal ganglia [
C. Deep intracerebral hemorrhage [
D. Angio CT scan in a patient with HANAC syndrome showing two aneurysms located in the intracranial portion of the right carotid artery [
Abdominal MRI showing bilateral renal cysts in a patient with HANAC syndrome [
Fluorescein angiography showing typical retinal arteriolar tortuosity (arrows) in a patient with HANAC syndrome [
|
[
"S Alamowitch, E Plaisier, P Favrole, C Prost, Z Chen, T Van Agtmael, B Marro, P Ronco. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome.. Neurology 2009;73:1873-82",
"X Ayrignac, C Carra-Dalliere, N Menjot de Champfleur, C Denier, P Aubourg, C Bellesme, G Castelnovo, J Pelletier, B Audoin, E Kaphan, J de Seze, N Collongues, F Blanc, JB Chanson, E Magnin, E Berger, S Vukusic, F Durand-Dubief, JP Camdessanche, M Cohen, C Lebrun-Frenay, D Brassat, M Clanet, P Vermersch, H Zephir, O Outteryck, S Wiertlewski, DA Laplaud, JC Ouallet, B Brochet, C Goizet, M Debouverie, S Pittion, G Edan, V Deburghgraeve, E Le Page, C Verny, P Amati-Bonneau, D Bonneau, D Hannequin, L Guyant-Maréchal, N Derache, GL Defer, T Moreau, M Giroud, AM Guennoc, P Clavelou, F Taithe, S Mathis, JP Neau, L Magy, JL Devoize, M Bataillard, J Masliah-Planchon, I Dorboz, E Tournier-Lasserve, T Levade, O Boespflug Tanguy, P Labauge. Adult-onset genetic leukoencephalopathies: A MRI pattern-based approach in a comprehensive study of 154 patients.. Brain 2015;138:284-92",
"G Breedveld, RF de Coo, MH Lequin, WFM Arts, P Heuting, DB Gould, SWM John, B Oostra, GMS Mancini. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly.. J Med Genet 2006;43:490-5",
"N Chassaing, A Causse, A Vigouroux, A Delahaye, JL Alessandri, O Boespflug-Tanguy, O Boute-Benejean, H Dollfus, B Duban-Bedu, B Gilbert-Dussardier, F Giuliano, M Gonzales, M Holder-Espinasse, B Isidor, ML Jacquemont, D Lacombe, D Martin-Coignard, M Mathieu-Dramard, S Odent, O Picone, L Pinson, C Quelin, S Sigaudy, A Toutain, C Thauvin-Robinet, J Kaplan, P Calvas. Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia.. Clin Genet 2014;86:326-34",
"I Coupry, I Sibon, B Mortemousque, F Rouanet, M Mine, C Goizet. Ophthalmological features associated with COL4A1 mutations.. Arch Ophthalmol. 2010;128:483-9",
"DP Gale, DD Oygar, F Lin, PD Oygar, N Khan, TM Connor, M Lapsley, PH Maxwell, GH Neild. A novel COL4A1 frameshift mutation in familial kidney disease: the importance of the C-terminal NC1 domain of type IV collagen.. Nephrol Dial Transplant. 2016;31:1908-14",
"DB Gould, FC Phalan, GJ Breedveld. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly.. Science 2005;308:1167-71",
"DB Gould, FC Phalan, SE van Mil, JP Sundberg, K Vahedi, P Massin, MG Bousser, P Heuting, JH Miner, E Tournier-Lasserve, SWM John. Role of COL4A1 in small-vessel disease and hemorrhagic stroke.. N Engl J Med 2006;354:1489-96",
"B Gunda, M Mine, T Kovács, C Hornyák, D Bereczki, G Várallyay, G Rudas, MP Audrezet, E Tournier-Lasserve. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy.. J Neurol. 2014;261:500-3",
"M Jeanne, C Labelle-Dumais, J Jorgensen, WB Kauffman, GM Mancini, J Favor, V Valant, SM Greenberg, J Rosand, DB Gould. COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.. Am J Hum Genet 2012;90:91-101",
"J Jen, AH Cohen, Q Yue, JT Stout, HV Vinters, S Nelson, RW Baloh. Hereditary endotheliopathy with retinopathy, nephropathy, and stroke. Neurology 1997;49:1322-30",
"S John, L Jehi, EM Manno, DS Conway, K Uchino. COL4A1 gene mutation--beyond a vascular syndrome.. Seizure 2015;31:19-21",
"A Joutel, C Corpechot, A Ducros, K Vahedi, H Chabriat, P Mouton, S Alamowitch, V Domenga, M Cécillion, E Marechal, J Maciazek, C Vayssiere, C Cruaud, EA Cabanis, MM Ruchoux, J Weissenbach, JF Bach, MG Bousser, E Tournier-Lasserve. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.. Nature 1996;383:707-10",
"J Livingston, D Doherty, S Orcesi, D Tonduti, A Piechiecchio, R La Piana, E Tournier-Lasserve, A Majumdar, S Tomkins, G Rice, R Kneen, M van der Knaap, Y Crow. COL4A1 mutations associated with a characteristic pattern of intracranial calcification.. Neuropediatrics. 2011;42:227-33",
"ME Meuwissen, DJ Halley, LS Smit, MH Lequin, JM Cobben, R de Coo, J van Harssel, S Sallevelt, G Woldringh, MS van der Knaap, LS de Vries, GM Mancini. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature.. Genet Med 2015;17:843-53",
"RA Ophoff, J DeYoung, SK Service. Hereditary vascular retinopathy, cerebrovascular vasculopathy, and hereditary endotheliopathy with retinopathy, nephropathy, and stroke map to a single locus on chromosome 3p21.1-p21.3. Am J Hum Genet 2001;69:447-53",
"E Plaisier, Z Chen, F Gekeler, S Benhassine, K Dahan, B Marro, S Alamowitch, M Paques, P Ronco. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain.. Am J Med Genet A. 2010;152A:2550-5",
"E Plaisier, O Gribouval, S Alamowitch, B Mougenot, C Prost, MC Verpont, B Marro, T Desmettre, SY Cohen, E Roullet, M Dracon, M Fardeau, T Van Agtmael, D Kerjaschki, C Antignac, P Ronco. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps.. N Engl J Med. 2007;357:2687-95",
"A Richards, AM van den Maagdenberg, JC Jen, D Kavanagh, P Bertram, D Spitzer, MK Liszewski, ML Barilla-Labarca, GM Terwindt, Y Kasai, M McLellan, MG Grand, KR Vanmolkot, B de Vries, J Wan, MJ Kane, H Mamsa, R Schafer, AH Stam, J Haan, PT de Jong, CW Storimans, MJ van Schooneveld, JA Oosterhuis, A Gschwendter, M Dichgans, KE Kotschet, S Hodgkinson, TA Hardy, MB Delatycki, RA Hajj-Ali, PH Kothari, SF Nelson, RR Frants, RW Baloh, MD Ferrari, JP Atkinson. C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy.. Nat Genet 2007;39:1068-70",
"E Rødahl, PM Knappskog, J Majewski, S Johansson, W Telstad, J Kråkenes, H Boman. Variants of anterior segment dysgenesis and cerebral involvement in a large family with a novel COL4A1 mutation.. Am J Ophthalmol 2013;155:946-53",
"S Shah, S Ellard, R Kneen, M Lim, N Osborne, J Rankin, N Stoodley, M van der Knaap, A Whitney, P Jardine. Childhood presentation of COL4A1 mutations.. Dev Med Child Neurol 2012;54:569-74",
"S Shah, Y Kumar, B McLean, A Churchill, N Stoodley, J Rankin, P Rizzu, M van der Knaap, P. Jardine. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly.. Eur J Paediatr Neurol. 2010;14:182-7",
"I Sibon, I Coupry, P Menegon, JP Bouchet, P Gorry, I Burgelin, P Calvas, I Orignac, V Dousset, D Lacombe, JM Orgogozo, B Arveiler, C Goizet. COL4A1 mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke.. Ann Neurol 2007;62:177-84",
"K Vahedi, N Kubi, M Boukobza, M Arnoult, P Massin, DB Gould, E Tournier-Lasserve, MG Bousser. COL4A1 mutation in patient with sporadic recurrent intracerebral hemorrhage.. Stroke 2007;38:1461-4",
"MS van der Knaap, LM Smit, F Barkhof, YA Pijnenburg, S Zweegman, HW Niessen, S Imhof, P Heutink. Neonatal porencephaly and adult stroke related to mutations in collagen IV A1.. Ann Neurol 2006;59:504-11",
"E Verbeek, ME Meuwissen, FW Verheijen, PP Govaert, DJ Licht, DS Kuo, CJ Poulton, R Schot, MH Lequin, J Dudink, DJ Halley, RI de Coo, JC den Hollander, R Oegema, DB Gould, GM Mancini. COL4A2 mutation associated with familial porencephaly and small-vessel disease.. Eur J Hum Genet 2012;20:844-51",
"XY Xia, N Li, X Cao, QY Wu, TF Li, C Zhang, WW Li, YX Cui, XJ Li, CY Xue. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family.. BMC Med Genet 2014;15:97",
"Y Yoneda, K Haginoya, H Arai, S Yamaoka, Y Tsurusaki, H Doi, N Miyake, K Yokochi, H Osaka, M Kato, N Matsumoto, H Saitsu. De novo and inherited mutations in COL4A2, encoding the type IV collagen α2 chain cause porencephaly.. Am J Hum Genet 2012;90:86-90",
"Y Yoneda, K Haginoya, M Kato, H Osaka, K Yokochi, H Arai, A Kakita, T Yamamoto, Y Otsuki, S Shimizu, T Wada, N Koyama, Y Mino, N Kondo, S Takahashi, S Hirabayashi, J Takanashi, A Okumura, T Kumagai, S Hirai, M Nabetani, S Saitoh, A Hattori, M Yamasaki, A Kumakura, Y Sugo, K Nishiyama, S Miyatake, Y Tsurusaki, H Doi, N Miyake, N Matsumoto, H Saitsu. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly.. Ann Neurol 2013;73:48-57",
"JC Zenteno, J Crespi, B Buentello-Volante, JA Buil, F Bassaganyas, JI Vela-Segarra, J Diaz-Cascjosa, MT Marieges. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity.. Graefes Arch Clin Exp Ophthalmol 2014;252:1789-94"
] |
25/6/2009
|
7/7/2016
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
collagen-2
|
collagen-2
|
[
"Achondrogenesis Type II",
"Stickler Syndrome Type 1",
"Kniest Dysplasia",
"Spondyloepiphyseal Dysplasia Congenita (SEDC)",
"Platyspondylic Dysplasia, Torrance Type",
"Spondyloperipheral Dysplasia",
"Spondyloepimetaphyseal Dysplasia (SEMD), Strudwick Type",
"Hypochondrogenesis",
"Spondyloepiphyseal Dysplasia with Metatarsal shortening",
"Collagen alpha-1(II) chain",
"COL2A1",
"Type II Collagen Disorders",
"Overview"
] |
Type II Collagen Disorders Overview
|
Pernille Axél Gregersen, Ravi Savarirayan
|
Summary The purpose of this Describe the Provide an Review the Review Inform
|
## Clinical Characteristics of Type II Collagen Disorders
Type II collagen is an essential component of the cartilage extracellular matrix, and of major importance in endochondral bone formation, growth, and normal joint function. It is also necessary for normal development and function of the eye and the inner ear. Type II collagen disorders encompass a diverse group of clinical phenotypes characterized by skeletal dysplasia, ocular manifestations (e.g., cataract, myopia, subluxation of the lens, vitreous abnormalities, retinal detachment), hearing impairment, and orofacial features [
The spectrum of severity ranges from severe perinatal-lethal disorders to milder conditions presenting in adulthood with premature arthrosis as the primary feature. Considerable phenotypic overlap notwithstanding, discriminating features can aid in the specific diagnosis (see
Achondrogenesis,
Hypochondrogenesis,
Platyspondylic dysplasia, type Torrance,
Kniest dysplasia,
Spondyloepiphyseal dysplasia congenita (SEDC),
Spondyloepimetaphyseal dysplasia (SEMD),
Spondyloperipheral dysplasia,
Spondyloepiphyseal dysplasia (SED) with metatarsal shortening,
Stickler syndrome,
Mild spondyloepiphyseal dysplasia (SED) with premature arthrosis
Note: Achondrogenesis,
SEDC,
Clinical and Radiographic Features of Type II Collagen Disorders from Most to Least Severe
PRS = Pierre Robin sequence; SED = spondyloepiphyseal dysplasia; SEDC = spondyloepiphyseal dysplasia congenita; SEMD = spondyloepimetaphyseal dysplasia
Features distinguishing this disorder from other type II collagen disorders
Can be very difficult to distinguish prenatally
There is currently no clear genotype-phenotype correlation in type II collagen disorders, and there is significant phenotypic overlap. However, data do support some general rules [
Missense variants in the Gly position of the Gly-X-Y repeat motif cause substitution of glycine to a bulkier amino acid, interfering with triple helix formation. This dominant-negative effect is generally seen in the more severe
In Kniest dysplasia,
Arginine-to-cysteine substitutions are most often associated with non-lethal phenotypes [
In Stickler syndrome,
Penetrance in type II collagen disorders is high, if not complete; only rare instances of apparently reduced penetrance have been reported [
Achondrogenesis,
SED with metatarsal shortening,
The exact prevalence of type II collagen disorders is not known. However, Stickler syndrome,
• Achondrogenesis,
• Hypochondrogenesis,
• Platyspondylic dysplasia, type Torrance,
• Kniest dysplasia,
• Spondyloepiphyseal dysplasia congenita (SEDC),
• Spondyloepimetaphyseal dysplasia (SEMD),
• Spondyloperipheral dysplasia,
• Spondyloepiphyseal dysplasia (SED) with metatarsal shortening,
• Stickler syndrome,
• Mild spondyloepiphyseal dysplasia (SED) with premature arthrosis
• Missense variants in the Gly position of the Gly-X-Y repeat motif cause substitution of glycine to a bulkier amino acid, interfering with triple helix formation. This dominant-negative effect is generally seen in the more severe
• In Kniest dysplasia,
• Arginine-to-cysteine substitutions are most often associated with non-lethal phenotypes [
• In Stickler syndrome,
## Clinical Description
Type II collagen is an essential component of the cartilage extracellular matrix, and of major importance in endochondral bone formation, growth, and normal joint function. It is also necessary for normal development and function of the eye and the inner ear. Type II collagen disorders encompass a diverse group of clinical phenotypes characterized by skeletal dysplasia, ocular manifestations (e.g., cataract, myopia, subluxation of the lens, vitreous abnormalities, retinal detachment), hearing impairment, and orofacial features [
The spectrum of severity ranges from severe perinatal-lethal disorders to milder conditions presenting in adulthood with premature arthrosis as the primary feature. Considerable phenotypic overlap notwithstanding, discriminating features can aid in the specific diagnosis (see
Achondrogenesis,
Hypochondrogenesis,
Platyspondylic dysplasia, type Torrance,
Kniest dysplasia,
Spondyloepiphyseal dysplasia congenita (SEDC),
Spondyloepimetaphyseal dysplasia (SEMD),
Spondyloperipheral dysplasia,
Spondyloepiphyseal dysplasia (SED) with metatarsal shortening,
Stickler syndrome,
Mild spondyloepiphyseal dysplasia (SED) with premature arthrosis
Note: Achondrogenesis,
SEDC,
Clinical and Radiographic Features of Type II Collagen Disorders from Most to Least Severe
PRS = Pierre Robin sequence; SED = spondyloepiphyseal dysplasia; SEDC = spondyloepiphyseal dysplasia congenita; SEMD = spondyloepimetaphyseal dysplasia
Features distinguishing this disorder from other type II collagen disorders
Can be very difficult to distinguish prenatally
• Achondrogenesis,
• Hypochondrogenesis,
• Platyspondylic dysplasia, type Torrance,
• Kniest dysplasia,
• Spondyloepiphyseal dysplasia congenita (SEDC),
• Spondyloepimetaphyseal dysplasia (SEMD),
• Spondyloperipheral dysplasia,
• Spondyloepiphyseal dysplasia (SED) with metatarsal shortening,
• Stickler syndrome,
• Mild spondyloepiphyseal dysplasia (SED) with premature arthrosis
## Most Severe (often lethal perinatally)
Note: Achondrogenesis,
## Severe / Moderately Severe (neonatal presentation)
SEDC,
## Intermediate (neonatal/childhood/adolescent presentation)
## Mild (adolescent/adult presentation)
Clinical and Radiographic Features of Type II Collagen Disorders from Most to Least Severe
PRS = Pierre Robin sequence; SED = spondyloepiphyseal dysplasia; SEDC = spondyloepiphyseal dysplasia congenita; SEMD = spondyloepimetaphyseal dysplasia
Features distinguishing this disorder from other type II collagen disorders
Can be very difficult to distinguish prenatally
## Genotype-Phenotype Correlations
There is currently no clear genotype-phenotype correlation in type II collagen disorders, and there is significant phenotypic overlap. However, data do support some general rules [
Missense variants in the Gly position of the Gly-X-Y repeat motif cause substitution of glycine to a bulkier amino acid, interfering with triple helix formation. This dominant-negative effect is generally seen in the more severe
In Kniest dysplasia,
Arginine-to-cysteine substitutions are most often associated with non-lethal phenotypes [
In Stickler syndrome,
• Missense variants in the Gly position of the Gly-X-Y repeat motif cause substitution of glycine to a bulkier amino acid, interfering with triple helix formation. This dominant-negative effect is generally seen in the more severe
• In Kniest dysplasia,
• Arginine-to-cysteine substitutions are most often associated with non-lethal phenotypes [
• In Stickler syndrome,
## Penetrance
Penetrance in type II collagen disorders is high, if not complete; only rare instances of apparently reduced penetrance have been reported [
## Nomenclature
Achondrogenesis,
SED with metatarsal shortening,
## Prevalence
The exact prevalence of type II collagen disorders is not known. However, Stickler syndrome,
## Evaluation Strategies to Identify the Genetic Cause of a Type II Collagen Disorder in a Proband
Establishing a specific genetic cause of a type II collagen disorder:
Can aid in discussions of prognosis (which are beyond the scope of this
Is based on clinical and radiologic findings and the identification of a pathogenic variant in
Note: As no formal clinical diagnostic criteria exist, specific diagnosis should be confirmed by genetic testing.
For an introduction to multigene panels click
• Can aid in discussions of prognosis (which are beyond the scope of this
• Is based on clinical and radiologic findings and the identification of a pathogenic variant in
• Note: As no formal clinical diagnostic criteria exist, specific diagnosis should be confirmed by genetic testing.
• For an introduction to multigene panels click
## Differential Diagnosis of Type II Collagen Disorders
The differential diagnosis of type II collagen disorders includes a range of disorders, from severe often lethal skeletal dysplasia with abnormal ossification and major skeletal abnormalities to milder conditions with limited clinical and radiographic findings. Disorders with a known genetic etiology are listed in
Disorders with Known Genetic Etiology to Consider in the Differential Diagnosis of Type II Collagen Disorders
AD = autosomal dominant; ALP = alkaline phosphatase; AR = autosomal recessive; MOI = mode of inheritance; SED = spondyloepiphyseal dysplasia
The most severe type II collagen disorders include
Comprising characteristic type II collagen ocular, auditory, and orofacial abnormalities (i.e., high myopia, retinal detachment, hearing impairment, Pierre Robin sequence)
Severe to moderately severe type II collagen disorders include
Intermediate severity type II collagen disorders include
Shortening of the third and/or fourth toes is a classic distinguishing hallmark of SED with metatarsal shortening.
Disorders of Unknown Etiology to Consider in the Differential Diagnosis of Type II Collagen Disorders
Intermediate severity type II collagen disorders include
Comprising characteristic type II collagen ocular, auditory, and orofacial abnormalities (i.e., high myopia, retinal detachment, hearing impairment, Pierre Robin sequence)
Mild severity type II collagen disorders include
## Management
Clinical practice guidelines for type II collagen disorders have been published [
To establish the extent of disease and needs in an individual diagnosed with a type II collagen disorder, the evaluations summarized in
Type II Collagen Disorders: Recommended Evaluations Following Initial Diagnosis
Often already performed to establish diagnosis
To assess extent of skeletal malformations
Flexion-extension radiograph
Flexion-extension MRI if instability & compression seen on radiographs or interpretation on radiographs is limited (e.g., in young persons w/delayed ossification in upper cervical spine)
Pulmonary function tests
Polysomnography
To assess extent of respiratory insufficiency in severe presentations (PRS, small thorax, pulmonary hypoplasia)
To identify sleep apnea (central sleep apnea as result of unrecognized unstable cervical spine, obstructive sleep apnea as result of tracheobronchomalacia & cleft palate sequelae)
To identify respiratory insufficiency in those w/severe kyphoscoliosis
Hearing eval
Eval for cleft palate
Clinical exam
Referral to orthopedic surgeon if indicated
Referral to PT if indicated
Adapted from
MOI = mode of inheritance; PRS = Pierre Robin sequence; PT = physical therapist
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Type II Collagen Disorders: Treatment of Manifestations
Supported ventilation (e.g., CPAP)
Surgery for cleft palate
Referral to pulmonologist & sleep medicine physician
Supported ventilation (e.g., CPAP)
Surgery for PRS
Refractive errors should be corrected w/spectacles.
Persons at risk should be informed about signs & symptoms of retinal detachment & advised about immediate eval & treatment when symptoms occur.
Mgmt of vitreoretinal complications by expert ophthalmologist familiar w/ophthalmic complications
Consider prophylactic retinopexy in Stickler syndrome,
Referral to orthopedic surgeon for eval
Referral to PT
Referral to OT if indicated
Analgesics
Advice on joint-friendly activities (e.g., swimming, cycling)
Consider need for mobility device.
Avoidance of physical activities that strain joints when possible
Guided growth surgery
Osteotomy
Referral to
Referral to psychologist
Adapted from
CPAP = continuous positive airway pressure; OT = occupational therapist; PRS = Pierre Robin sequence; PT = physical therapist
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Type II Collagen Disorders: Recommended Surveillance
Flexion-extension radiograph
Flexion-extension MRI if instability & compression on radiographs or limited interpretation on radiographs
Clinical exam
Radiographs when indicated
Pulmonary function tests
Polysomnography
Annually unless complications
Consider prophylactic retinopexy in Stickler syndrome,
Hearing eval
Eval for cleft palate & palatal insufficiency
Clinical exam
Referral to orthopedic surgeon if indicated
Referral to PT if indicated
Adapted from
PT = physical therapist
In individuals with cervical spine instability, extreme neck extension and neck flexion and contact sports should be avoided.
In case of general anesthesia, the cervical spine should be assessed by imaging prior to the procedure [
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from recommended surveillance in order to avoid/prevent common complications.
See
In individuals with a small pelvis, delivery by cesarean section should be considered. However, each individual should be assessed by an obstetrician familiar with skeletal dysplasia [
Search
• Often already performed to establish diagnosis
• To assess extent of skeletal malformations
• Flexion-extension radiograph
• Flexion-extension MRI if instability & compression seen on radiographs or interpretation on radiographs is limited (e.g., in young persons w/delayed ossification in upper cervical spine)
• Pulmonary function tests
• Polysomnography
• To assess extent of respiratory insufficiency in severe presentations (PRS, small thorax, pulmonary hypoplasia)
• To identify sleep apnea (central sleep apnea as result of unrecognized unstable cervical spine, obstructive sleep apnea as result of tracheobronchomalacia & cleft palate sequelae)
• To identify respiratory insufficiency in those w/severe kyphoscoliosis
• Hearing eval
• Eval for cleft palate
• Clinical exam
• Referral to orthopedic surgeon if indicated
• Referral to PT if indicated
• Supported ventilation (e.g., CPAP)
• Surgery for cleft palate
• Referral to pulmonologist & sleep medicine physician
• Supported ventilation (e.g., CPAP)
• Surgery for PRS
• Refractive errors should be corrected w/spectacles.
• Persons at risk should be informed about signs & symptoms of retinal detachment & advised about immediate eval & treatment when symptoms occur.
• Mgmt of vitreoretinal complications by expert ophthalmologist familiar w/ophthalmic complications
• Consider prophylactic retinopexy in Stickler syndrome,
• Referral to orthopedic surgeon for eval
• Referral to PT
• Referral to OT if indicated
• Analgesics
• Advice on joint-friendly activities (e.g., swimming, cycling)
• Consider need for mobility device.
• Avoidance of physical activities that strain joints when possible
• Guided growth surgery
• Osteotomy
• Referral to
• Referral to psychologist
• Flexion-extension radiograph
• Flexion-extension MRI if instability & compression on radiographs or limited interpretation on radiographs
• Clinical exam
• Radiographs when indicated
• Pulmonary function tests
• Polysomnography
• Annually unless complications
• Consider prophylactic retinopexy in Stickler syndrome,
• Hearing eval
• Eval for cleft palate & palatal insufficiency
• Clinical exam
• Referral to orthopedic surgeon if indicated
• Referral to PT if indicated
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a type II collagen disorder, the evaluations summarized in
Type II Collagen Disorders: Recommended Evaluations Following Initial Diagnosis
Often already performed to establish diagnosis
To assess extent of skeletal malformations
Flexion-extension radiograph
Flexion-extension MRI if instability & compression seen on radiographs or interpretation on radiographs is limited (e.g., in young persons w/delayed ossification in upper cervical spine)
Pulmonary function tests
Polysomnography
To assess extent of respiratory insufficiency in severe presentations (PRS, small thorax, pulmonary hypoplasia)
To identify sleep apnea (central sleep apnea as result of unrecognized unstable cervical spine, obstructive sleep apnea as result of tracheobronchomalacia & cleft palate sequelae)
To identify respiratory insufficiency in those w/severe kyphoscoliosis
Hearing eval
Eval for cleft palate
Clinical exam
Referral to orthopedic surgeon if indicated
Referral to PT if indicated
Adapted from
MOI = mode of inheritance; PRS = Pierre Robin sequence; PT = physical therapist
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Often already performed to establish diagnosis
• To assess extent of skeletal malformations
• Flexion-extension radiograph
• Flexion-extension MRI if instability & compression seen on radiographs or interpretation on radiographs is limited (e.g., in young persons w/delayed ossification in upper cervical spine)
• Pulmonary function tests
• Polysomnography
• To assess extent of respiratory insufficiency in severe presentations (PRS, small thorax, pulmonary hypoplasia)
• To identify sleep apnea (central sleep apnea as result of unrecognized unstable cervical spine, obstructive sleep apnea as result of tracheobronchomalacia & cleft palate sequelae)
• To identify respiratory insufficiency in those w/severe kyphoscoliosis
• Hearing eval
• Eval for cleft palate
• Clinical exam
• Referral to orthopedic surgeon if indicated
• Referral to PT if indicated
## Treatment of Manifestations
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Type II Collagen Disorders: Treatment of Manifestations
Supported ventilation (e.g., CPAP)
Surgery for cleft palate
Referral to pulmonologist & sleep medicine physician
Supported ventilation (e.g., CPAP)
Surgery for PRS
Refractive errors should be corrected w/spectacles.
Persons at risk should be informed about signs & symptoms of retinal detachment & advised about immediate eval & treatment when symptoms occur.
Mgmt of vitreoretinal complications by expert ophthalmologist familiar w/ophthalmic complications
Consider prophylactic retinopexy in Stickler syndrome,
Referral to orthopedic surgeon for eval
Referral to PT
Referral to OT if indicated
Analgesics
Advice on joint-friendly activities (e.g., swimming, cycling)
Consider need for mobility device.
Avoidance of physical activities that strain joints when possible
Guided growth surgery
Osteotomy
Referral to
Referral to psychologist
Adapted from
CPAP = continuous positive airway pressure; OT = occupational therapist; PRS = Pierre Robin sequence; PT = physical therapist
• Supported ventilation (e.g., CPAP)
• Surgery for cleft palate
• Referral to pulmonologist & sleep medicine physician
• Supported ventilation (e.g., CPAP)
• Surgery for PRS
• Refractive errors should be corrected w/spectacles.
• Persons at risk should be informed about signs & symptoms of retinal detachment & advised about immediate eval & treatment when symptoms occur.
• Mgmt of vitreoretinal complications by expert ophthalmologist familiar w/ophthalmic complications
• Consider prophylactic retinopexy in Stickler syndrome,
• Referral to orthopedic surgeon for eval
• Referral to PT
• Referral to OT if indicated
• Analgesics
• Advice on joint-friendly activities (e.g., swimming, cycling)
• Consider need for mobility device.
• Avoidance of physical activities that strain joints when possible
• Guided growth surgery
• Osteotomy
• Referral to
• Referral to psychologist
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Type II Collagen Disorders: Recommended Surveillance
Flexion-extension radiograph
Flexion-extension MRI if instability & compression on radiographs or limited interpretation on radiographs
Clinical exam
Radiographs when indicated
Pulmonary function tests
Polysomnography
Annually unless complications
Consider prophylactic retinopexy in Stickler syndrome,
Hearing eval
Eval for cleft palate & palatal insufficiency
Clinical exam
Referral to orthopedic surgeon if indicated
Referral to PT if indicated
Adapted from
PT = physical therapist
• Flexion-extension radiograph
• Flexion-extension MRI if instability & compression on radiographs or limited interpretation on radiographs
• Clinical exam
• Radiographs when indicated
• Pulmonary function tests
• Polysomnography
• Annually unless complications
• Consider prophylactic retinopexy in Stickler syndrome,
• Hearing eval
• Eval for cleft palate & palatal insufficiency
• Clinical exam
• Referral to orthopedic surgeon if indicated
• Referral to PT if indicated
## Agents/Circumstances to Avoid
In individuals with cervical spine instability, extreme neck extension and neck flexion and contact sports should be avoided.
In case of general anesthesia, the cervical spine should be assessed by imaging prior to the procedure [
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from recommended surveillance in order to avoid/prevent common complications.
See
## Pregnancy Management
In individuals with a small pelvis, delivery by cesarean section should be considered. However, each individual should be assessed by an obstetrician familiar with skeletal dysplasia [
## Therapies Under Investigation
Search
## Genetic Counseling
Type II collagen disorders are typically inherited in an autosomal dominant manner.
Autosomal recessive inheritance of type II collagen disorders has been reported in several families to date [
Most individuals diagnosed with a severe type II collagen disorder have the disorder as the result of a
Many individuals diagnosed with a milder type II collagen disorder have an affected parent. Clinical variability within a family can be extensive; however, severe and mild forms are not seen in family members with the same pathogenic variant (i.e., the specific type II collagen diagnosis appears to run true in a family, but with variable expressivity).
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in mildly affected family members. Therefore,
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism * [
* A parent with somatic and gonadal mosaicism for a
If a parent of the proband is affected and/or is known to have the
Penetrance in type II collagen disorders is high; however, intrafamilial variability among heterozygous family members can be extensive. Note: Severe and mild forms are not seen in family members with the same pathogenic variant (i.e., the specific type II collagen diagnosis appears to run true in a family, but with variable expressivity).
If the
If the parents have not been tested for the
Each child of an individual with a type II collagen disorder has a 50% chance of inheriting the
Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with a type II collagen disorder may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals are distinct from those of the parents, and the affected individuals may have serious sequelae and poor outcomes [
The parents of an affected individual are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
In the families described by
If both parents are known to be heterozygous for a
Heterozygous sibs are predicted to be either unaffected or mildly affected. Homozygous sibs will be affected in a manner similar to the affected individual but, because of variable expressivity, may have a more or less severe clinical outcome.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals diagnosed with a severe type II collagen disorder have the disorder as the result of a
• Many individuals diagnosed with a milder type II collagen disorder have an affected parent. Clinical variability within a family can be extensive; however, severe and mild forms are not seen in family members with the same pathogenic variant (i.e., the specific type II collagen diagnosis appears to run true in a family, but with variable expressivity).
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in mildly affected family members. Therefore,
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism * [
• * A parent with somatic and gonadal mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism * [
• * A parent with somatic and gonadal mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism * [
• * A parent with somatic and gonadal mosaicism for a
• If a parent of the proband is affected and/or is known to have the
• Penetrance in type II collagen disorders is high; however, intrafamilial variability among heterozygous family members can be extensive. Note: Severe and mild forms are not seen in family members with the same pathogenic variant (i.e., the specific type II collagen diagnosis appears to run true in a family, but with variable expressivity).
• If the
• If the parents have not been tested for the
• Each child of an individual with a type II collagen disorder has a 50% chance of inheriting the
• Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with a type II collagen disorder may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals are distinct from those of the parents, and the affected individuals may have serious sequelae and poor outcomes [
• The parents of an affected individual are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• In the families described by
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygous sibs are predicted to be either unaffected or mildly affected. Homozygous sibs will be affected in a manner similar to the affected individual but, because of variable expressivity, may have a more or less severe clinical outcome.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
## Mode of Inheritance
Type II collagen disorders are typically inherited in an autosomal dominant manner.
Autosomal recessive inheritance of type II collagen disorders has been reported in several families to date [
## Autosomal Dominant Inheritance – Risk to Family Members
Most individuals diagnosed with a severe type II collagen disorder have the disorder as the result of a
Many individuals diagnosed with a milder type II collagen disorder have an affected parent. Clinical variability within a family can be extensive; however, severe and mild forms are not seen in family members with the same pathogenic variant (i.e., the specific type II collagen diagnosis appears to run true in a family, but with variable expressivity).
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in mildly affected family members. Therefore,
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism * [
* A parent with somatic and gonadal mosaicism for a
If a parent of the proband is affected and/or is known to have the
Penetrance in type II collagen disorders is high; however, intrafamilial variability among heterozygous family members can be extensive. Note: Severe and mild forms are not seen in family members with the same pathogenic variant (i.e., the specific type II collagen diagnosis appears to run true in a family, but with variable expressivity).
If the
If the parents have not been tested for the
Each child of an individual with a type II collagen disorder has a 50% chance of inheriting the
Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with a type II collagen disorder may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals are distinct from those of the parents, and the affected individuals may have serious sequelae and poor outcomes [
• Most individuals diagnosed with a severe type II collagen disorder have the disorder as the result of a
• Many individuals diagnosed with a milder type II collagen disorder have an affected parent. Clinical variability within a family can be extensive; however, severe and mild forms are not seen in family members with the same pathogenic variant (i.e., the specific type II collagen diagnosis appears to run true in a family, but with variable expressivity).
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in mildly affected family members. Therefore,
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism * [
• * A parent with somatic and gonadal mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism * [
• * A parent with somatic and gonadal mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism * [
• * A parent with somatic and gonadal mosaicism for a
• If a parent of the proband is affected and/or is known to have the
• Penetrance in type II collagen disorders is high; however, intrafamilial variability among heterozygous family members can be extensive. Note: Severe and mild forms are not seen in family members with the same pathogenic variant (i.e., the specific type II collagen diagnosis appears to run true in a family, but with variable expressivity).
• If the
• If the parents have not been tested for the
• Each child of an individual with a type II collagen disorder has a 50% chance of inheriting the
• Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with a type II collagen disorder may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals are distinct from those of the parents, and the affected individuals may have serious sequelae and poor outcomes [
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected individual are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
In the families described by
If both parents are known to be heterozygous for a
Heterozygous sibs are predicted to be either unaffected or mildly affected. Homozygous sibs will be affected in a manner similar to the affected individual but, because of variable expressivity, may have a more or less severe clinical outcome.
• The parents of an affected individual are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• In the families described by
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygous sibs are predicted to be either unaffected or mildly affected. Homozygous sibs will be affected in a manner similar to the affected individual but, because of variable expressivity, may have a more or less severe clinical outcome.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
United Kingdom
Australia
•
•
•
•
•
•
•
• United Kingdom
•
•
•
•
• United Kingdom
•
•
• Australia
•
•
•
•
•
## Chapter Notes
Dr Supriya Raj provided help with the tables, references, and proofreading.
24 October 2024 (sw) Comprehensive update posted live
25 April 2019 (sw) Review posted live
22 January 2019 (rs) Original submission
• 24 October 2024 (sw) Comprehensive update posted live
• 25 April 2019 (sw) Review posted live
• 22 January 2019 (rs) Original submission
## Acknowledgments
Dr Supriya Raj provided help with the tables, references, and proofreading.
## Revision History
24 October 2024 (sw) Comprehensive update posted live
25 April 2019 (sw) Review posted live
22 January 2019 (rs) Original submission
• 24 October 2024 (sw) Comprehensive update posted live
• 25 April 2019 (sw) Review posted live
• 22 January 2019 (rs) Original submission
## References
## Literature Cited
|
[] |
25/4/2019
|
24/10/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
coq10-def
|
coq10-def
|
[
"Primary Ubiquinone Deficiency",
"Coenzyme Q Deficiency",
"CoQ Deficiency",
"Primary CoQ10 Deficiency",
"Ubiquinone Deficiency",
"2-methoxy-6-polyprenyl-1,4-benzoquinol methylase, mitochondrial",
"All trans-polyprenyl-diphosphate synthase PDSS1",
"All trans-polyprenyl-diphosphate synthase PDSS2",
"Atypical kinase ADCK3, mitochondrial",
"Atypical kinase COQ8B, mitochondrial",
"NADPH-dependent 3-demethoxyubiquinone 3-hydroxylase, mitochondrial",
"Para-hydroxybenzoate--polyprenyltransferase, mitochondrial",
"Ubiquinone biosynthesis monooxygenase COQ6, mitochondrial",
"Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial",
"Ubiquinone biosynthesis protein COQ9, mitochondrial",
"COQ2",
"COQ4",
"COQ5",
"COQ6",
"COQ7",
"COQ8A",
"COQ8B",
"COQ9",
"PDSS1",
"PDSS2",
"Primary Coenzyme Q10 Deficiency",
"Overview"
] |
Primary Coenzyme Q
|
Leonardo Salviati, Eva Trevisson, Caterina Agosto, Mara Doimo, Placido Navas
|
Summary The purpose of this overview is to: Briefly describe the Increase the awareness of clinicians regarding Review the Provide an Review Inform
|
## Clinical Characteristics of Primary Coenzyme Q
Primary deficiency of coenzyme Q
Primary CoQ
The manifestations of primary CoQ
The broad age of onset of primary CoQ
The
The age of onset and clinical severity range from fatal neonatal encephalopathy with hypotonia [
Individuals with
Distal motor neuropathy has been reported in several individuals with
Given the small number of affected individuals described to date, clinical data are insufficient to make any generalizations about other neurologic manifestations (e.g., dystonia, spasticity, seizures, intellectual disability).
Renal involvement usually manifests as proteinuria in infancy. Affected individuals often present initially with SRNS that leads to ESKD, followed by an encephalomyopathy with seizures and stroke-like episodes resulting in severe neurologic impairment and ultimately death [
Some affected individuals manifest only SRNS with onset in the first or second decade of life and slow progression to ESKD without extrarenal manifestations [
One of the two individuals in a family with
Neonatal-onset
Optic atrophy has been reported in some individuals with
Children with severe multisystem CoQ
Individuals with later-onset disease show better response to supplementation with high-dose oral CoQ
The main clinical features include SRNS, which can be:
Isolated [
Associated with encephalomyopathy [
Adult-onset retinitis pigmentosa can be an isolated manifestation or can be associated with late-onset multiple system atrophy [
Isolated [
Progressive with cerebellar atrophy in addition to intellectual disability, epilepsy, stroke-like episodes, and/or exercise intolerance [
• Neonatal-onset
• Isolated [
• Associated with encephalomyopathy [
• Isolated [
• Progressive with cerebellar atrophy in addition to intellectual disability, epilepsy, stroke-like episodes, and/or exercise intolerance [
## Clinical Manifestations
The manifestations of primary CoQ
The broad age of onset of primary CoQ
The
The age of onset and clinical severity range from fatal neonatal encephalopathy with hypotonia [
Individuals with
Distal motor neuropathy has been reported in several individuals with
Given the small number of affected individuals described to date, clinical data are insufficient to make any generalizations about other neurologic manifestations (e.g., dystonia, spasticity, seizures, intellectual disability).
Renal involvement usually manifests as proteinuria in infancy. Affected individuals often present initially with SRNS that leads to ESKD, followed by an encephalomyopathy with seizures and stroke-like episodes resulting in severe neurologic impairment and ultimately death [
Some affected individuals manifest only SRNS with onset in the first or second decade of life and slow progression to ESKD without extrarenal manifestations [
One of the two individuals in a family with
Neonatal-onset
Optic atrophy has been reported in some individuals with
Children with severe multisystem CoQ
Individuals with later-onset disease show better response to supplementation with high-dose oral CoQ
The main clinical features include SRNS, which can be:
Isolated [
Associated with encephalomyopathy [
Adult-onset retinitis pigmentosa can be an isolated manifestation or can be associated with late-onset multiple system atrophy [
Isolated [
Progressive with cerebellar atrophy in addition to intellectual disability, epilepsy, stroke-like episodes, and/or exercise intolerance [
• Neonatal-onset
• Isolated [
• Associated with encephalomyopathy [
• Isolated [
• Progressive with cerebellar atrophy in addition to intellectual disability, epilepsy, stroke-like episodes, and/or exercise intolerance [
## Principal Clinical Manifestations
The age of onset and clinical severity range from fatal neonatal encephalopathy with hypotonia [
Individuals with
Distal motor neuropathy has been reported in several individuals with
Given the small number of affected individuals described to date, clinical data are insufficient to make any generalizations about other neurologic manifestations (e.g., dystonia, spasticity, seizures, intellectual disability).
Renal involvement usually manifests as proteinuria in infancy. Affected individuals often present initially with SRNS that leads to ESKD, followed by an encephalomyopathy with seizures and stroke-like episodes resulting in severe neurologic impairment and ultimately death [
Some affected individuals manifest only SRNS with onset in the first or second decade of life and slow progression to ESKD without extrarenal manifestations [
One of the two individuals in a family with
Neonatal-onset
Optic atrophy has been reported in some individuals with
Children with severe multisystem CoQ
Individuals with later-onset disease show better response to supplementation with high-dose oral CoQ
• Neonatal-onset
## Phenotypes of
The main clinical features include SRNS, which can be:
Isolated [
Associated with encephalomyopathy [
Adult-onset retinitis pigmentosa can be an isolated manifestation or can be associated with late-onset multiple system atrophy [
Isolated [
Progressive with cerebellar atrophy in addition to intellectual disability, epilepsy, stroke-like episodes, and/or exercise intolerance [
• Isolated [
• Associated with encephalomyopathy [
• Isolated [
• Progressive with cerebellar atrophy in addition to intellectual disability, epilepsy, stroke-like episodes, and/or exercise intolerance [
## Laboratory Findings
## Genetic Causes of Primary Coenzyme Q
Primary Coenzyme Q
HCM = hypertrophic cardiomyopathy; ID = intellectual disability; SNHL = sensorineural hearing loss; SRNS = steroid-resistant nephrotic syndrome
Genes are listed in alphanumeric order.
Encephalopathy comprises a wide spectrum of brain involvement with different clinical and neuroradiologic features, often not further explained by the reporting authors.
Adult-onset multisystem atrophy-like phenotype [
Severe hypotonia, respiratory insufficiency, cerebellar hypoplasia, slowly progressive neurologic deterioration, spasticity, and intellectual disability
The link between
Because individuals with
## Differential Diagnosis of Primary Coenzyme Q
Note: It is important to consider primary coenzyme Q
## Evaluation Strategies to Identify the Genetic Cause of Primary Coenzyme Q
Establishing a specific genetic cause of primary coenzyme Q
Allows initiation of a specific treatment;
Can aid in discussions of prognosis (which are beyond the scope of this
Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.
The diagnosis of primary CoQ
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
In the past, biochemical testing was the primary method for diagnosing CoQ
Reduced levels of CoQ
Note: While CoQ
Reduced activities of complex I+III and II+III of the mitochondrial respiratory chain on frozen muscle homogenates
These enzymatic activities, which depend on endogenous CoQ
Plasma CoQ
• Allows initiation of a specific treatment;
• Can aid in discussions of prognosis (which are beyond the scope of this
• Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.
• Reduced levels of CoQ
• Note: While CoQ
• Reduced activities of complex I+III and II+III of the mitochondrial respiratory chain on frozen muscle homogenates
• These enzymatic activities, which depend on endogenous CoQ
## Molecular Genetic Testing
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
## Biochemical Testing
In the past, biochemical testing was the primary method for diagnosing CoQ
Reduced levels of CoQ
Note: While CoQ
Reduced activities of complex I+III and II+III of the mitochondrial respiratory chain on frozen muscle homogenates
These enzymatic activities, which depend on endogenous CoQ
Plasma CoQ
• Reduced levels of CoQ
• Note: While CoQ
• Reduced activities of complex I+III and II+III of the mitochondrial respiratory chain on frozen muscle homogenates
• These enzymatic activities, which depend on endogenous CoQ
## Management
No clinical practice guidelines for management of primary coenzyme Q
To establish the extent of disease and needs in an individual diagnosed with primary CoQ
Primary Coenzyme Q
Assessment of functional neurologic status by pediatric neurologist
Brain MRI
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
Need for durable medical equipment &/or adaptive devices
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl eval for gastrointestinal dysmotility, aspiration risk, & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Possible retinopathy & optic atrophy
Possible need for low vision services
Community or
Social work involvement for parental support;
Home nursing referral.
HCM = hypertrophic cardiomyopathy; MOI = mode of inheritance; SNHL = sensorineural hearing loss
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
There is no cure for primary CoQ
Treatment should be instituted as early as possible because it can limit disease progression and reverse some manifestations [
Response is highly variable, and depends on both the specific genetic defect and disease severity, but also other unknown factors.
A recent study that investigated the effect of supplementation with high-dose oral CoQ
Data for response to high-dose oral CoQ
Ubiquinol, the reduced form of CoQ
Short-chain quinone analogs such as idebenone [
Bypass therapy with analogs of the quinone ring [
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Primary Coenzyme Q
See Steroid-Resistant Nephrotic Syndrome Overview,
ACE inhibitors may be used in combination w/CoQ
Kidney transplantation is an option for those w/ESKD.
To maintain muscle strength & mobility & prevent contractures
Consider need for adaptive positioning devices.
Certain ASMs require monitoring of medication levels.
Education of parents/caregivers
ASM = anti-seizure medication
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
While monitoring the existing manifestations of primary CoQ
In individuals with adult-onset neurologic findings and individuals with apparently isolated SRNS: assessment for evidence of autonomic dysfunction and movement disorders (parkinsonism, cerebellar ataxia, pyramidal signs) every one to two years
Urine analysis for proteinuria and assessment of kidney function
Ophthalmologic evaluation and electroretinogram for evidence of retinopathy and to determine need for low vison services
Hearing evaluation with attention to possible sensorineural hearing loss
Note: Because cardiomyopathy to date has been found only in the most severe phenotype (i.e., neonatal onset), cardiac evaluation should be performed at the time of diagnosis but not periodically unless cardiac involvement has been documented.
Given the importance of early CoQ
If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
If the pathogenic variants in the family are not known and the diagnosis has been established by biochemical findings, one can consider measuring CoQ
See
• Assessment of functional neurologic status by pediatric neurologist
• Brain MRI
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• Need for durable medical equipment &/or adaptive devices
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl eval for gastrointestinal dysmotility, aspiration risk, & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Possible retinopathy & optic atrophy
• Possible need for low vision services
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Ubiquinol, the reduced form of CoQ
• Short-chain quinone analogs such as idebenone [
• Bypass therapy with analogs of the quinone ring [
• See Steroid-Resistant Nephrotic Syndrome Overview,
• ACE inhibitors may be used in combination w/CoQ
• Kidney transplantation is an option for those w/ESKD.
• To maintain muscle strength & mobility & prevent contractures
• Consider need for adaptive positioning devices.
• Certain ASMs require monitoring of medication levels.
• Education of parents/caregivers
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• In individuals with adult-onset neurologic findings and individuals with apparently isolated SRNS: assessment for evidence of autonomic dysfunction and movement disorders (parkinsonism, cerebellar ataxia, pyramidal signs) every one to two years
• Urine analysis for proteinuria and assessment of kidney function
• Ophthalmologic evaluation and electroretinogram for evidence of retinopathy and to determine need for low vison services
• Hearing evaluation with attention to possible sensorineural hearing loss
• If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
• If the pathogenic variants in the family are not known and the diagnosis has been established by biochemical findings, one can consider measuring CoQ
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with primary CoQ
Primary Coenzyme Q
Assessment of functional neurologic status by pediatric neurologist
Brain MRI
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
Need for durable medical equipment &/or adaptive devices
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl eval for gastrointestinal dysmotility, aspiration risk, & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Possible retinopathy & optic atrophy
Possible need for low vision services
Community or
Social work involvement for parental support;
Home nursing referral.
HCM = hypertrophic cardiomyopathy; MOI = mode of inheritance; SNHL = sensorineural hearing loss
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Assessment of functional neurologic status by pediatric neurologist
• Brain MRI
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• Need for durable medical equipment &/or adaptive devices
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl eval for gastrointestinal dysmotility, aspiration risk, & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Possible retinopathy & optic atrophy
• Possible need for low vision services
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
There is no cure for primary CoQ
Treatment should be instituted as early as possible because it can limit disease progression and reverse some manifestations [
Response is highly variable, and depends on both the specific genetic defect and disease severity, but also other unknown factors.
A recent study that investigated the effect of supplementation with high-dose oral CoQ
Data for response to high-dose oral CoQ
Ubiquinol, the reduced form of CoQ
Short-chain quinone analogs such as idebenone [
Bypass therapy with analogs of the quinone ring [
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Primary Coenzyme Q
See Steroid-Resistant Nephrotic Syndrome Overview,
ACE inhibitors may be used in combination w/CoQ
Kidney transplantation is an option for those w/ESKD.
To maintain muscle strength & mobility & prevent contractures
Consider need for adaptive positioning devices.
Certain ASMs require monitoring of medication levels.
Education of parents/caregivers
ASM = anti-seizure medication
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Ubiquinol, the reduced form of CoQ
• Short-chain quinone analogs such as idebenone [
• Bypass therapy with analogs of the quinone ring [
• See Steroid-Resistant Nephrotic Syndrome Overview,
• ACE inhibitors may be used in combination w/CoQ
• Kidney transplantation is an option for those w/ESKD.
• To maintain muscle strength & mobility & prevent contractures
• Consider need for adaptive positioning devices.
• Certain ASMs require monitoring of medication levels.
• Education of parents/caregivers
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Pharmacologic Treatment
Treatment should be instituted as early as possible because it can limit disease progression and reverse some manifestations [
Response is highly variable, and depends on both the specific genetic defect and disease severity, but also other unknown factors.
A recent study that investigated the effect of supplementation with high-dose oral CoQ
Data for response to high-dose oral CoQ
Ubiquinol, the reduced form of CoQ
Short-chain quinone analogs such as idebenone [
Bypass therapy with analogs of the quinone ring [
• Ubiquinol, the reduced form of CoQ
• Short-chain quinone analogs such as idebenone [
• Bypass therapy with analogs of the quinone ring [
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Primary Coenzyme Q
See Steroid-Resistant Nephrotic Syndrome Overview,
ACE inhibitors may be used in combination w/CoQ
Kidney transplantation is an option for those w/ESKD.
To maintain muscle strength & mobility & prevent contractures
Consider need for adaptive positioning devices.
Certain ASMs require monitoring of medication levels.
Education of parents/caregivers
ASM = anti-seizure medication
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
• See Steroid-Resistant Nephrotic Syndrome Overview,
• ACE inhibitors may be used in combination w/CoQ
• Kidney transplantation is an option for those w/ESKD.
• To maintain muscle strength & mobility & prevent contractures
• Consider need for adaptive positioning devices.
• Certain ASMs require monitoring of medication levels.
• Education of parents/caregivers
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Surveillance
While monitoring the existing manifestations of primary CoQ
In individuals with adult-onset neurologic findings and individuals with apparently isolated SRNS: assessment for evidence of autonomic dysfunction and movement disorders (parkinsonism, cerebellar ataxia, pyramidal signs) every one to two years
Urine analysis for proteinuria and assessment of kidney function
Ophthalmologic evaluation and electroretinogram for evidence of retinopathy and to determine need for low vison services
Hearing evaluation with attention to possible sensorineural hearing loss
Note: Because cardiomyopathy to date has been found only in the most severe phenotype (i.e., neonatal onset), cardiac evaluation should be performed at the time of diagnosis but not periodically unless cardiac involvement has been documented.
• In individuals with adult-onset neurologic findings and individuals with apparently isolated SRNS: assessment for evidence of autonomic dysfunction and movement disorders (parkinsonism, cerebellar ataxia, pyramidal signs) every one to two years
• Urine analysis for proteinuria and assessment of kidney function
• Ophthalmologic evaluation and electroretinogram for evidence of retinopathy and to determine need for low vison services
• Hearing evaluation with attention to possible sensorineural hearing loss
## Evaluation of Relatives at Risk
Given the importance of early CoQ
If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
If the pathogenic variants in the family are not known and the diagnosis has been established by biochemical findings, one can consider measuring CoQ
See
• If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
• If the pathogenic variants in the family are not known and the diagnosis has been established by biochemical findings, one can consider measuring CoQ
## Genetic Counseling
Primary coenzyme Q
Primary CoQ
The parents of an individual with a confirmed molecular genetic diagnosis of primary CoQ
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a primary CoQ
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a primary CoQ
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the primary CoQ
See Management,
Once the primary CoQ
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an individual with a confirmed molecular genetic diagnosis of primary CoQ
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a primary CoQ
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a primary CoQ
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Mode of Inheritance
Primary coenzyme Q
Primary CoQ
## Risk to Family Members (Autosomal Recessive Inheritance)
The parents of an individual with a confirmed molecular genetic diagnosis of primary CoQ
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a primary CoQ
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a primary CoQ
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an individual with a confirmed molecular genetic diagnosis of primary CoQ
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a primary CoQ
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a primary CoQ
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the primary CoQ
## Related Genetic Counseling Issues
See Management,
## Prenatal Testing and Preimplantation Genetic Testing
Once the primary CoQ
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Chapter Notes
Leonardo Salviati (
Leonardo Salviati and Eva Trevisson are also interested in hearing from clinicians treating families affected by primary CoQ
Contact Drs Salviati and Trevisson to inquire about review of variants of uncertain significance in any of the genes listed in
This work is supported by Telethon Italy Grants GGP13222 and GGP14187, a grant from Fondazione CARIPARO, and University of Padova Grant CPDA123573/12 (to LS); Ministry of Health Grant GR-2009-1578914 (to ET); and grants from Fondazione IRP Città della Speranza (to LS and ET).
Caterina Agosto, MD (2023-present) Mara Doimo, PhD (2017-present) Leonardo Salviati, MD, PhD (2017-present) Eva Trevisson, MD, PhD (2017-present)Placido Navas, PhD (2017-present)
8 June 2023 (bp) Comprehensive update posted live; scope changed to overview
26 January 2017 (bp) Review posted live
20 February 2015 (ls) Original submission
• 8 June 2023 (bp) Comprehensive update posted live; scope changed to overview
• 26 January 2017 (bp) Review posted live
• 20 February 2015 (ls) Original submission
## Author Notes
Leonardo Salviati (
Leonardo Salviati and Eva Trevisson are also interested in hearing from clinicians treating families affected by primary CoQ
Contact Drs Salviati and Trevisson to inquire about review of variants of uncertain significance in any of the genes listed in
## Acknowledgments
This work is supported by Telethon Italy Grants GGP13222 and GGP14187, a grant from Fondazione CARIPARO, and University of Padova Grant CPDA123573/12 (to LS); Ministry of Health Grant GR-2009-1578914 (to ET); and grants from Fondazione IRP Città della Speranza (to LS and ET).
## Author History
Caterina Agosto, MD (2023-present) Mara Doimo, PhD (2017-present) Leonardo Salviati, MD, PhD (2017-present) Eva Trevisson, MD, PhD (2017-present)Placido Navas, PhD (2017-present)
## Revision History
8 June 2023 (bp) Comprehensive update posted live; scope changed to overview
26 January 2017 (bp) Review posted live
20 February 2015 (ls) Original submission
• 8 June 2023 (bp) Comprehensive update posted live; scope changed to overview
• 26 January 2017 (bp) Review posted live
• 20 February 2015 (ls) Original submission
## Key Sections in this
## References
## Literature Cited
|
[] |
26/1/2017
|
8/6/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
costello
|
costello
|
[
"GTPase HRas",
"HRAS",
"HRAS-Related Costello Syndrome"
] |
Karen W Gripp, K Nicole Weaver
|
Summary While the majority of individuals with The diagnosis of Costello syndrome is established in a proband with suggestive clinical findings and a heterozygous Costello syndrome is an autosomal dominant disorder typically caused by a
|
## Diagnosis
No consensus clinical diagnostic criteria for
Costello syndrome
On ultrasound examination:
Increased nuchal thickness
Polyhydramnios (>90%)
Characteristic ulnar deviation of the wrists
Short humeri and femurs
Fetal tachycardia (various forms of atrial tachycardia)
Preterm delivery
Severe postnatal feeding difficulties extending throughout early childhood
Failure to thrive
Short stature
Macrocephaly (relative or absolute)
Coarse facial features (See
Curly or sparse, fine hair
Loose, soft skin
Increased pigmentation
Deep palmar and plantar creases
Papillomata of face and/or perianal region (typically absent in infancy but may appear in childhood)
Hyperkeratosis and calluses
Premature aging with hair loss
Diffuse hypotonia, joint laxity, and low muscle mass
Ulnar deviation of wrists and fingers; splayed fingers resulting in characteristic hand posture
Spatulate finger pads, abnormal fingernails
Tight Achilles tendons (often evolving throughout childhood)
Positional foot deformity
Vertical talus
Kyphoscoliosis
Pectus carinatum, pectus excavatum, asymmetric rib cage
Developmental hip dysplasia
Cardiac hypertrophy, usually hypertrophic cardiomyopathy (i.e., idiopathic subaortic stenosis, asymmetric septal hypertrophy), although other forms (e.g., biventricular hypertrophy) have been reported
Congenital heart defects, usually valvular pulmonic stenosis
Arrhythmia, usually supraventricular tachycardia. Most distinctive is chaotic atrial rhythm / multifocal atrial tachycardia or ectopic atrial tachycardia (known as non-reentrant tachycardias)
Aortic dilatation (typically mild, noted in fewer than 10% of individuals)
Hypertension
Chiari I malformation (may develop over time)
Hydrocephalus
Syringomyelia
Tethered cord
Seizures
Developmental delay or intellectual disability
Findings suggestive of autism spectrum disorder in early infancy (that typically improve by age four years)
Sociable, outgoing personality
Anxiety
Posterior fossa crowding with cerebellar tonsillar ectopia or herniation
Tethered cord
Ventriculomegaly or hydrocephalus
Because Costello syndrome is typically caused by a
The clinical diagnosis of Costello syndrome can be
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the clinical findings suggest the diagnosis of Costello syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of Costello syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Costello Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
More than 95% of pathogenic variants causing Costello syndrome affect amino acid residues p.Gly12 or p.Gly13.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Costello syndrome is caused by pathogenic activating
• On ultrasound examination:
• Increased nuchal thickness
• Polyhydramnios (>90%)
• Characteristic ulnar deviation of the wrists
• Short humeri and femurs
• Increased nuchal thickness
• Polyhydramnios (>90%)
• Characteristic ulnar deviation of the wrists
• Short humeri and femurs
• Fetal tachycardia (various forms of atrial tachycardia)
• Preterm delivery
• Increased nuchal thickness
• Polyhydramnios (>90%)
• Characteristic ulnar deviation of the wrists
• Short humeri and femurs
• Severe postnatal feeding difficulties extending throughout early childhood
• Failure to thrive
• Short stature
• Macrocephaly (relative or absolute)
• Coarse facial features (See
• Curly or sparse, fine hair
• Loose, soft skin
• Increased pigmentation
• Deep palmar and plantar creases
• Papillomata of face and/or perianal region (typically absent in infancy but may appear in childhood)
• Hyperkeratosis and calluses
• Premature aging with hair loss
• Diffuse hypotonia, joint laxity, and low muscle mass
• Ulnar deviation of wrists and fingers; splayed fingers resulting in characteristic hand posture
• Spatulate finger pads, abnormal fingernails
• Tight Achilles tendons (often evolving throughout childhood)
• Positional foot deformity
• Vertical talus
• Kyphoscoliosis
• Pectus carinatum, pectus excavatum, asymmetric rib cage
• Developmental hip dysplasia
• Cardiac hypertrophy, usually hypertrophic cardiomyopathy (i.e., idiopathic subaortic stenosis, asymmetric septal hypertrophy), although other forms (e.g., biventricular hypertrophy) have been reported
• Congenital heart defects, usually valvular pulmonic stenosis
• Arrhythmia, usually supraventricular tachycardia. Most distinctive is chaotic atrial rhythm / multifocal atrial tachycardia or ectopic atrial tachycardia (known as non-reentrant tachycardias)
• Aortic dilatation (typically mild, noted in fewer than 10% of individuals)
• Hypertension
• Chiari I malformation (may develop over time)
• Hydrocephalus
• Syringomyelia
• Tethered cord
• Seizures
• Developmental delay or intellectual disability
• Findings suggestive of autism spectrum disorder in early infancy (that typically improve by age four years)
• Sociable, outgoing personality
• Anxiety
• Posterior fossa crowding with cerebellar tonsillar ectopia or herniation
• Tethered cord
• Ventriculomegaly or hydrocephalus
• For an introduction to multigene panels click
## Suggestive Findings
Costello syndrome
On ultrasound examination:
Increased nuchal thickness
Polyhydramnios (>90%)
Characteristic ulnar deviation of the wrists
Short humeri and femurs
Fetal tachycardia (various forms of atrial tachycardia)
Preterm delivery
Severe postnatal feeding difficulties extending throughout early childhood
Failure to thrive
Short stature
Macrocephaly (relative or absolute)
Coarse facial features (See
Curly or sparse, fine hair
Loose, soft skin
Increased pigmentation
Deep palmar and plantar creases
Papillomata of face and/or perianal region (typically absent in infancy but may appear in childhood)
Hyperkeratosis and calluses
Premature aging with hair loss
Diffuse hypotonia, joint laxity, and low muscle mass
Ulnar deviation of wrists and fingers; splayed fingers resulting in characteristic hand posture
Spatulate finger pads, abnormal fingernails
Tight Achilles tendons (often evolving throughout childhood)
Positional foot deformity
Vertical talus
Kyphoscoliosis
Pectus carinatum, pectus excavatum, asymmetric rib cage
Developmental hip dysplasia
Cardiac hypertrophy, usually hypertrophic cardiomyopathy (i.e., idiopathic subaortic stenosis, asymmetric septal hypertrophy), although other forms (e.g., biventricular hypertrophy) have been reported
Congenital heart defects, usually valvular pulmonic stenosis
Arrhythmia, usually supraventricular tachycardia. Most distinctive is chaotic atrial rhythm / multifocal atrial tachycardia or ectopic atrial tachycardia (known as non-reentrant tachycardias)
Aortic dilatation (typically mild, noted in fewer than 10% of individuals)
Hypertension
Chiari I malformation (may develop over time)
Hydrocephalus
Syringomyelia
Tethered cord
Seizures
Developmental delay or intellectual disability
Findings suggestive of autism spectrum disorder in early infancy (that typically improve by age four years)
Sociable, outgoing personality
Anxiety
Posterior fossa crowding with cerebellar tonsillar ectopia or herniation
Tethered cord
Ventriculomegaly or hydrocephalus
Because Costello syndrome is typically caused by a
• On ultrasound examination:
• Increased nuchal thickness
• Polyhydramnios (>90%)
• Characteristic ulnar deviation of the wrists
• Short humeri and femurs
• Increased nuchal thickness
• Polyhydramnios (>90%)
• Characteristic ulnar deviation of the wrists
• Short humeri and femurs
• Fetal tachycardia (various forms of atrial tachycardia)
• Preterm delivery
• Increased nuchal thickness
• Polyhydramnios (>90%)
• Characteristic ulnar deviation of the wrists
• Short humeri and femurs
• Severe postnatal feeding difficulties extending throughout early childhood
• Failure to thrive
• Short stature
• Macrocephaly (relative or absolute)
• Coarse facial features (See
• Curly or sparse, fine hair
• Loose, soft skin
• Increased pigmentation
• Deep palmar and plantar creases
• Papillomata of face and/or perianal region (typically absent in infancy but may appear in childhood)
• Hyperkeratosis and calluses
• Premature aging with hair loss
• Diffuse hypotonia, joint laxity, and low muscle mass
• Ulnar deviation of wrists and fingers; splayed fingers resulting in characteristic hand posture
• Spatulate finger pads, abnormal fingernails
• Tight Achilles tendons (often evolving throughout childhood)
• Positional foot deformity
• Vertical talus
• Kyphoscoliosis
• Pectus carinatum, pectus excavatum, asymmetric rib cage
• Developmental hip dysplasia
• Cardiac hypertrophy, usually hypertrophic cardiomyopathy (i.e., idiopathic subaortic stenosis, asymmetric septal hypertrophy), although other forms (e.g., biventricular hypertrophy) have been reported
• Congenital heart defects, usually valvular pulmonic stenosis
• Arrhythmia, usually supraventricular tachycardia. Most distinctive is chaotic atrial rhythm / multifocal atrial tachycardia or ectopic atrial tachycardia (known as non-reentrant tachycardias)
• Aortic dilatation (typically mild, noted in fewer than 10% of individuals)
• Hypertension
• Chiari I malformation (may develop over time)
• Hydrocephalus
• Syringomyelia
• Tethered cord
• Seizures
• Developmental delay or intellectual disability
• Findings suggestive of autism spectrum disorder in early infancy (that typically improve by age four years)
• Sociable, outgoing personality
• Anxiety
• Posterior fossa crowding with cerebellar tonsillar ectopia or herniation
• Tethered cord
• Ventriculomegaly or hydrocephalus
## Clinical Findings
On ultrasound examination:
Increased nuchal thickness
Polyhydramnios (>90%)
Characteristic ulnar deviation of the wrists
Short humeri and femurs
Fetal tachycardia (various forms of atrial tachycardia)
Preterm delivery
Severe postnatal feeding difficulties extending throughout early childhood
Failure to thrive
Short stature
Macrocephaly (relative or absolute)
Coarse facial features (See
Curly or sparse, fine hair
Loose, soft skin
Increased pigmentation
Deep palmar and plantar creases
Papillomata of face and/or perianal region (typically absent in infancy but may appear in childhood)
Hyperkeratosis and calluses
Premature aging with hair loss
Diffuse hypotonia, joint laxity, and low muscle mass
Ulnar deviation of wrists and fingers; splayed fingers resulting in characteristic hand posture
Spatulate finger pads, abnormal fingernails
Tight Achilles tendons (often evolving throughout childhood)
Positional foot deformity
Vertical talus
Kyphoscoliosis
Pectus carinatum, pectus excavatum, asymmetric rib cage
Developmental hip dysplasia
Cardiac hypertrophy, usually hypertrophic cardiomyopathy (i.e., idiopathic subaortic stenosis, asymmetric septal hypertrophy), although other forms (e.g., biventricular hypertrophy) have been reported
Congenital heart defects, usually valvular pulmonic stenosis
Arrhythmia, usually supraventricular tachycardia. Most distinctive is chaotic atrial rhythm / multifocal atrial tachycardia or ectopic atrial tachycardia (known as non-reentrant tachycardias)
Aortic dilatation (typically mild, noted in fewer than 10% of individuals)
Hypertension
Chiari I malformation (may develop over time)
Hydrocephalus
Syringomyelia
Tethered cord
Seizures
Developmental delay or intellectual disability
Findings suggestive of autism spectrum disorder in early infancy (that typically improve by age four years)
Sociable, outgoing personality
Anxiety
Posterior fossa crowding with cerebellar tonsillar ectopia or herniation
Tethered cord
Ventriculomegaly or hydrocephalus
• On ultrasound examination:
• Increased nuchal thickness
• Polyhydramnios (>90%)
• Characteristic ulnar deviation of the wrists
• Short humeri and femurs
• Increased nuchal thickness
• Polyhydramnios (>90%)
• Characteristic ulnar deviation of the wrists
• Short humeri and femurs
• Fetal tachycardia (various forms of atrial tachycardia)
• Preterm delivery
• Increased nuchal thickness
• Polyhydramnios (>90%)
• Characteristic ulnar deviation of the wrists
• Short humeri and femurs
• Severe postnatal feeding difficulties extending throughout early childhood
• Failure to thrive
• Short stature
• Macrocephaly (relative or absolute)
• Coarse facial features (See
• Curly or sparse, fine hair
• Loose, soft skin
• Increased pigmentation
• Deep palmar and plantar creases
• Papillomata of face and/or perianal region (typically absent in infancy but may appear in childhood)
• Hyperkeratosis and calluses
• Premature aging with hair loss
• Diffuse hypotonia, joint laxity, and low muscle mass
• Ulnar deviation of wrists and fingers; splayed fingers resulting in characteristic hand posture
• Spatulate finger pads, abnormal fingernails
• Tight Achilles tendons (often evolving throughout childhood)
• Positional foot deformity
• Vertical talus
• Kyphoscoliosis
• Pectus carinatum, pectus excavatum, asymmetric rib cage
• Developmental hip dysplasia
• Cardiac hypertrophy, usually hypertrophic cardiomyopathy (i.e., idiopathic subaortic stenosis, asymmetric septal hypertrophy), although other forms (e.g., biventricular hypertrophy) have been reported
• Congenital heart defects, usually valvular pulmonic stenosis
• Arrhythmia, usually supraventricular tachycardia. Most distinctive is chaotic atrial rhythm / multifocal atrial tachycardia or ectopic atrial tachycardia (known as non-reentrant tachycardias)
• Aortic dilatation (typically mild, noted in fewer than 10% of individuals)
• Hypertension
• Chiari I malformation (may develop over time)
• Hydrocephalus
• Syringomyelia
• Tethered cord
• Seizures
• Developmental delay or intellectual disability
• Findings suggestive of autism spectrum disorder in early infancy (that typically improve by age four years)
• Sociable, outgoing personality
• Anxiety
• Posterior fossa crowding with cerebellar tonsillar ectopia or herniation
• Tethered cord
• Ventriculomegaly or hydrocephalus
## Family History
Because Costello syndrome is typically caused by a
## Establishing the Diagnosis
The clinical diagnosis of Costello syndrome can be
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the clinical findings suggest the diagnosis of Costello syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of Costello syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Costello Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
More than 95% of pathogenic variants causing Costello syndrome affect amino acid residues p.Gly12 or p.Gly13.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Costello syndrome is caused by pathogenic activating
• For an introduction to multigene panels click
## Option 1
When the clinical findings suggest the diagnosis of Costello syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the diagnosis of Costello syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Costello Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
More than 95% of pathogenic variants causing Costello syndrome affect amino acid residues p.Gly12 or p.Gly13.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Costello syndrome is caused by pathogenic activating
## Clinical Characteristics
To date, more than 100 individuals have been identified with a pathogenic variant in
Costello Syndrome: Frequency of Select Features
Inability to eat by mouth is common throughout infancy & early childhood.
Weight gain remains slow, even w/feeding tube use & high caloric intake.
Based on
GH = growth hormone; HCM = hypertrophic cardiomyopathy
Failure to thrive and severe feeding difficulties are almost universal and typically require a gastrostomy tube. Anecdotally, affected children have very high caloric needs. Even after nutrition is improved through supplemental feeding, growth restriction persists; therefore, aggressive (hypercaloric) feeding therapy is not effective. Children are typically able to take oral feeds beginning between ages two and four years.
Normative growth charts, derived from measurements of individuals who had not used growth hormone, document very slow weight gain in early infancy as well as short stature, with the 95th centile for individuals with Costello syndrome falling into the low-normal range of typical age-matched individuals [
Hypotonia may be severe with low muscle mass and a skeletal myopathy phenotype [
Progressive postnatal cerebellar overgrowth may result in the development of Chiari I malformation, syringomyelia, and hydrocephalus [
EEG abnormalities are seen in approximately one third of individuals; between 20% and 50% have seizures [
A few neonates can present with very severe HCM that is lethal. In other infants, progressively severe HCM and/or severe multifocal atrial tachycardia can lead to death in the first two years of life. Use of the MEK inhibitor trametinib may be considered in these individuals [
Pulmonic valve stenosis is usually mild to moderate, and infrequently requires surgery or interventional catheterization.
Most children with HCM have either mild or moderate involvement. Of great interest are the few with moderate-to-severe involvement who appear to have "remodeling" over many years that gives the impression of disappearance of (or marked decrease in) left ventricular obstruction. Only a small number of these individuals are being followed, and their long-term natural history is incomplete [
Non-reentrant atrial tachycardias are generally self-limited but may persist or worsen in approximately one fourth of affected individuals. Non-reentrant atrial tachycardia occurs independently of HCM [
Older individuals (ages 16 to 40 years) with moderate HCM or new-onset arrhythmia (both atrial and ventricular) represent the greatest challenge, and the outcomes in these individuals are not known. Hypertension is not uncommon.
Mild-to-moderate aortic dilatation not associated with bicuspid aortic valve is reported in approximately 5% of affected individuals [
Primary vascular disease has rarely been reported.
Recognition memory in verbal memory functioning is relatively preserved compared to other cognitive tasks [
While the underlying mechanism in Costello syndrome is not known, the skills necessary for swallowing and speech development are both affected and appear closely correlated. The onset of speech frequently coincides with the willingness to feed orally.
Separation anxiety, seen in 39% of individuals with Costello syndrome, is more common in males than in females [
Limited detailed information is available on the quality of life in older individuals with Costello syndrome. Quality of life in individuals aged 16-34 years is compromised by four factors: limited relationships outside of the immediate circle of friends and family, lack of independence, male sex, and the presence of major medical issues [
Palmoplantar keratoderma is common and can affect function in severe cases [
More than half of a cohort of 43 individuals examined by an orthopedic surgeon with review of available radiographs showed ligamentous laxity, scoliosis, kyphosis, characteristic hand and wrist deformities, shoulder and elbow contractures, tight Achilles tendons, and flat feet [
Osteoporosis is common in young adults with Costello syndrome [
More severe complications (intrauterine hydrops, postnatal pulmonary effusions with respiratory compromise, and severe progressive HCM) have been reported in a few individuals with
Upper airway obstruction was seen more often in older children and young adults [
In older individuals, hypoglycemia may be related to growth hormone deficiency. Growth hormone deficiency is common (30%-50%) [
Several affected individuals have been diagnosed with hypothyroidism requiring thyroid hormone replacement.
Other endocrine issues may include delayed or dysregulated puberty including precocious puberty.
In a meta-analysis of 234 publications reporting 621 individuals from 35 countries, more than 9% had cancer, including rhabdomyosarcoma, transitional cell carcinoma of the bladder, and neuroblastoma. Cumulative incidence by age 20 years was 13% for cancer and 11% for cancer-free death. Death rate was 3%-4% until age three years. Survival after cancer appeared reduced [
Rhabdomyosarcoma and neuroblastoma, tumors of early childhood, present in Costello syndrome at ages comparable to the general population. In contrast, transitional cell carcinoma of the bladder, which occurs in older adults (70% occurs in adults age >65 years) in the general population, may be found in adolescents with Costello syndrome. The ages at presentation in the three individuals with Costello syndrome with transitional cell carcinoma of the bladder were ten, 11, and 16 years. A review of cystoscopy findings in 13 individuals aged ten years or older found a macroscopic bladder lesion in 10/13 on first exam. Histology showed low-grade epithelial dysplasia in 7/10 (70%) and papillary urothelial neoplasm of low-malignant potential (PUNLMP) or low-grade bladder cancer in 3/10 (30%) [
Pyloric stenosis occurs more commonly in Costello syndrome than in the general population [
Craniosynostosis of the sagittal and/or coronal sutures requiring surgical repair has been reported in several individuals [
Cryptorchidism is frequent, structural ureteral or renal abnormalities may be found, and urachal remnants have been noted in multiple individuals [
Adult-onset gastroesophageal reflux was present in four individuals in
Dental abnormalities, including enamel defects, occur frequently. Malocclusion with maxillary first molars positioned posteriorly to the mandibular first molars is common and may contribute to obstructive sleep apnea [
In addition to the common vision disturbance and nystagmus, less common eye abnormalities include retinal dystrophy [
Adolescents may appear older than their chronologic age because of worsening kyphoscoliosis, sparse hair, and prematurely aged skin.
Tethered cord is relatively common.
One individual with somatic mosaicism (20%-30% of DNA derived from buccal cells had the pathogenic
In a systematic review of 146 individuals with an
Because few affected individuals with
The p.Gly13 amino acid appears to be the second most commonly affected residue, with
The suggestion of
The possibility of a milder or attenuated phenotype was noted in individuals with the pathogenic variants
Two unrelated individuals with
Five individuals with the rare
In rare instances related to the underlying pathogenic
In one individual with early-lethal Costello syndrome due to the rare
In a recent meta-analysis of cancer risk in Costello syndrome, the rate of cancer and death associated with p.Gly12Ser were lower when compared to all other pathogenic variants affecting the same amino acid (tumor risk assessed to be 9.2% for p.Gly12Ser, 38.7% for p.Gly12Ala, and 37.5% for p.Gly12Cys) (P <0.05). Higher mortality for p.Gly12Cys, p.Gly12Asp,
Penetrance for Costello syndrome is 100% to date [
Costello reported the first individuals with this condition in 1971, providing follow up in 1977 and 1996 [
Early examples of Costello syndrome were reported as:
AMICABLE syndrome (
Faciocutaneous-skeletal syndrome [
The birth prevalence of Costello syndrome is estimated to be 1:380,000 in the United Kingdom [
• Inability to eat by mouth is common throughout infancy & early childhood.
• Weight gain remains slow, even w/feeding tube use & high caloric intake.
• Pyloric stenosis occurs more commonly in Costello syndrome than in the general population [
• Craniosynostosis of the sagittal and/or coronal sutures requiring surgical repair has been reported in several individuals [
• Cryptorchidism is frequent, structural ureteral or renal abnormalities may be found, and urachal remnants have been noted in multiple individuals [
• Adult-onset gastroesophageal reflux was present in four individuals in
• Dental abnormalities, including enamel defects, occur frequently. Malocclusion with maxillary first molars positioned posteriorly to the mandibular first molars is common and may contribute to obstructive sleep apnea [
• In addition to the common vision disturbance and nystagmus, less common eye abnormalities include retinal dystrophy [
• Adolescents may appear older than their chronologic age because of worsening kyphoscoliosis, sparse hair, and prematurely aged skin.
• The p.Gly13 amino acid appears to be the second most commonly affected residue, with
• The suggestion of
• The possibility of a milder or attenuated phenotype was noted in individuals with the pathogenic variants
• Two unrelated individuals with
• Five individuals with the rare
• AMICABLE syndrome (
• Faciocutaneous-skeletal syndrome [
## Clinical Description
To date, more than 100 individuals have been identified with a pathogenic variant in
Costello Syndrome: Frequency of Select Features
Inability to eat by mouth is common throughout infancy & early childhood.
Weight gain remains slow, even w/feeding tube use & high caloric intake.
Based on
GH = growth hormone; HCM = hypertrophic cardiomyopathy
Failure to thrive and severe feeding difficulties are almost universal and typically require a gastrostomy tube. Anecdotally, affected children have very high caloric needs. Even after nutrition is improved through supplemental feeding, growth restriction persists; therefore, aggressive (hypercaloric) feeding therapy is not effective. Children are typically able to take oral feeds beginning between ages two and four years.
Normative growth charts, derived from measurements of individuals who had not used growth hormone, document very slow weight gain in early infancy as well as short stature, with the 95th centile for individuals with Costello syndrome falling into the low-normal range of typical age-matched individuals [
Hypotonia may be severe with low muscle mass and a skeletal myopathy phenotype [
Progressive postnatal cerebellar overgrowth may result in the development of Chiari I malformation, syringomyelia, and hydrocephalus [
EEG abnormalities are seen in approximately one third of individuals; between 20% and 50% have seizures [
A few neonates can present with very severe HCM that is lethal. In other infants, progressively severe HCM and/or severe multifocal atrial tachycardia can lead to death in the first two years of life. Use of the MEK inhibitor trametinib may be considered in these individuals [
Pulmonic valve stenosis is usually mild to moderate, and infrequently requires surgery or interventional catheterization.
Most children with HCM have either mild or moderate involvement. Of great interest are the few with moderate-to-severe involvement who appear to have "remodeling" over many years that gives the impression of disappearance of (or marked decrease in) left ventricular obstruction. Only a small number of these individuals are being followed, and their long-term natural history is incomplete [
Non-reentrant atrial tachycardias are generally self-limited but may persist or worsen in approximately one fourth of affected individuals. Non-reentrant atrial tachycardia occurs independently of HCM [
Older individuals (ages 16 to 40 years) with moderate HCM or new-onset arrhythmia (both atrial and ventricular) represent the greatest challenge, and the outcomes in these individuals are not known. Hypertension is not uncommon.
Mild-to-moderate aortic dilatation not associated with bicuspid aortic valve is reported in approximately 5% of affected individuals [
Primary vascular disease has rarely been reported.
Recognition memory in verbal memory functioning is relatively preserved compared to other cognitive tasks [
While the underlying mechanism in Costello syndrome is not known, the skills necessary for swallowing and speech development are both affected and appear closely correlated. The onset of speech frequently coincides with the willingness to feed orally.
Separation anxiety, seen in 39% of individuals with Costello syndrome, is more common in males than in females [
Limited detailed information is available on the quality of life in older individuals with Costello syndrome. Quality of life in individuals aged 16-34 years is compromised by four factors: limited relationships outside of the immediate circle of friends and family, lack of independence, male sex, and the presence of major medical issues [
Palmoplantar keratoderma is common and can affect function in severe cases [
More than half of a cohort of 43 individuals examined by an orthopedic surgeon with review of available radiographs showed ligamentous laxity, scoliosis, kyphosis, characteristic hand and wrist deformities, shoulder and elbow contractures, tight Achilles tendons, and flat feet [
Osteoporosis is common in young adults with Costello syndrome [
More severe complications (intrauterine hydrops, postnatal pulmonary effusions with respiratory compromise, and severe progressive HCM) have been reported in a few individuals with
Upper airway obstruction was seen more often in older children and young adults [
In older individuals, hypoglycemia may be related to growth hormone deficiency. Growth hormone deficiency is common (30%-50%) [
Several affected individuals have been diagnosed with hypothyroidism requiring thyroid hormone replacement.
Other endocrine issues may include delayed or dysregulated puberty including precocious puberty.
In a meta-analysis of 234 publications reporting 621 individuals from 35 countries, more than 9% had cancer, including rhabdomyosarcoma, transitional cell carcinoma of the bladder, and neuroblastoma. Cumulative incidence by age 20 years was 13% for cancer and 11% for cancer-free death. Death rate was 3%-4% until age three years. Survival after cancer appeared reduced [
Rhabdomyosarcoma and neuroblastoma, tumors of early childhood, present in Costello syndrome at ages comparable to the general population. In contrast, transitional cell carcinoma of the bladder, which occurs in older adults (70% occurs in adults age >65 years) in the general population, may be found in adolescents with Costello syndrome. The ages at presentation in the three individuals with Costello syndrome with transitional cell carcinoma of the bladder were ten, 11, and 16 years. A review of cystoscopy findings in 13 individuals aged ten years or older found a macroscopic bladder lesion in 10/13 on first exam. Histology showed low-grade epithelial dysplasia in 7/10 (70%) and papillary urothelial neoplasm of low-malignant potential (PUNLMP) or low-grade bladder cancer in 3/10 (30%) [
Pyloric stenosis occurs more commonly in Costello syndrome than in the general population [
Craniosynostosis of the sagittal and/or coronal sutures requiring surgical repair has been reported in several individuals [
Cryptorchidism is frequent, structural ureteral or renal abnormalities may be found, and urachal remnants have been noted in multiple individuals [
Adult-onset gastroesophageal reflux was present in four individuals in
Dental abnormalities, including enamel defects, occur frequently. Malocclusion with maxillary first molars positioned posteriorly to the mandibular first molars is common and may contribute to obstructive sleep apnea [
In addition to the common vision disturbance and nystagmus, less common eye abnormalities include retinal dystrophy [
Adolescents may appear older than their chronologic age because of worsening kyphoscoliosis, sparse hair, and prematurely aged skin.
Tethered cord is relatively common.
One individual with somatic mosaicism (20%-30% of DNA derived from buccal cells had the pathogenic
• Inability to eat by mouth is common throughout infancy & early childhood.
• Weight gain remains slow, even w/feeding tube use & high caloric intake.
• Pyloric stenosis occurs more commonly in Costello syndrome than in the general population [
• Craniosynostosis of the sagittal and/or coronal sutures requiring surgical repair has been reported in several individuals [
• Cryptorchidism is frequent, structural ureteral or renal abnormalities may be found, and urachal remnants have been noted in multiple individuals [
• Adult-onset gastroesophageal reflux was present in four individuals in
• Dental abnormalities, including enamel defects, occur frequently. Malocclusion with maxillary first molars positioned posteriorly to the mandibular first molars is common and may contribute to obstructive sleep apnea [
• In addition to the common vision disturbance and nystagmus, less common eye abnormalities include retinal dystrophy [
• Adolescents may appear older than their chronologic age because of worsening kyphoscoliosis, sparse hair, and prematurely aged skin.
## Genotype-Phenotype Correlations
In a systematic review of 146 individuals with an
Because few affected individuals with
The p.Gly13 amino acid appears to be the second most commonly affected residue, with
The suggestion of
The possibility of a milder or attenuated phenotype was noted in individuals with the pathogenic variants
Two unrelated individuals with
Five individuals with the rare
In rare instances related to the underlying pathogenic
In one individual with early-lethal Costello syndrome due to the rare
In a recent meta-analysis of cancer risk in Costello syndrome, the rate of cancer and death associated with p.Gly12Ser were lower when compared to all other pathogenic variants affecting the same amino acid (tumor risk assessed to be 9.2% for p.Gly12Ser, 38.7% for p.Gly12Ala, and 37.5% for p.Gly12Cys) (P <0.05). Higher mortality for p.Gly12Cys, p.Gly12Asp,
• The p.Gly13 amino acid appears to be the second most commonly affected residue, with
• The suggestion of
• The possibility of a milder or attenuated phenotype was noted in individuals with the pathogenic variants
• Two unrelated individuals with
• Five individuals with the rare
## Penetrance
Penetrance for Costello syndrome is 100% to date [
## Nomenclature
Costello reported the first individuals with this condition in 1971, providing follow up in 1977 and 1996 [
Early examples of Costello syndrome were reported as:
AMICABLE syndrome (
Faciocutaneous-skeletal syndrome [
• AMICABLE syndrome (
• Faciocutaneous-skeletal syndrome [
## Prevalence
The birth prevalence of Costello syndrome is estimated to be 1:380,000 in the United Kingdom [
## Genetically Related (Allelic) Disorders
Schimmelpenning-Feuerstein-Mims syndrome (also referred to as linear sebaceous nevus syndrome [OMIM
Cutaneous-skeletal hypophosphatemia syndrome consists of ectodermal findings including epidermal nevi and elevated fibroblast growth factor 23 with hypophosphatemia and can be due to mosaic
• Schimmelpenning-Feuerstein-Mims syndrome (also referred to as linear sebaceous nevus syndrome [OMIM
• Cutaneous-skeletal hypophosphatemia syndrome consists of ectodermal findings including epidermal nevi and elevated fibroblast growth factor 23 with hypophosphatemia and can be due to mosaic
## Differential Diagnosis
No other loci have been identified as causative of
Note: While Costello syndrome is difficult to distinguish from CFC syndrome or Noonan syndrome in infants and young children, the distinction between Costello syndrome and Noonan syndrome is clearer in older children.
Disorders of Interest in the Differential Diagnosis of Costello Syndrome
Resembles CS in infants & young children
Hypotonia
Nystagmus
Mild-to-moderate ID
Postnatal growth deficiency
Feeding difficulties (may be less severe than in CS)
Dolichocephaly, high forehead, & slightly coarse facial features
Pulmonic valve stenosis & ASD
HCM
Lips not as thick & prominent
Hair more consistently sparse or curly
Eyebrows typically sparse or absent
Skin abnormalities incl severe atopic dermatitis, keratosis pilaris, & ichthyosis; absence of papillomata
Malignant tumors rarely reported
Resembles CS in infants & young children
Short stature
DD of variable degree & mild ID
Congenital heart defects incl pulmonary valve stenosis often w/dysplasia; HMC (may be present at birth or appear in infancy or childhood); ASD & VSD; branch pulmonary artery stenosis; tetralogy of Fallot
Cryptorchidism
Distinctive combination of pectus carinatum & pectus excavatum
Broad or webbed neck
Characteristic facies
Varied coagulation defects & lymphatic dysplasia
Birth length usually normal
Final adult height near lower limit of normal
In newborns: apparent "overgrowth" (more accurately: ↑ birth weight due to edema); protruding tongue; coarse facial features; hypoglycemia; HCM
Embryonal tumors
Macrosomia
Macroglossia
Visceromegaly
Omphalocele
Ear creases/pits
Adrenocortical cytomegaly
Renal abnormalities
Soft skin
Ligamentous laxity of small joints
Full lips
Friendly personality w/anxious demeanor in adolescence
ID
Specific cognitive profile
Unique personality characteristics
Distinctive facial features
Cardiovascular disease (elastin arteriopathy)
Range of connective tissue abnormalities
Hypercalcemia
AD = autosomal dominant; AR = autosomal recessive; ASD = atrial septal defect; CS = Costello syndrome; CNV = copy number variant; DD = developmental delay; HCM = hypertrophic cardiomyopathy; ID = intellectual disability; MOI = mode of inheritance; VSD = ventricular septal defects; WBSCR = Williams-Beuren syndrome critical region
The ~40% incidence of hypertrophic cardiomyopathy in individuals with a molecular diagnosis of CFC is similar to that observed in Costello syndrome [
Noonan syndrome is most often inherited in an autosomal dominant manner. Noonan syndrome caused by pathogenic variants in
• Resembles CS in infants & young children
• Hypotonia
• Nystagmus
• Mild-to-moderate ID
• Postnatal growth deficiency
• Feeding difficulties (may be less severe than in CS)
• Dolichocephaly, high forehead, & slightly coarse facial features
• Pulmonic valve stenosis & ASD
• HCM
• Lips not as thick & prominent
• Hair more consistently sparse or curly
• Eyebrows typically sparse or absent
• Skin abnormalities incl severe atopic dermatitis, keratosis pilaris, & ichthyosis; absence of papillomata
• Malignant tumors rarely reported
• Resembles CS in infants & young children
• Short stature
• DD of variable degree & mild ID
• Congenital heart defects incl pulmonary valve stenosis often w/dysplasia; HMC (may be present at birth or appear in infancy or childhood); ASD & VSD; branch pulmonary artery stenosis; tetralogy of Fallot
• Cryptorchidism
• Distinctive combination of pectus carinatum & pectus excavatum
• Broad or webbed neck
• Characteristic facies
• Varied coagulation defects & lymphatic dysplasia
• Birth length usually normal
• Final adult height near lower limit of normal
• In newborns: apparent "overgrowth" (more accurately: ↑ birth weight due to edema); protruding tongue; coarse facial features; hypoglycemia; HCM
• Embryonal tumors
• Macrosomia
• Macroglossia
• Visceromegaly
• Omphalocele
• Ear creases/pits
• Adrenocortical cytomegaly
• Renal abnormalities
• Soft skin
• Ligamentous laxity of small joints
• Full lips
• Friendly personality w/anxious demeanor in adolescence
• ID
• Specific cognitive profile
• Unique personality characteristics
• Distinctive facial features
• Cardiovascular disease (elastin arteriopathy)
• Range of connective tissue abnormalities
• Hypercalcemia
## Management
Clinical practice guidelines for the management of
To establish the extent of disease and needs in an individual diagnosed with Costello syndrome, the evaluations summarized in
Costello Syndrome: Recommended Evaluations Following Initial Diagnosis
Severe oral feeding difficulties are common in infants & young children; a feeding tube is typically necessary.
FTT is common even with adequate caloric intake.
Brain MRI for Chiari I malformation
MRI & radiographs of lower spine to assess for tethered cord
Spinal cord MRI if syringomyelia suspected
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Assessment of males for cryptorchidism
Renal ultrasound for structural anomalies
Nystagmus & vision disturbance are common.
Retinal dystrophy & keratoconus are rare.
Community or
Social work involvement for parental support
Home nursing referral
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
ADHD = attention-deficient/hyperactivity disorder; CS = Costello syndrome; FTT = failure to thrive; GERD = gastroesophageal reflux disease; GH = growth hormone; HCM = hypertrophic cardiomyopathy
Costello Syndrome: Targeted Therapy
MEK inhibitors have been used for severe cardiac hypertrophy in persons w/Costello syndrome & should be considered for treatment of HCM w/heart failure that is refractory to standard treatment.
HCM = hypertrophic cardiomyopathy
There is no cure for Costello syndrome. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Costello Syndrome: Treatment of Manifestations
Feeding therapy
Gastrostomy tube placement is commonly required for persistent feeding issues.
May need Nissen fundoplication for GERD & irritability
May consider pureed foods by G-tube
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Pharmacologic & surgical treatment (myectomy) have been used for severe cardiac hypertrophy.
Consider MedicAlert
OSA may cause sleep disturbance.
Tracheostomy w/ or w/o ventilatory support is required for some.
Mandibular distraction may be considered.
Tonsil/adenoid surgery may also be considered.
Surgical tendon lengthening (usually Achilles tendon) is often required.
Hip joint abnormalities may require surgical intervention.
Nystagmus: no treatment
Visual impairment: educational intervention
Refractive error: spectacle correction
Keratoconus: specialist eval & treatment
Anesthesia may pose a risk in those w/unrecognized HCM &/or predisposition to some types of atrial tachycardia.
Relatively high doses of medication may be required for sedation. No standardized information is available; review of medical records documenting previous dosages may provide guidance.
Ensure appropriate social work involvement to connect families w/ local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; GH = growth hormone; HCM = hypertrophic cardiomyopathy; OSA = obstructive sleep apnea; OT = occupational therapy; PT = physical therapy; SBE = subacute bacterial endocarditis
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
It is suggested that treatment of confirmed growth hormone deficiency should proceed only after a cardiac evaluation for hypertrophic cardiomyopathy.
True GH deficiency requires GH replacement. Three individuals with GH deficiency showed increased growth velocity without adverse effects after three to seven years of replacement therapy, but two continued to have short stature [
It is unclear from the literature if the use of GH is beneficial in individuals with Costello syndrome with partial GH deficiency. An abnormal GH response on testing and a good initial growth response have been reported [
Bladder carcinoma occurred in an individual age 16 years treated with GH [
A rhabdomyosarcoma was diagnosed in an individual age 26 months receiving GH from age 12 months [
On review of 35 affected individuals, 16 had documented GH deficiency (46%). Thirteen of these 16 received GH treatment (37%). In this cohort, 7/35 had tumors, including four rhabdomyosarcomas, one pituitary adenoma, one benign bladder tumor, and one bladder carcinoma. Of the seven with tumors, four (57%) were naïve to GH at the time of tumor diagnosis and three (43%) received GH prior to tumor diagnosis. Of the individuals who developed rhabdomyosarcoma, two never received GH, one received GH after tumor diagnosis, and one received GH prior to the diagnosis of rhabdomyosarcoma [
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation, osteopenia).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Costello Syndrome: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
By cardiologist familiar w/spectrum of cardiac disease in CS & its natural history
Transitioning from pediatric cardiologist to adult specialist when age appropriate
CS = Costello syndrome; GH = growth hormone
General guidelines [
To date, neither screening approach has been shown to be beneficial; studies are ongoing. The most important factor for early tumor detection is parental and physician awareness of the increased cancer risk [
Because elevated catecholamine metabolites were observed in individuals with Costello syndrome without an identifiable tumor, it was concluded that screening for abnormal catecholamine metabolites is not helpful [
Aggressive feeding therapy in infancy and early childhood is not likely to improve oral intake and may result in oral aversion.
Neuroblastoma screening by measuring catecholamine metabolites is not helpful because elevated values were observed in individuals without an identifiable tumor.
See
Search
• Severe oral feeding difficulties are common in infants & young children; a feeding tube is typically necessary.
• FTT is common even with adequate caloric intake.
• Brain MRI for Chiari I malformation
• MRI & radiographs of lower spine to assess for tethered cord
• Spinal cord MRI if syringomyelia suspected
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Assessment of males for cryptorchidism
• Renal ultrasound for structural anomalies
• Nystagmus & vision disturbance are common.
• Retinal dystrophy & keratoconus are rare.
• Community or
• Social work involvement for parental support
• Home nursing referral
• Feeding therapy
• Gastrostomy tube placement is commonly required for persistent feeding issues.
• May need Nissen fundoplication for GERD & irritability
• May consider pureed foods by G-tube
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Pharmacologic & surgical treatment (myectomy) have been used for severe cardiac hypertrophy.
• Consider MedicAlert
• OSA may cause sleep disturbance.
• Tracheostomy w/ or w/o ventilatory support is required for some.
• Mandibular distraction may be considered.
• Tonsil/adenoid surgery may also be considered.
• Surgical tendon lengthening (usually Achilles tendon) is often required.
• Hip joint abnormalities may require surgical intervention.
• Nystagmus: no treatment
• Visual impairment: educational intervention
• Refractive error: spectacle correction
• Keratoconus: specialist eval & treatment
• Anesthesia may pose a risk in those w/unrecognized HCM &/or predisposition to some types of atrial tachycardia.
• Relatively high doses of medication may be required for sedation. No standardized information is available; review of medical records documenting previous dosages may provide guidance.
• Ensure appropriate social work involvement to connect families w/ local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• True GH deficiency requires GH replacement. Three individuals with GH deficiency showed increased growth velocity without adverse effects after three to seven years of replacement therapy, but two continued to have short stature [
• It is unclear from the literature if the use of GH is beneficial in individuals with Costello syndrome with partial GH deficiency. An abnormal GH response on testing and a good initial growth response have been reported [
• True GH deficiency requires GH replacement. Three individuals with GH deficiency showed increased growth velocity without adverse effects after three to seven years of replacement therapy, but two continued to have short stature [
• It is unclear from the literature if the use of GH is beneficial in individuals with Costello syndrome with partial GH deficiency. An abnormal GH response on testing and a good initial growth response have been reported [
• Bladder carcinoma occurred in an individual age 16 years treated with GH [
• A rhabdomyosarcoma was diagnosed in an individual age 26 months receiving GH from age 12 months [
• On review of 35 affected individuals, 16 had documented GH deficiency (46%). Thirteen of these 16 received GH treatment (37%). In this cohort, 7/35 had tumors, including four rhabdomyosarcomas, one pituitary adenoma, one benign bladder tumor, and one bladder carcinoma. Of the seven with tumors, four (57%) were naïve to GH at the time of tumor diagnosis and three (43%) received GH prior to tumor diagnosis. Of the individuals who developed rhabdomyosarcoma, two never received GH, one received GH after tumor diagnosis, and one received GH prior to the diagnosis of rhabdomyosarcoma [
• Bladder carcinoma occurred in an individual age 16 years treated with GH [
• A rhabdomyosarcoma was diagnosed in an individual age 26 months receiving GH from age 12 months [
• On review of 35 affected individuals, 16 had documented GH deficiency (46%). Thirteen of these 16 received GH treatment (37%). In this cohort, 7/35 had tumors, including four rhabdomyosarcomas, one pituitary adenoma, one benign bladder tumor, and one bladder carcinoma. Of the seven with tumors, four (57%) were naïve to GH at the time of tumor diagnosis and three (43%) received GH prior to tumor diagnosis. Of the individuals who developed rhabdomyosarcoma, two never received GH, one received GH after tumor diagnosis, and one received GH prior to the diagnosis of rhabdomyosarcoma [
• True GH deficiency requires GH replacement. Three individuals with GH deficiency showed increased growth velocity without adverse effects after three to seven years of replacement therapy, but two continued to have short stature [
• It is unclear from the literature if the use of GH is beneficial in individuals with Costello syndrome with partial GH deficiency. An abnormal GH response on testing and a good initial growth response have been reported [
• Bladder carcinoma occurred in an individual age 16 years treated with GH [
• A rhabdomyosarcoma was diagnosed in an individual age 26 months receiving GH from age 12 months [
• On review of 35 affected individuals, 16 had documented GH deficiency (46%). Thirteen of these 16 received GH treatment (37%). In this cohort, 7/35 had tumors, including four rhabdomyosarcomas, one pituitary adenoma, one benign bladder tumor, and one bladder carcinoma. Of the seven with tumors, four (57%) were naïve to GH at the time of tumor diagnosis and three (43%) received GH prior to tumor diagnosis. Of the individuals who developed rhabdomyosarcoma, two never received GH, one received GH after tumor diagnosis, and one received GH prior to the diagnosis of rhabdomyosarcoma [
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation, osteopenia).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• By cardiologist familiar w/spectrum of cardiac disease in CS & its natural history
• Transitioning from pediatric cardiologist to adult specialist when age appropriate
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Costello syndrome, the evaluations summarized in
Costello Syndrome: Recommended Evaluations Following Initial Diagnosis
Severe oral feeding difficulties are common in infants & young children; a feeding tube is typically necessary.
FTT is common even with adequate caloric intake.
Brain MRI for Chiari I malformation
MRI & radiographs of lower spine to assess for tethered cord
Spinal cord MRI if syringomyelia suspected
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Assessment of males for cryptorchidism
Renal ultrasound for structural anomalies
Nystagmus & vision disturbance are common.
Retinal dystrophy & keratoconus are rare.
Community or
Social work involvement for parental support
Home nursing referral
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
ADHD = attention-deficient/hyperactivity disorder; CS = Costello syndrome; FTT = failure to thrive; GERD = gastroesophageal reflux disease; GH = growth hormone; HCM = hypertrophic cardiomyopathy
• Severe oral feeding difficulties are common in infants & young children; a feeding tube is typically necessary.
• FTT is common even with adequate caloric intake.
• Brain MRI for Chiari I malformation
• MRI & radiographs of lower spine to assess for tethered cord
• Spinal cord MRI if syringomyelia suspected
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Assessment of males for cryptorchidism
• Renal ultrasound for structural anomalies
• Nystagmus & vision disturbance are common.
• Retinal dystrophy & keratoconus are rare.
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
Costello Syndrome: Targeted Therapy
MEK inhibitors have been used for severe cardiac hypertrophy in persons w/Costello syndrome & should be considered for treatment of HCM w/heart failure that is refractory to standard treatment.
HCM = hypertrophic cardiomyopathy
There is no cure for Costello syndrome. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Costello Syndrome: Treatment of Manifestations
Feeding therapy
Gastrostomy tube placement is commonly required for persistent feeding issues.
May need Nissen fundoplication for GERD & irritability
May consider pureed foods by G-tube
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Pharmacologic & surgical treatment (myectomy) have been used for severe cardiac hypertrophy.
Consider MedicAlert
OSA may cause sleep disturbance.
Tracheostomy w/ or w/o ventilatory support is required for some.
Mandibular distraction may be considered.
Tonsil/adenoid surgery may also be considered.
Surgical tendon lengthening (usually Achilles tendon) is often required.
Hip joint abnormalities may require surgical intervention.
Nystagmus: no treatment
Visual impairment: educational intervention
Refractive error: spectacle correction
Keratoconus: specialist eval & treatment
Anesthesia may pose a risk in those w/unrecognized HCM &/or predisposition to some types of atrial tachycardia.
Relatively high doses of medication may be required for sedation. No standardized information is available; review of medical records documenting previous dosages may provide guidance.
Ensure appropriate social work involvement to connect families w/ local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; GH = growth hormone; HCM = hypertrophic cardiomyopathy; OSA = obstructive sleep apnea; OT = occupational therapy; PT = physical therapy; SBE = subacute bacterial endocarditis
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
It is suggested that treatment of confirmed growth hormone deficiency should proceed only after a cardiac evaluation for hypertrophic cardiomyopathy.
True GH deficiency requires GH replacement. Three individuals with GH deficiency showed increased growth velocity without adverse effects after three to seven years of replacement therapy, but two continued to have short stature [
It is unclear from the literature if the use of GH is beneficial in individuals with Costello syndrome with partial GH deficiency. An abnormal GH response on testing and a good initial growth response have been reported [
Bladder carcinoma occurred in an individual age 16 years treated with GH [
A rhabdomyosarcoma was diagnosed in an individual age 26 months receiving GH from age 12 months [
On review of 35 affected individuals, 16 had documented GH deficiency (46%). Thirteen of these 16 received GH treatment (37%). In this cohort, 7/35 had tumors, including four rhabdomyosarcomas, one pituitary adenoma, one benign bladder tumor, and one bladder carcinoma. Of the seven with tumors, four (57%) were naïve to GH at the time of tumor diagnosis and three (43%) received GH prior to tumor diagnosis. Of the individuals who developed rhabdomyosarcoma, two never received GH, one received GH after tumor diagnosis, and one received GH prior to the diagnosis of rhabdomyosarcoma [
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation, osteopenia).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Feeding therapy
• Gastrostomy tube placement is commonly required for persistent feeding issues.
• May need Nissen fundoplication for GERD & irritability
• May consider pureed foods by G-tube
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Pharmacologic & surgical treatment (myectomy) have been used for severe cardiac hypertrophy.
• Consider MedicAlert
• OSA may cause sleep disturbance.
• Tracheostomy w/ or w/o ventilatory support is required for some.
• Mandibular distraction may be considered.
• Tonsil/adenoid surgery may also be considered.
• Surgical tendon lengthening (usually Achilles tendon) is often required.
• Hip joint abnormalities may require surgical intervention.
• Nystagmus: no treatment
• Visual impairment: educational intervention
• Refractive error: spectacle correction
• Keratoconus: specialist eval & treatment
• Anesthesia may pose a risk in those w/unrecognized HCM &/or predisposition to some types of atrial tachycardia.
• Relatively high doses of medication may be required for sedation. No standardized information is available; review of medical records documenting previous dosages may provide guidance.
• Ensure appropriate social work involvement to connect families w/ local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• True GH deficiency requires GH replacement. Three individuals with GH deficiency showed increased growth velocity without adverse effects after three to seven years of replacement therapy, but two continued to have short stature [
• It is unclear from the literature if the use of GH is beneficial in individuals with Costello syndrome with partial GH deficiency. An abnormal GH response on testing and a good initial growth response have been reported [
• True GH deficiency requires GH replacement. Three individuals with GH deficiency showed increased growth velocity without adverse effects after three to seven years of replacement therapy, but two continued to have short stature [
• It is unclear from the literature if the use of GH is beneficial in individuals with Costello syndrome with partial GH deficiency. An abnormal GH response on testing and a good initial growth response have been reported [
• Bladder carcinoma occurred in an individual age 16 years treated with GH [
• A rhabdomyosarcoma was diagnosed in an individual age 26 months receiving GH from age 12 months [
• On review of 35 affected individuals, 16 had documented GH deficiency (46%). Thirteen of these 16 received GH treatment (37%). In this cohort, 7/35 had tumors, including four rhabdomyosarcomas, one pituitary adenoma, one benign bladder tumor, and one bladder carcinoma. Of the seven with tumors, four (57%) were naïve to GH at the time of tumor diagnosis and three (43%) received GH prior to tumor diagnosis. Of the individuals who developed rhabdomyosarcoma, two never received GH, one received GH after tumor diagnosis, and one received GH prior to the diagnosis of rhabdomyosarcoma [
• Bladder carcinoma occurred in an individual age 16 years treated with GH [
• A rhabdomyosarcoma was diagnosed in an individual age 26 months receiving GH from age 12 months [
• On review of 35 affected individuals, 16 had documented GH deficiency (46%). Thirteen of these 16 received GH treatment (37%). In this cohort, 7/35 had tumors, including four rhabdomyosarcomas, one pituitary adenoma, one benign bladder tumor, and one bladder carcinoma. Of the seven with tumors, four (57%) were naïve to GH at the time of tumor diagnosis and three (43%) received GH prior to tumor diagnosis. Of the individuals who developed rhabdomyosarcoma, two never received GH, one received GH after tumor diagnosis, and one received GH prior to the diagnosis of rhabdomyosarcoma [
• True GH deficiency requires GH replacement. Three individuals with GH deficiency showed increased growth velocity without adverse effects after three to seven years of replacement therapy, but two continued to have short stature [
• It is unclear from the literature if the use of GH is beneficial in individuals with Costello syndrome with partial GH deficiency. An abnormal GH response on testing and a good initial growth response have been reported [
• Bladder carcinoma occurred in an individual age 16 years treated with GH [
• A rhabdomyosarcoma was diagnosed in an individual age 26 months receiving GH from age 12 months [
• On review of 35 affected individuals, 16 had documented GH deficiency (46%). Thirteen of these 16 received GH treatment (37%). In this cohort, 7/35 had tumors, including four rhabdomyosarcomas, one pituitary adenoma, one benign bladder tumor, and one bladder carcinoma. Of the seven with tumors, four (57%) were naïve to GH at the time of tumor diagnosis and three (43%) received GH prior to tumor diagnosis. Of the individuals who developed rhabdomyosarcoma, two never received GH, one received GH after tumor diagnosis, and one received GH prior to the diagnosis of rhabdomyosarcoma [
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation, osteopenia).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Targeted Therapy
Costello Syndrome: Targeted Therapy
MEK inhibitors have been used for severe cardiac hypertrophy in persons w/Costello syndrome & should be considered for treatment of HCM w/heart failure that is refractory to standard treatment.
HCM = hypertrophic cardiomyopathy
## Supportive Care
There is no cure for Costello syndrome. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Costello Syndrome: Treatment of Manifestations
Feeding therapy
Gastrostomy tube placement is commonly required for persistent feeding issues.
May need Nissen fundoplication for GERD & irritability
May consider pureed foods by G-tube
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Pharmacologic & surgical treatment (myectomy) have been used for severe cardiac hypertrophy.
Consider MedicAlert
OSA may cause sleep disturbance.
Tracheostomy w/ or w/o ventilatory support is required for some.
Mandibular distraction may be considered.
Tonsil/adenoid surgery may also be considered.
Surgical tendon lengthening (usually Achilles tendon) is often required.
Hip joint abnormalities may require surgical intervention.
Nystagmus: no treatment
Visual impairment: educational intervention
Refractive error: spectacle correction
Keratoconus: specialist eval & treatment
Anesthesia may pose a risk in those w/unrecognized HCM &/or predisposition to some types of atrial tachycardia.
Relatively high doses of medication may be required for sedation. No standardized information is available; review of medical records documenting previous dosages may provide guidance.
Ensure appropriate social work involvement to connect families w/ local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; GH = growth hormone; HCM = hypertrophic cardiomyopathy; OSA = obstructive sleep apnea; OT = occupational therapy; PT = physical therapy; SBE = subacute bacterial endocarditis
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
It is suggested that treatment of confirmed growth hormone deficiency should proceed only after a cardiac evaluation for hypertrophic cardiomyopathy.
True GH deficiency requires GH replacement. Three individuals with GH deficiency showed increased growth velocity without adverse effects after three to seven years of replacement therapy, but two continued to have short stature [
It is unclear from the literature if the use of GH is beneficial in individuals with Costello syndrome with partial GH deficiency. An abnormal GH response on testing and a good initial growth response have been reported [
Bladder carcinoma occurred in an individual age 16 years treated with GH [
A rhabdomyosarcoma was diagnosed in an individual age 26 months receiving GH from age 12 months [
On review of 35 affected individuals, 16 had documented GH deficiency (46%). Thirteen of these 16 received GH treatment (37%). In this cohort, 7/35 had tumors, including four rhabdomyosarcomas, one pituitary adenoma, one benign bladder tumor, and one bladder carcinoma. Of the seven with tumors, four (57%) were naïve to GH at the time of tumor diagnosis and three (43%) received GH prior to tumor diagnosis. Of the individuals who developed rhabdomyosarcoma, two never received GH, one received GH after tumor diagnosis, and one received GH prior to the diagnosis of rhabdomyosarcoma [
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation, osteopenia).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Feeding therapy
• Gastrostomy tube placement is commonly required for persistent feeding issues.
• May need Nissen fundoplication for GERD & irritability
• May consider pureed foods by G-tube
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Pharmacologic & surgical treatment (myectomy) have been used for severe cardiac hypertrophy.
• Consider MedicAlert
• OSA may cause sleep disturbance.
• Tracheostomy w/ or w/o ventilatory support is required for some.
• Mandibular distraction may be considered.
• Tonsil/adenoid surgery may also be considered.
• Surgical tendon lengthening (usually Achilles tendon) is often required.
• Hip joint abnormalities may require surgical intervention.
• Nystagmus: no treatment
• Visual impairment: educational intervention
• Refractive error: spectacle correction
• Keratoconus: specialist eval & treatment
• Anesthesia may pose a risk in those w/unrecognized HCM &/or predisposition to some types of atrial tachycardia.
• Relatively high doses of medication may be required for sedation. No standardized information is available; review of medical records documenting previous dosages may provide guidance.
• Ensure appropriate social work involvement to connect families w/ local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• True GH deficiency requires GH replacement. Three individuals with GH deficiency showed increased growth velocity without adverse effects after three to seven years of replacement therapy, but two continued to have short stature [
• It is unclear from the literature if the use of GH is beneficial in individuals with Costello syndrome with partial GH deficiency. An abnormal GH response on testing and a good initial growth response have been reported [
• True GH deficiency requires GH replacement. Three individuals with GH deficiency showed increased growth velocity without adverse effects after three to seven years of replacement therapy, but two continued to have short stature [
• It is unclear from the literature if the use of GH is beneficial in individuals with Costello syndrome with partial GH deficiency. An abnormal GH response on testing and a good initial growth response have been reported [
• Bladder carcinoma occurred in an individual age 16 years treated with GH [
• A rhabdomyosarcoma was diagnosed in an individual age 26 months receiving GH from age 12 months [
• On review of 35 affected individuals, 16 had documented GH deficiency (46%). Thirteen of these 16 received GH treatment (37%). In this cohort, 7/35 had tumors, including four rhabdomyosarcomas, one pituitary adenoma, one benign bladder tumor, and one bladder carcinoma. Of the seven with tumors, four (57%) were naïve to GH at the time of tumor diagnosis and three (43%) received GH prior to tumor diagnosis. Of the individuals who developed rhabdomyosarcoma, two never received GH, one received GH after tumor diagnosis, and one received GH prior to the diagnosis of rhabdomyosarcoma [
• Bladder carcinoma occurred in an individual age 16 years treated with GH [
• A rhabdomyosarcoma was diagnosed in an individual age 26 months receiving GH from age 12 months [
• On review of 35 affected individuals, 16 had documented GH deficiency (46%). Thirteen of these 16 received GH treatment (37%). In this cohort, 7/35 had tumors, including four rhabdomyosarcomas, one pituitary adenoma, one benign bladder tumor, and one bladder carcinoma. Of the seven with tumors, four (57%) were naïve to GH at the time of tumor diagnosis and three (43%) received GH prior to tumor diagnosis. Of the individuals who developed rhabdomyosarcoma, two never received GH, one received GH after tumor diagnosis, and one received GH prior to the diagnosis of rhabdomyosarcoma [
• True GH deficiency requires GH replacement. Three individuals with GH deficiency showed increased growth velocity without adverse effects after three to seven years of replacement therapy, but two continued to have short stature [
• It is unclear from the literature if the use of GH is beneficial in individuals with Costello syndrome with partial GH deficiency. An abnormal GH response on testing and a good initial growth response have been reported [
• Bladder carcinoma occurred in an individual age 16 years treated with GH [
• A rhabdomyosarcoma was diagnosed in an individual age 26 months receiving GH from age 12 months [
• On review of 35 affected individuals, 16 had documented GH deficiency (46%). Thirteen of these 16 received GH treatment (37%). In this cohort, 7/35 had tumors, including four rhabdomyosarcomas, one pituitary adenoma, one benign bladder tumor, and one bladder carcinoma. Of the seven with tumors, four (57%) were naïve to GH at the time of tumor diagnosis and three (43%) received GH prior to tumor diagnosis. Of the individuals who developed rhabdomyosarcoma, two never received GH, one received GH after tumor diagnosis, and one received GH prior to the diagnosis of rhabdomyosarcoma [
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation, osteopenia).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
##
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
##
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation, osteopenia).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation, osteopenia).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
##
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Costello Syndrome: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
By cardiologist familiar w/spectrum of cardiac disease in CS & its natural history
Transitioning from pediatric cardiologist to adult specialist when age appropriate
CS = Costello syndrome; GH = growth hormone
General guidelines [
To date, neither screening approach has been shown to be beneficial; studies are ongoing. The most important factor for early tumor detection is parental and physician awareness of the increased cancer risk [
Because elevated catecholamine metabolites were observed in individuals with Costello syndrome without an identifiable tumor, it was concluded that screening for abnormal catecholamine metabolites is not helpful [
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• By cardiologist familiar w/spectrum of cardiac disease in CS & its natural history
• Transitioning from pediatric cardiologist to adult specialist when age appropriate
## Agents/Circumstances to Avoid
Aggressive feeding therapy in infancy and early childhood is not likely to improve oral intake and may result in oral aversion.
Neuroblastoma screening by measuring catecholamine metabolites is not helpful because elevated values were observed in individuals without an identifiable tumor.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
To date, most individuals with Costello syndrome have the disorder as the result of a
An association with advanced parental age has been documented [
Rarely, an individual with Costello syndrome has the disorder as the result of an
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
* A parent with somatic and germline mosaicism for an
If the
If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
If the parents have not been tested for the
Each child of an individual with an attenuated phenotype has a 50% chance of inheriting the
Individuals with characteristic Costello syndrome typically do not reproduce.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of children with Costello syndrome.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• To date, most individuals with Costello syndrome have the disorder as the result of a
• An association with advanced parental age has been documented [
• Rarely, an individual with Costello syndrome has the disorder as the result of an
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and germline mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and germline mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and germline mosaicism for an
• If the
• If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the parents have not been tested for the
• Each child of an individual with an attenuated phenotype has a 50% chance of inheriting the
• Individuals with characteristic Costello syndrome typically do not reproduce.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of children with Costello syndrome.
## Mode of Inheritance
## Risk to Family Members
To date, most individuals with Costello syndrome have the disorder as the result of a
An association with advanced parental age has been documented [
Rarely, an individual with Costello syndrome has the disorder as the result of an
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
* A parent with somatic and germline mosaicism for an
If the
If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
If the parents have not been tested for the
Each child of an individual with an attenuated phenotype has a 50% chance of inheriting the
Individuals with characteristic Costello syndrome typically do not reproduce.
• To date, most individuals with Costello syndrome have the disorder as the result of a
• An association with advanced parental age has been documented [
• Rarely, an individual with Costello syndrome has the disorder as the result of an
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and germline mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and germline mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and germline mosaicism for an
• If the
• If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the parents have not been tested for the
• Each child of an individual with an attenuated phenotype has a 50% chance of inheriting the
• Individuals with characteristic Costello syndrome typically do not reproduce.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of children with Costello syndrome.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of children with Costello syndrome.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
• United Kingdom
•
•
•
•
•
•
•
•
•
## Molecular Genetics
HRAS-Related Costello Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for HRAS-Related Costello Syndrome (
The RAS oncogenes,
Amino acid changes lead either to decreased GTPase activity (if amino acids 12, 13, 59, 61, or 63 are involved), so that oncogenic RAS mutated proteins are locked in the active GTP-bound state, or decreased nucleotide affinity and, hence, increased exchange of bound GDP for cytosolic GTP (if amino acids 116, 117, 119, or 146 are affected). Single-nucleotide pathogenic variants cause an accumulation of activated RAS-GTP complexes, leading to continuous signal transduction by facilitating accumulation of constitutively active, GTP-bound RAS protein.
CS = Costello syndrome
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
The RAS oncogenes,
Amino acid changes lead either to decreased GTPase activity (if amino acids 12, 13, 59, 61, or 63 are involved), so that oncogenic RAS mutated proteins are locked in the active GTP-bound state, or decreased nucleotide affinity and, hence, increased exchange of bound GDP for cytosolic GTP (if amino acids 116, 117, 119, or 146 are affected). Single-nucleotide pathogenic variants cause an accumulation of activated RAS-GTP complexes, leading to continuous signal transduction by facilitating accumulation of constitutively active, GTP-bound RAS protein.
CS = Costello syndrome
Variants listed in the table have been provided by the authors.
## Chapter Notes
Dr Karen Gripp is a codirector of the Professional Advisory Committee of the Costello Syndrome Family Network. She is a member of the ClinGen expert panels on RASopathies and inherited cancer syndromes.
Dr Nicole Weaver is a member of the Professional Advisory Committee of the Costello Syndrome Family Network. She is a member of the ClinGen expert panel on congenital heart disease.
Special thanks to Sandra Taylor, Executive Director, and Mary Ernst, President of the Costello Syndrome Family Network; Lisa Schoyer, Chair of the Research Advisory Committee, and Colin Stone, President of the International Costello Syndrome Support Group; the individuals with Costello syndrome and their families; and our colleagues on the Professional Advisory Committee.
Karen W Gripp, MD, FAAP, FACMG (2006-present)Angela E Lin, MD, FAAP, FACMG; Harvard Medical School (2006-2019)Katherine A Rauen, MD, PhD; University of California, Davis (2019-2023) K Nicole Weaver, MD, FAAP, FACMG (2023-present)
21 December 2023 (gm) Comprehensive update posted live
29 August 2019 (bp) Comprehensive update posted live
12 January 2012 (me) Comprehensive update posted live
19 May 2009 (me) Comprehensive update posted live
29 August 2006 (me) Review posted live
2 March 2006 (kg) Original submission
• 21 December 2023 (gm) Comprehensive update posted live
• 29 August 2019 (bp) Comprehensive update posted live
• 12 January 2012 (me) Comprehensive update posted live
• 19 May 2009 (me) Comprehensive update posted live
• 29 August 2006 (me) Review posted live
• 2 March 2006 (kg) Original submission
## Author Notes
Dr Karen Gripp is a codirector of the Professional Advisory Committee of the Costello Syndrome Family Network. She is a member of the ClinGen expert panels on RASopathies and inherited cancer syndromes.
Dr Nicole Weaver is a member of the Professional Advisory Committee of the Costello Syndrome Family Network. She is a member of the ClinGen expert panel on congenital heart disease.
## Acknowledgments
Special thanks to Sandra Taylor, Executive Director, and Mary Ernst, President of the Costello Syndrome Family Network; Lisa Schoyer, Chair of the Research Advisory Committee, and Colin Stone, President of the International Costello Syndrome Support Group; the individuals with Costello syndrome and their families; and our colleagues on the Professional Advisory Committee.
## Author History
Karen W Gripp, MD, FAAP, FACMG (2006-present)Angela E Lin, MD, FAAP, FACMG; Harvard Medical School (2006-2019)Katherine A Rauen, MD, PhD; University of California, Davis (2019-2023) K Nicole Weaver, MD, FAAP, FACMG (2023-present)
## Revision History
21 December 2023 (gm) Comprehensive update posted live
29 August 2019 (bp) Comprehensive update posted live
12 January 2012 (me) Comprehensive update posted live
19 May 2009 (me) Comprehensive update posted live
29 August 2006 (me) Review posted live
2 March 2006 (kg) Original submission
• 21 December 2023 (gm) Comprehensive update posted live
• 29 August 2019 (bp) Comprehensive update posted live
• 12 January 2012 (me) Comprehensive update posted live
• 19 May 2009 (me) Comprehensive update posted live
• 29 August 2006 (me) Review posted live
• 2 March 2006 (kg) Original submission
## Key Sections in this
## References
## Literature Cited
Four girls who attended the 2005 Costello Syndrome Conference in St Louis show several characteristic features, including the friendly, sociable personality associated with Costello syndrome.
A. The two girls, both age ten years, have full cheeks, full lips, ocular hypertelorism, downslanted eyes, and a full nasal tip. Note that the girl on the left has coarse curly hair, whereas the girl on the right has straight, fine hair.
B. Two girls ages six and nine years show the typical hand posture, wide mouth, and full lips. The darker complexion is attributed to Latino descent in one and African American descent in the other.
Typical facial features seen in a boy age eight years of northern European background (A) and a Hispanic girl age ~11 years (B) with Costello syndrome
Reprinted with permission from
|
[] |
29/8/2006
|
21/12/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
cpt1a
|
cpt1a
|
[
"CPT1A Deficiency",
"Hepatic Carnitine Palmitoyltransferase 1 Deficiency",
"CPT1A Deficiency",
"Hepatic Carnitine Palmitoyltransferase 1 Deficiency",
"Carnitine O-palmitoyltransferase 1, liver isoform",
"CPT1A",
"Carnitine Palmitoyltransferase 1A Deficiency"
] |
Carnitine Palmitoyltransferase 1A Deficiency
|
Kristen Lee, Amanda Pritchard, Ayesha Ahmad
|
Summary Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a disorder of long-chain fatty acid oxidation. Clinical manifestations usually occur in an individual with a concurrent febrile or gastrointestinal illness when energy demands are increased; onset of manifestations are usually rapid. The recognized presentations are: (1) out-of-range newborn screen (individual may be without features or with hepatic encephalopathy, hypoketotic hypoglycemia, and sudden onset of liver failure) and (2) later-onset manifestations (in the absence of newborn screening), including hepatic encephalopathy, hypoglycemia, absent or low levels of ketones, and elevated serum concentrations of liver transaminases, ammonia, and creatine kinase. Between episodes of hepatic encephalopathy, individuals appear developmentally and cognitively normal unless previous metabolic decompensation has resulted in neurologic damage. Acute fatty liver of pregnancy, in which the fetus has biallelic pathogenic variants in The diagnosis of CPT1A deficiency is established in a proband with biallelic pathogenic variants in CPT1A deficiency is inherited in an autosomal recessive manner. When both parents are carriers of a
|
## Diagnosis
No consensus clinical diagnostic criteria for carnitine palmitoyltransferase 1A (CPT1A) deficiency have been published.
Cutoffs for C0 and C0:C16+C18 vary by state. If the NBS is abnormal, follow-up acylcarnitine profile and measurement of plasma-free and total carnitine is recommended. However, since acylcarnitine measurements in infants with CPT1A deficiency can normalize after the initial NBS [
While most newborns with an out-of-range NBS are asymptomatic, the following medical interventions need to begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether this a true positive NBS result and to establish the diagnosis of CPT1A deficiency:
Avoidance of prolonged fasting
Anticipatory guidance to the family regarding signs and manifestations of concern (lethargy, poor feeding) that would warrant emergent evaluation
Symptomatic CPT1A deficiency is defined as an individual who has either atypical findings associated with later-onset CPT1A deficiency or untreated infantile-onset CPT1A deficiency resulting from any of the following: NBS not performed, metabolic abnormalities not sufficiently elevated to be considered "out of range" at time of NBS resulting in a false negative, or caregivers not adherent with recommended treatment following a positive NBS result.
Note: NBS may not identify all affected individuals, especially if metabolic abnormalities are in range at the time of NBS. NBS with acylcarnitine profile alone (without molecular genetic testing) often misses individuals homozygous for the
Lethargy, altered mental status, and/or seizures (related to hypoglycemia)
Hepatomegaly
Muscle weakness
Sudden unexplained death
The diagnosis of CPT1A deficiency
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
When NBS results and/or other laboratory findings suggest the diagnosis of CPT1A deficiency, molecular genetic testing approaches can include
Note: A limited number of clinical laboratories may only offer targeted molecular testing for a single common
A
For an introduction to multigene panels click
A symptomatic individual who has findings associated with later diagnosis of CPT1A deficiency or untreated infantile-onset CPT1A deficiency (resulting from NBS not performed or not detected during NBS) typically can be evaluated with a multigene fatty acid oxidation disorder panel or other similar panel. Single-gene testing can be performed if the plasma acylcarnitine and total serum carnitine results and ratios are strongly suggestive of CPT1A deficiency.
When the individual is critically ill or the diagnosis of CPT1A deficiency has not been specifically considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Carnitine Palmitoyltransferase 1A Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequence analysis also detects the common
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Exon and multiexon deletions have been rarely reported [
• Avoidance of prolonged fasting
• Anticipatory guidance to the family regarding signs and manifestations of concern (lethargy, poor feeding) that would warrant emergent evaluation
• Lethargy, altered mental status, and/or seizures (related to hypoglycemia)
• Hepatomegaly
• Muscle weakness
• Sudden unexplained death
• Note: A limited number of clinical laboratories may only offer targeted molecular testing for a single common
• A
• For an introduction to multigene panels click
## Suggestive Findings
Cutoffs for C0 and C0:C16+C18 vary by state. If the NBS is abnormal, follow-up acylcarnitine profile and measurement of plasma-free and total carnitine is recommended. However, since acylcarnitine measurements in infants with CPT1A deficiency can normalize after the initial NBS [
While most newborns with an out-of-range NBS are asymptomatic, the following medical interventions need to begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether this a true positive NBS result and to establish the diagnosis of CPT1A deficiency:
Avoidance of prolonged fasting
Anticipatory guidance to the family regarding signs and manifestations of concern (lethargy, poor feeding) that would warrant emergent evaluation
Symptomatic CPT1A deficiency is defined as an individual who has either atypical findings associated with later-onset CPT1A deficiency or untreated infantile-onset CPT1A deficiency resulting from any of the following: NBS not performed, metabolic abnormalities not sufficiently elevated to be considered "out of range" at time of NBS resulting in a false negative, or caregivers not adherent with recommended treatment following a positive NBS result.
Note: NBS may not identify all affected individuals, especially if metabolic abnormalities are in range at the time of NBS. NBS with acylcarnitine profile alone (without molecular genetic testing) often misses individuals homozygous for the
Lethargy, altered mental status, and/or seizures (related to hypoglycemia)
Hepatomegaly
Muscle weakness
Sudden unexplained death
• Avoidance of prolonged fasting
• Anticipatory guidance to the family regarding signs and manifestations of concern (lethargy, poor feeding) that would warrant emergent evaluation
• Lethargy, altered mental status, and/or seizures (related to hypoglycemia)
• Hepatomegaly
• Muscle weakness
• Sudden unexplained death
## Scenario 1: Infantile Onset (including abnormal newborn screening result and symptomatic neonate)
Cutoffs for C0 and C0:C16+C18 vary by state. If the NBS is abnormal, follow-up acylcarnitine profile and measurement of plasma-free and total carnitine is recommended. However, since acylcarnitine measurements in infants with CPT1A deficiency can normalize after the initial NBS [
While most newborns with an out-of-range NBS are asymptomatic, the following medical interventions need to begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether this a true positive NBS result and to establish the diagnosis of CPT1A deficiency:
Avoidance of prolonged fasting
Anticipatory guidance to the family regarding signs and manifestations of concern (lethargy, poor feeding) that would warrant emergent evaluation
• Avoidance of prolonged fasting
• Anticipatory guidance to the family regarding signs and manifestations of concern (lethargy, poor feeding) that would warrant emergent evaluation
## Scenario 2: Symptomatic Individual
Symptomatic CPT1A deficiency is defined as an individual who has either atypical findings associated with later-onset CPT1A deficiency or untreated infantile-onset CPT1A deficiency resulting from any of the following: NBS not performed, metabolic abnormalities not sufficiently elevated to be considered "out of range" at time of NBS resulting in a false negative, or caregivers not adherent with recommended treatment following a positive NBS result.
Note: NBS may not identify all affected individuals, especially if metabolic abnormalities are in range at the time of NBS. NBS with acylcarnitine profile alone (without molecular genetic testing) often misses individuals homozygous for the
Lethargy, altered mental status, and/or seizures (related to hypoglycemia)
Hepatomegaly
Muscle weakness
Sudden unexplained death
• Lethargy, altered mental status, and/or seizures (related to hypoglycemia)
• Hepatomegaly
• Muscle weakness
• Sudden unexplained death
## Establishing the Diagnosis
The diagnosis of CPT1A deficiency
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
When NBS results and/or other laboratory findings suggest the diagnosis of CPT1A deficiency, molecular genetic testing approaches can include
Note: A limited number of clinical laboratories may only offer targeted molecular testing for a single common
A
For an introduction to multigene panels click
A symptomatic individual who has findings associated with later diagnosis of CPT1A deficiency or untreated infantile-onset CPT1A deficiency (resulting from NBS not performed or not detected during NBS) typically can be evaluated with a multigene fatty acid oxidation disorder panel or other similar panel. Single-gene testing can be performed if the plasma acylcarnitine and total serum carnitine results and ratios are strongly suggestive of CPT1A deficiency.
When the individual is critically ill or the diagnosis of CPT1A deficiency has not been specifically considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Carnitine Palmitoyltransferase 1A Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequence analysis also detects the common
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Exon and multiexon deletions have been rarely reported [
• Note: A limited number of clinical laboratories may only offer targeted molecular testing for a single common
• A
• For an introduction to multigene panels click
## Scenario 1: Abnormal NBS Result
When NBS results and/or other laboratory findings suggest the diagnosis of CPT1A deficiency, molecular genetic testing approaches can include
Note: A limited number of clinical laboratories may only offer targeted molecular testing for a single common
A
For an introduction to multigene panels click
• Note: A limited number of clinical laboratories may only offer targeted molecular testing for a single common
• A
• For an introduction to multigene panels click
## Scenario 2: Symptomatic Individual
A symptomatic individual who has findings associated with later diagnosis of CPT1A deficiency or untreated infantile-onset CPT1A deficiency (resulting from NBS not performed or not detected during NBS) typically can be evaluated with a multigene fatty acid oxidation disorder panel or other similar panel. Single-gene testing can be performed if the plasma acylcarnitine and total serum carnitine results and ratios are strongly suggestive of CPT1A deficiency.
When the individual is critically ill or the diagnosis of CPT1A deficiency has not been specifically considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Carnitine Palmitoyltransferase 1A Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequence analysis also detects the common
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Exon and multiexon deletions have been rarely reported [
## Specialized Biochemical Testing
## Clinical Characteristics
The mitochondrial membrane protein encoded by
Thus, clinical manifestations of CPT1A deficiency usually occur with a febrile or gastrointestinal illness when energy demands are increased. Although the precipitating illness may be a relatively common infectious disease, onset of manifestations is usually rapid. Age of onset of manifestations can vary from the newborn period to adulthood, and some individuals are asymptomatic.
Recognition of CPT1A deficiency and initiating management to prevent lipolysis reduces the episodes of decompensation [
After the neonatal period, hypoglycemia is more likely to be present in individuals with CPT1A deficiency who have an intercurrent illness or prolonged fasting.
Hepatomegaly is commonly reported. Laboratory findings include elevated liver enzymes and may include hyperammonemia.
Long-term liver damage is uncommon but has been reported [
Between episodes of metabolic decompensation, individuals with CPT1A deficiency typically appear developmentally and cognitively normal unless previous metabolic decompensation has resulted in neurologic damage (leading to motor and/or speech delays).
In a study using whole-genome high-coverage sequence data of Arctic populations, p.Pro479Leu was identified as deleterious and associated with increased infant mortality in circum-Arctic populations [
In Finland, there are multiple individuals homozygous for the
CPT1A deficiency has been previously described as nonketotic hypoglycemia, hepatic CPT deficiency, hepatic CPT1, and L-CPT1 deficiency.
CPT1A deficiency appears to be relatively rare in the general population. Combined results of NBS programs in Australia, Germany, and the United States show an incidence of CPT1A deficiency of 1:750,000-2,000,000 [
The prevalence of CPT1A deficiency is higher in a few populations with known founder variants.
The prevalence of CPT1A deficiency in Alaskan infants is 1:780 live births [
The carrier rate for the
The incidence of homozygosity for
The
## Clinical Description
The mitochondrial membrane protein encoded by
Thus, clinical manifestations of CPT1A deficiency usually occur with a febrile or gastrointestinal illness when energy demands are increased. Although the precipitating illness may be a relatively common infectious disease, onset of manifestations is usually rapid. Age of onset of manifestations can vary from the newborn period to adulthood, and some individuals are asymptomatic.
Recognition of CPT1A deficiency and initiating management to prevent lipolysis reduces the episodes of decompensation [
After the neonatal period, hypoglycemia is more likely to be present in individuals with CPT1A deficiency who have an intercurrent illness or prolonged fasting.
Hepatomegaly is commonly reported. Laboratory findings include elevated liver enzymes and may include hyperammonemia.
Long-term liver damage is uncommon but has been reported [
Between episodes of metabolic decompensation, individuals with CPT1A deficiency typically appear developmentally and cognitively normal unless previous metabolic decompensation has resulted in neurologic damage (leading to motor and/or speech delays).
## Genotype-Phenotype Correlations
In a study using whole-genome high-coverage sequence data of Arctic populations, p.Pro479Leu was identified as deleterious and associated with increased infant mortality in circum-Arctic populations [
In Finland, there are multiple individuals homozygous for the
## Nomenclature
CPT1A deficiency has been previously described as nonketotic hypoglycemia, hepatic CPT deficiency, hepatic CPT1, and L-CPT1 deficiency.
## Prevalence
CPT1A deficiency appears to be relatively rare in the general population. Combined results of NBS programs in Australia, Germany, and the United States show an incidence of CPT1A deficiency of 1:750,000-2,000,000 [
The prevalence of CPT1A deficiency is higher in a few populations with known founder variants.
The prevalence of CPT1A deficiency in Alaskan infants is 1:780 live births [
The carrier rate for the
The incidence of homozygosity for
The
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
A number of other fetal fatty acid oxidation defects are associated with a similar risk to the heterozygous mother of developing acute fatty liver of pregnancy, typically in the third trimester, prompting further investigation of the newborn for a fatty acid oxidation defect.
The absence (or paucity) of ketone bodies during a period of hypoglycemia should increase suspicion for one of the disorders of fatty acid oxidation or the carnitine cycle, including carnitine palmitoyltransferase 1A (CPT1A) deficiency.
Selected genes of interest in the differential diagnosis of CPT1A deficiency are listed in
Selected Genes of Interest in the Differential Diagnosis of Carnitine Palmitoyltransferase 1A Deficiency
AD = autosomal dominant; AR = autosomal recessive; CoA = coenzyme A; CPT1A = carnitine palmitoyltransferase 1A; HMG = 3-hydroxy-3-methylglutaryl; MT = mitochondrial; MOI = mode of inheritance; XL = X-linked
Ornithine transcarbamylase deficiency is inherited in an X-linked manner. The rest of the urea cycle disorders (deficiencies of NAGS, CPS1, ASS1, ASL, ARG1, ORNT1, and citrin) are inherited in an autosomal recessive manner.
Pathogenic variants in
Pathogenic variants in
## Management
No clinical practice guidelines for carnitine palmitoyltransferase 1A (CPT1A) deficiency have been published. In the absence of published consensus guidelines, the following recommendations are based on available evidence and literature on the subject.
When CPT1A deficiency is suspected during the diagnostic evaluation (for example, because of a suggestive carnitine and acylcarnitine profile; see
Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (e.g., malnutrition, growth failure) require a multidisciplinary approach including multiple subspecialists, with oversight and expertise from a specialized metabolic center.
Guidelines and current management strategies for the treatment of CPT1A deficiency and other long-chain fatty acid oxidation disorders can be found at
The British Inherited Metabolic Disease Group (BIMDG) website has a specific emergency management protocol for CPT1A deficiency (see
To establish the extent of disease and needs in an individual diagnosed with CPT1A deficiency, the evaluations summarized in
Carnitine Palmitoyltransferase 1A Deficiency: Recommended Evaluations Following Initial Diagnosis
Transfer to specialty center w/experience in mgmt of inherited metabolic diseases is strongly recommended.
Consider short hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
If symptomatic, common presenting features are hypoketotic hypoglycemia (leading to lethargy/altered mental status), hepatomegaly/liver failure & seizures, usually precipitated by fasting or acute illness.
This presentation is rare in newborns (however, when present, it usually manifests w/concurrent febrile or gastrointestinal illness & onset is rapid).
Blood chemistries incl BUN, creatinine, glucose, electrolytes, & CK
STAT ammonia
Carnitine level
Liver function tests
Urinalysis
Gastroenterologist (if concerns exist for hepatic function)
Nephologist (if concerns exist for renal tubular acidosis)
Neurologist (if concerns exist for encephalopathy & seizures)
BUN = blood urea nitrogen; CK = creatine kinase; CPT1A = carnitine palmitoyltransferase 1A; MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
There is no cure for CPT1A deficiency.
Neonates and infants require frequent feedings every two to three hours.
In older individuals, overnight feedings, a bedtime snack, or 2 g/kg of uncooked cornstarch as a source of complex carbohydrates at bedtime to ensure sufficient glucose supply overnight have been used. Overnight feedings may not be necessary in those without an intercurrent illness or with pathogenic variants associated with milder disease (see
A healthy diet containing no more than 20%-30% of total energy from dietary fat may be followed.
In the absence of an intercurrent infection with fever or other stressing conditions, the following maximum fasting times are suggested:
Up to eight hours in infants between ages six and 12 months
Up to ten hours during the second year of life
Up to 12 hours after age two years
Other recommendations include a general rule of thumb to avoid fasting for longer than four hours between birth and age four months, then add an additional hour of fasting for each month of age up to 12 months (see
To avoid excessive fasting in sick individuals:
In sick infants, breastfeeding may need to be replaced or alternated with metabolic formula containing medium-chain triglycerides (see
Increase frequency of feeds to reduce risk of metabolic crisis (see
Carnitine Palmitoyltransferase 1A Deficiency: Targeted Therapies
Synthetic 7-carbon triglyceride (source for acetyl-CoA & anaplerotic propionyl-CoA)
Provides C5-ketone bodies that can cross blood-brain barrier, therefore providing substrates for the brain, & correcting secondary depletion of TCA cycle intermediates
To provide ~30% of daily caloric intake
Maximum dosing goal 2g/kg/day
Actual maximum dose 15%-42% of total daily caloric intake from triheptanoin
Remainder of diet modified to maintain appropriate caloric intake & balance
Use of MCT oil OR triheptanoin is recommended
MCT oil may be used if triheptanoin is not available or not tolerated.
CoA = coenzyme A; FDA = Food and Drug Administration; LC-FAOD = long-chain fatty acid oxidation disorders; MCT = medium-chain triglycerides; TCA = tricarboxylic acid
The FDA recommends discontinuing MCT products prior to initiation of triheptanoin therapy. In the retrospective study by
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Carnitine Palmitoyltransferase 1A Deficiency: Acute Treatment
Alternative energy sources, hydration, & correction of hypoketotic hypoglycemia;
Sufficient amounts of IV fluid containing at least 10% dextrose w/age-appropriate electrolytes as quickly as possible to correct hypoglycemia & to prevent lipolysis & subsequent mobilization of fatty acids into mitochondria;
1.5x maintenance rate to provide 8-10 mg/kg/min of glucose.
↑ frequency of feeding during illness.
Provide ~1/3 of total calories as triheptanoin or MCT oil during periods of illness (see
Plasma CK level
Urine myoglobin
ALT = alanine transaminase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; CK = creatine kinase; IV = intravenous; MCT = medium chain triglycerides; PT = prothrombin time; PTT= partial thromboplastin time
Carnitine Palmitoyltransferase 1A Deficiency: Routine Long-Term Treatment
Frequent feedings for infants/young children
Consider awakening infant for feeding or overnight enteral feeding w/cornstarch if necessary.
Frequent snacks between meals & before bedtime high in carbohydrates
Cornstarch feedings provide a slow-release carbohydrate to prevent hypoglycemia during sleep.
Cornstarch is generally only tolerated around age ≥1 yr due to pancreatic amylase activity.
Maximum fasting intervals ↑ based on age of infant (see
Factors that elicit a hypoketotic hypoglycemic crisis & early signs of decompensation;
Risks of fasting;
Risks during surgery, when both metabolic stress & fasting occur.
MCT = medium-chain triglycerides; OT = occupational therapist; PT = physical therapist; SLP = speech-language pathologist
Restriction of dietary fat intake is somewhat controversial with the mild and/or asymptomatic forms (such as that caused by
Carnitine Palmitoyltransferase 1A Deficiency: Recommended Surveillance
Measure length, weight, & head circumference.
Assess feeding skills in infants/toddlers.
Assess adherence to dietary recommendations.
Plasma carnitine panel (total, free, esters)
Plasma acylcarnitine profile
RBC or plasma essential fatty acids
Vitamins A, D, & E concentrations
CBC, comprehensive metabolic panel, CK
At each visit dependent on diet mgmt recommendations
As clinically indicated; may be dependent on frequency of clinic visits & age (e.g., more frequent assessments when younger)
ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; CK = creatine kinase; MCT = medium-chain triglycerides; OFC = occipital frontal circumference; PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cells
Based on level/degree of fat restriction
Avoid fasting, including during periods of preparation and recovery from planned surgery or sedation (see
Potentially hepatotoxic agents such as valproate and salicylate should be used with caution if there is evidence of hepatic dysfunction [
Avoid viral or bacterial infections.
Avoid overfeeding in individuals without acute illness to reduce long-term risk of obesity.
See
Serious complications including hemolysis, elevated liver enzymes, and low platelets (HELPP)-like syndrome and acute fatty liver of pregnancy (AFLP) in a pregnant individual previously undiagnosed with CPT1A deficiency with an unaffected fetus have been reported. CPT1 enzyme activity was undetectable and molecular testing identified a homozygous pathogenic variant in the mother; the child was reported as unaffected [
Management of women with CPT1A deficiency during pregnancy should include avoidance of fasting, hypoglycemia, dehydration, and catabolic stress. Dietary management includes a low-fat, high-carbohydrate diet with use of triheptanoin or MCT oil. Use of triheptanoin has not been studied in pregnancy. Intrapartum management should include provision of adequate glucose infusion rate with intravenous fluids to prevent hypoglycemia, maintain anabolism, and prevent dehydration (IV infusion of 10% glucose at 1.5 times maintenance). Management by a team comprising a maternal-fetal medicine specialist and a medical/biochemical geneticist is highly recommended.
A pregnant mother who did not have CPT1A deficiency developed AFLP in two successive pregnancies; both children were subsequently shown to have deficient CPT1 enzyme activity; no molecular genetic testing was performed (though family was Inuit) [
Although data are limited, it is prudent to counsel heterozygous females who are carrying a fetus with biallelic
Women who have had one child with CPT1A deficiency following an uneventful pregnancy remain at risk for AFLP in subsequent pregnancies with an affected fetus. In any pregnancies that follow identification of a child with CPT1A deficiency, it is recommended that liver function testing be performed at each prenatal visit during the first two trimesters and more frequently during the third trimester, when the risk for AFLP is greatest. Management by a team comprising a maternal-fetal medicine specialist and a medical/biochemical geneticist is highly recommended.
Search
• Transfer to specialty center w/experience in mgmt of inherited metabolic diseases is strongly recommended.
• Consider short hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
• If symptomatic, common presenting features are hypoketotic hypoglycemia (leading to lethargy/altered mental status), hepatomegaly/liver failure & seizures, usually precipitated by fasting or acute illness.
• This presentation is rare in newborns (however, when present, it usually manifests w/concurrent febrile or gastrointestinal illness & onset is rapid).
• Blood chemistries incl BUN, creatinine, glucose, electrolytes, & CK
• STAT ammonia
• Carnitine level
• Liver function tests
• Urinalysis
• Gastroenterologist (if concerns exist for hepatic function)
• Nephologist (if concerns exist for renal tubular acidosis)
• Neurologist (if concerns exist for encephalopathy & seizures)
• Neonates and infants require frequent feedings every two to three hours.
• In older individuals, overnight feedings, a bedtime snack, or 2 g/kg of uncooked cornstarch as a source of complex carbohydrates at bedtime to ensure sufficient glucose supply overnight have been used. Overnight feedings may not be necessary in those without an intercurrent illness or with pathogenic variants associated with milder disease (see
• A healthy diet containing no more than 20%-30% of total energy from dietary fat may be followed.
• In the absence of an intercurrent infection with fever or other stressing conditions, the following maximum fasting times are suggested:
• Up to eight hours in infants between ages six and 12 months
• Up to ten hours during the second year of life
• Up to 12 hours after age two years
• Other recommendations include a general rule of thumb to avoid fasting for longer than four hours between birth and age four months, then add an additional hour of fasting for each month of age up to 12 months (see
• Up to eight hours in infants between ages six and 12 months
• Up to ten hours during the second year of life
• Up to 12 hours after age two years
• Up to eight hours in infants between ages six and 12 months
• Up to ten hours during the second year of life
• Up to 12 hours after age two years
• In sick infants, breastfeeding may need to be replaced or alternated with metabolic formula containing medium-chain triglycerides (see
• Increase frequency of feeds to reduce risk of metabolic crisis (see
• Synthetic 7-carbon triglyceride (source for acetyl-CoA & anaplerotic propionyl-CoA)
• Provides C5-ketone bodies that can cross blood-brain barrier, therefore providing substrates for the brain, & correcting secondary depletion of TCA cycle intermediates
• To provide ~30% of daily caloric intake
• Maximum dosing goal 2g/kg/day
• Actual maximum dose 15%-42% of total daily caloric intake from triheptanoin
• Remainder of diet modified to maintain appropriate caloric intake & balance
• Use of MCT oil OR triheptanoin is recommended
• MCT oil may be used if triheptanoin is not available or not tolerated.
• Alternative energy sources, hydration, & correction of hypoketotic hypoglycemia;
• Sufficient amounts of IV fluid containing at least 10% dextrose w/age-appropriate electrolytes as quickly as possible to correct hypoglycemia & to prevent lipolysis & subsequent mobilization of fatty acids into mitochondria;
• 1.5x maintenance rate to provide 8-10 mg/kg/min of glucose.
• ↑ frequency of feeding during illness.
• Provide ~1/3 of total calories as triheptanoin or MCT oil during periods of illness (see
• Plasma CK level
• Urine myoglobin
• Frequent feedings for infants/young children
• Consider awakening infant for feeding or overnight enteral feeding w/cornstarch if necessary.
• Frequent snacks between meals & before bedtime high in carbohydrates
• Cornstarch feedings provide a slow-release carbohydrate to prevent hypoglycemia during sleep.
• Cornstarch is generally only tolerated around age ≥1 yr due to pancreatic amylase activity.
• Maximum fasting intervals ↑ based on age of infant (see
• Factors that elicit a hypoketotic hypoglycemic crisis & early signs of decompensation;
• Risks of fasting;
• Risks during surgery, when both metabolic stress & fasting occur.
• Measure length, weight, & head circumference.
• Assess feeding skills in infants/toddlers.
• Assess adherence to dietary recommendations.
• Plasma carnitine panel (total, free, esters)
• Plasma acylcarnitine profile
• RBC or plasma essential fatty acids
• Vitamins A, D, & E concentrations
• CBC, comprehensive metabolic panel, CK
• At each visit dependent on diet mgmt recommendations
• As clinically indicated; may be dependent on frequency of clinic visits & age (e.g., more frequent assessments when younger)
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CPT1A deficiency, the evaluations summarized in
Carnitine Palmitoyltransferase 1A Deficiency: Recommended Evaluations Following Initial Diagnosis
Transfer to specialty center w/experience in mgmt of inherited metabolic diseases is strongly recommended.
Consider short hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
If symptomatic, common presenting features are hypoketotic hypoglycemia (leading to lethargy/altered mental status), hepatomegaly/liver failure & seizures, usually precipitated by fasting or acute illness.
This presentation is rare in newborns (however, when present, it usually manifests w/concurrent febrile or gastrointestinal illness & onset is rapid).
Blood chemistries incl BUN, creatinine, glucose, electrolytes, & CK
STAT ammonia
Carnitine level
Liver function tests
Urinalysis
Gastroenterologist (if concerns exist for hepatic function)
Nephologist (if concerns exist for renal tubular acidosis)
Neurologist (if concerns exist for encephalopathy & seizures)
BUN = blood urea nitrogen; CK = creatine kinase; CPT1A = carnitine palmitoyltransferase 1A; MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Transfer to specialty center w/experience in mgmt of inherited metabolic diseases is strongly recommended.
• Consider short hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
• If symptomatic, common presenting features are hypoketotic hypoglycemia (leading to lethargy/altered mental status), hepatomegaly/liver failure & seizures, usually precipitated by fasting or acute illness.
• This presentation is rare in newborns (however, when present, it usually manifests w/concurrent febrile or gastrointestinal illness & onset is rapid).
• Blood chemistries incl BUN, creatinine, glucose, electrolytes, & CK
• STAT ammonia
• Carnitine level
• Liver function tests
• Urinalysis
• Gastroenterologist (if concerns exist for hepatic function)
• Nephologist (if concerns exist for renal tubular acidosis)
• Neurologist (if concerns exist for encephalopathy & seizures)
## Treatment of Manifestations
There is no cure for CPT1A deficiency.
Neonates and infants require frequent feedings every two to three hours.
In older individuals, overnight feedings, a bedtime snack, or 2 g/kg of uncooked cornstarch as a source of complex carbohydrates at bedtime to ensure sufficient glucose supply overnight have been used. Overnight feedings may not be necessary in those without an intercurrent illness or with pathogenic variants associated with milder disease (see
A healthy diet containing no more than 20%-30% of total energy from dietary fat may be followed.
In the absence of an intercurrent infection with fever or other stressing conditions, the following maximum fasting times are suggested:
Up to eight hours in infants between ages six and 12 months
Up to ten hours during the second year of life
Up to 12 hours after age two years
Other recommendations include a general rule of thumb to avoid fasting for longer than four hours between birth and age four months, then add an additional hour of fasting for each month of age up to 12 months (see
To avoid excessive fasting in sick individuals:
In sick infants, breastfeeding may need to be replaced or alternated with metabolic formula containing medium-chain triglycerides (see
Increase frequency of feeds to reduce risk of metabolic crisis (see
Carnitine Palmitoyltransferase 1A Deficiency: Targeted Therapies
Synthetic 7-carbon triglyceride (source for acetyl-CoA & anaplerotic propionyl-CoA)
Provides C5-ketone bodies that can cross blood-brain barrier, therefore providing substrates for the brain, & correcting secondary depletion of TCA cycle intermediates
To provide ~30% of daily caloric intake
Maximum dosing goal 2g/kg/day
Actual maximum dose 15%-42% of total daily caloric intake from triheptanoin
Remainder of diet modified to maintain appropriate caloric intake & balance
Use of MCT oil OR triheptanoin is recommended
MCT oil may be used if triheptanoin is not available or not tolerated.
CoA = coenzyme A; FDA = Food and Drug Administration; LC-FAOD = long-chain fatty acid oxidation disorders; MCT = medium-chain triglycerides; TCA = tricarboxylic acid
The FDA recommends discontinuing MCT products prior to initiation of triheptanoin therapy. In the retrospective study by
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Carnitine Palmitoyltransferase 1A Deficiency: Acute Treatment
Alternative energy sources, hydration, & correction of hypoketotic hypoglycemia;
Sufficient amounts of IV fluid containing at least 10% dextrose w/age-appropriate electrolytes as quickly as possible to correct hypoglycemia & to prevent lipolysis & subsequent mobilization of fatty acids into mitochondria;
1.5x maintenance rate to provide 8-10 mg/kg/min of glucose.
↑ frequency of feeding during illness.
Provide ~1/3 of total calories as triheptanoin or MCT oil during periods of illness (see
Plasma CK level
Urine myoglobin
ALT = alanine transaminase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; CK = creatine kinase; IV = intravenous; MCT = medium chain triglycerides; PT = prothrombin time; PTT= partial thromboplastin time
Carnitine Palmitoyltransferase 1A Deficiency: Routine Long-Term Treatment
Frequent feedings for infants/young children
Consider awakening infant for feeding or overnight enteral feeding w/cornstarch if necessary.
Frequent snacks between meals & before bedtime high in carbohydrates
Cornstarch feedings provide a slow-release carbohydrate to prevent hypoglycemia during sleep.
Cornstarch is generally only tolerated around age ≥1 yr due to pancreatic amylase activity.
Maximum fasting intervals ↑ based on age of infant (see
Factors that elicit a hypoketotic hypoglycemic crisis & early signs of decompensation;
Risks of fasting;
Risks during surgery, when both metabolic stress & fasting occur.
MCT = medium-chain triglycerides; OT = occupational therapist; PT = physical therapist; SLP = speech-language pathologist
Restriction of dietary fat intake is somewhat controversial with the mild and/or asymptomatic forms (such as that caused by
• Neonates and infants require frequent feedings every two to three hours.
• In older individuals, overnight feedings, a bedtime snack, or 2 g/kg of uncooked cornstarch as a source of complex carbohydrates at bedtime to ensure sufficient glucose supply overnight have been used. Overnight feedings may not be necessary in those without an intercurrent illness or with pathogenic variants associated with milder disease (see
• A healthy diet containing no more than 20%-30% of total energy from dietary fat may be followed.
• In the absence of an intercurrent infection with fever or other stressing conditions, the following maximum fasting times are suggested:
• Up to eight hours in infants between ages six and 12 months
• Up to ten hours during the second year of life
• Up to 12 hours after age two years
• Other recommendations include a general rule of thumb to avoid fasting for longer than four hours between birth and age four months, then add an additional hour of fasting for each month of age up to 12 months (see
• Up to eight hours in infants between ages six and 12 months
• Up to ten hours during the second year of life
• Up to 12 hours after age two years
• Up to eight hours in infants between ages six and 12 months
• Up to ten hours during the second year of life
• Up to 12 hours after age two years
• In sick infants, breastfeeding may need to be replaced or alternated with metabolic formula containing medium-chain triglycerides (see
• Increase frequency of feeds to reduce risk of metabolic crisis (see
• Synthetic 7-carbon triglyceride (source for acetyl-CoA & anaplerotic propionyl-CoA)
• Provides C5-ketone bodies that can cross blood-brain barrier, therefore providing substrates for the brain, & correcting secondary depletion of TCA cycle intermediates
• To provide ~30% of daily caloric intake
• Maximum dosing goal 2g/kg/day
• Actual maximum dose 15%-42% of total daily caloric intake from triheptanoin
• Remainder of diet modified to maintain appropriate caloric intake & balance
• Use of MCT oil OR triheptanoin is recommended
• MCT oil may be used if triheptanoin is not available or not tolerated.
• Alternative energy sources, hydration, & correction of hypoketotic hypoglycemia;
• Sufficient amounts of IV fluid containing at least 10% dextrose w/age-appropriate electrolytes as quickly as possible to correct hypoglycemia & to prevent lipolysis & subsequent mobilization of fatty acids into mitochondria;
• 1.5x maintenance rate to provide 8-10 mg/kg/min of glucose.
• ↑ frequency of feeding during illness.
• Provide ~1/3 of total calories as triheptanoin or MCT oil during periods of illness (see
• Plasma CK level
• Urine myoglobin
• Frequent feedings for infants/young children
• Consider awakening infant for feeding or overnight enteral feeding w/cornstarch if necessary.
• Frequent snacks between meals & before bedtime high in carbohydrates
• Cornstarch feedings provide a slow-release carbohydrate to prevent hypoglycemia during sleep.
• Cornstarch is generally only tolerated around age ≥1 yr due to pancreatic amylase activity.
• Maximum fasting intervals ↑ based on age of infant (see
• Factors that elicit a hypoketotic hypoglycemic crisis & early signs of decompensation;
• Risks of fasting;
• Risks during surgery, when both metabolic stress & fasting occur.
## Prevention of Primary Manifestations
Neonates and infants require frequent feedings every two to three hours.
In older individuals, overnight feedings, a bedtime snack, or 2 g/kg of uncooked cornstarch as a source of complex carbohydrates at bedtime to ensure sufficient glucose supply overnight have been used. Overnight feedings may not be necessary in those without an intercurrent illness or with pathogenic variants associated with milder disease (see
A healthy diet containing no more than 20%-30% of total energy from dietary fat may be followed.
In the absence of an intercurrent infection with fever or other stressing conditions, the following maximum fasting times are suggested:
Up to eight hours in infants between ages six and 12 months
Up to ten hours during the second year of life
Up to 12 hours after age two years
Other recommendations include a general rule of thumb to avoid fasting for longer than four hours between birth and age four months, then add an additional hour of fasting for each month of age up to 12 months (see
To avoid excessive fasting in sick individuals:
In sick infants, breastfeeding may need to be replaced or alternated with metabolic formula containing medium-chain triglycerides (see
Increase frequency of feeds to reduce risk of metabolic crisis (see
• Neonates and infants require frequent feedings every two to three hours.
• In older individuals, overnight feedings, a bedtime snack, or 2 g/kg of uncooked cornstarch as a source of complex carbohydrates at bedtime to ensure sufficient glucose supply overnight have been used. Overnight feedings may not be necessary in those without an intercurrent illness or with pathogenic variants associated with milder disease (see
• A healthy diet containing no more than 20%-30% of total energy from dietary fat may be followed.
• In the absence of an intercurrent infection with fever or other stressing conditions, the following maximum fasting times are suggested:
• Up to eight hours in infants between ages six and 12 months
• Up to ten hours during the second year of life
• Up to 12 hours after age two years
• Other recommendations include a general rule of thumb to avoid fasting for longer than four hours between birth and age four months, then add an additional hour of fasting for each month of age up to 12 months (see
• Up to eight hours in infants between ages six and 12 months
• Up to ten hours during the second year of life
• Up to 12 hours after age two years
• Up to eight hours in infants between ages six and 12 months
• Up to ten hours during the second year of life
• Up to 12 hours after age two years
• In sick infants, breastfeeding may need to be replaced or alternated with metabolic formula containing medium-chain triglycerides (see
• Increase frequency of feeds to reduce risk of metabolic crisis (see
## Targeted Therapies
Carnitine Palmitoyltransferase 1A Deficiency: Targeted Therapies
Synthetic 7-carbon triglyceride (source for acetyl-CoA & anaplerotic propionyl-CoA)
Provides C5-ketone bodies that can cross blood-brain barrier, therefore providing substrates for the brain, & correcting secondary depletion of TCA cycle intermediates
To provide ~30% of daily caloric intake
Maximum dosing goal 2g/kg/day
Actual maximum dose 15%-42% of total daily caloric intake from triheptanoin
Remainder of diet modified to maintain appropriate caloric intake & balance
Use of MCT oil OR triheptanoin is recommended
MCT oil may be used if triheptanoin is not available or not tolerated.
CoA = coenzyme A; FDA = Food and Drug Administration; LC-FAOD = long-chain fatty acid oxidation disorders; MCT = medium-chain triglycerides; TCA = tricarboxylic acid
The FDA recommends discontinuing MCT products prior to initiation of triheptanoin therapy. In the retrospective study by
• Synthetic 7-carbon triglyceride (source for acetyl-CoA & anaplerotic propionyl-CoA)
• Provides C5-ketone bodies that can cross blood-brain barrier, therefore providing substrates for the brain, & correcting secondary depletion of TCA cycle intermediates
• To provide ~30% of daily caloric intake
• Maximum dosing goal 2g/kg/day
• Actual maximum dose 15%-42% of total daily caloric intake from triheptanoin
• Remainder of diet modified to maintain appropriate caloric intake & balance
• Use of MCT oil OR triheptanoin is recommended
• MCT oil may be used if triheptanoin is not available or not tolerated.
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Carnitine Palmitoyltransferase 1A Deficiency: Acute Treatment
Alternative energy sources, hydration, & correction of hypoketotic hypoglycemia;
Sufficient amounts of IV fluid containing at least 10% dextrose w/age-appropriate electrolytes as quickly as possible to correct hypoglycemia & to prevent lipolysis & subsequent mobilization of fatty acids into mitochondria;
1.5x maintenance rate to provide 8-10 mg/kg/min of glucose.
↑ frequency of feeding during illness.
Provide ~1/3 of total calories as triheptanoin or MCT oil during periods of illness (see
Plasma CK level
Urine myoglobin
ALT = alanine transaminase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; CK = creatine kinase; IV = intravenous; MCT = medium chain triglycerides; PT = prothrombin time; PTT= partial thromboplastin time
Carnitine Palmitoyltransferase 1A Deficiency: Routine Long-Term Treatment
Frequent feedings for infants/young children
Consider awakening infant for feeding or overnight enteral feeding w/cornstarch if necessary.
Frequent snacks between meals & before bedtime high in carbohydrates
Cornstarch feedings provide a slow-release carbohydrate to prevent hypoglycemia during sleep.
Cornstarch is generally only tolerated around age ≥1 yr due to pancreatic amylase activity.
Maximum fasting intervals ↑ based on age of infant (see
Factors that elicit a hypoketotic hypoglycemic crisis & early signs of decompensation;
Risks of fasting;
Risks during surgery, when both metabolic stress & fasting occur.
MCT = medium-chain triglycerides; OT = occupational therapist; PT = physical therapist; SLP = speech-language pathologist
Restriction of dietary fat intake is somewhat controversial with the mild and/or asymptomatic forms (such as that caused by
• Alternative energy sources, hydration, & correction of hypoketotic hypoglycemia;
• Sufficient amounts of IV fluid containing at least 10% dextrose w/age-appropriate electrolytes as quickly as possible to correct hypoglycemia & to prevent lipolysis & subsequent mobilization of fatty acids into mitochondria;
• 1.5x maintenance rate to provide 8-10 mg/kg/min of glucose.
• ↑ frequency of feeding during illness.
• Provide ~1/3 of total calories as triheptanoin or MCT oil during periods of illness (see
• Plasma CK level
• Urine myoglobin
• Frequent feedings for infants/young children
• Consider awakening infant for feeding or overnight enteral feeding w/cornstarch if necessary.
• Frequent snacks between meals & before bedtime high in carbohydrates
• Cornstarch feedings provide a slow-release carbohydrate to prevent hypoglycemia during sleep.
• Cornstarch is generally only tolerated around age ≥1 yr due to pancreatic amylase activity.
• Maximum fasting intervals ↑ based on age of infant (see
• Factors that elicit a hypoketotic hypoglycemic crisis & early signs of decompensation;
• Risks of fasting;
• Risks during surgery, when both metabolic stress & fasting occur.
## Surveillance
Carnitine Palmitoyltransferase 1A Deficiency: Recommended Surveillance
Measure length, weight, & head circumference.
Assess feeding skills in infants/toddlers.
Assess adherence to dietary recommendations.
Plasma carnitine panel (total, free, esters)
Plasma acylcarnitine profile
RBC or plasma essential fatty acids
Vitamins A, D, & E concentrations
CBC, comprehensive metabolic panel, CK
At each visit dependent on diet mgmt recommendations
As clinically indicated; may be dependent on frequency of clinic visits & age (e.g., more frequent assessments when younger)
ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; CK = creatine kinase; MCT = medium-chain triglycerides; OFC = occipital frontal circumference; PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cells
Based on level/degree of fat restriction
• Measure length, weight, & head circumference.
• Assess feeding skills in infants/toddlers.
• Assess adherence to dietary recommendations.
• Plasma carnitine panel (total, free, esters)
• Plasma acylcarnitine profile
• RBC or plasma essential fatty acids
• Vitamins A, D, & E concentrations
• CBC, comprehensive metabolic panel, CK
• At each visit dependent on diet mgmt recommendations
• As clinically indicated; may be dependent on frequency of clinic visits & age (e.g., more frequent assessments when younger)
## Agents/Circumstances to Avoid
Avoid fasting, including during periods of preparation and recovery from planned surgery or sedation (see
Potentially hepatotoxic agents such as valproate and salicylate should be used with caution if there is evidence of hepatic dysfunction [
Avoid viral or bacterial infections.
Avoid overfeeding in individuals without acute illness to reduce long-term risk of obesity.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Serious complications including hemolysis, elevated liver enzymes, and low platelets (HELPP)-like syndrome and acute fatty liver of pregnancy (AFLP) in a pregnant individual previously undiagnosed with CPT1A deficiency with an unaffected fetus have been reported. CPT1 enzyme activity was undetectable and molecular testing identified a homozygous pathogenic variant in the mother; the child was reported as unaffected [
Management of women with CPT1A deficiency during pregnancy should include avoidance of fasting, hypoglycemia, dehydration, and catabolic stress. Dietary management includes a low-fat, high-carbohydrate diet with use of triheptanoin or MCT oil. Use of triheptanoin has not been studied in pregnancy. Intrapartum management should include provision of adequate glucose infusion rate with intravenous fluids to prevent hypoglycemia, maintain anabolism, and prevent dehydration (IV infusion of 10% glucose at 1.5 times maintenance). Management by a team comprising a maternal-fetal medicine specialist and a medical/biochemical geneticist is highly recommended.
A pregnant mother who did not have CPT1A deficiency developed AFLP in two successive pregnancies; both children were subsequently shown to have deficient CPT1 enzyme activity; no molecular genetic testing was performed (though family was Inuit) [
Although data are limited, it is prudent to counsel heterozygous females who are carrying a fetus with biallelic
Women who have had one child with CPT1A deficiency following an uneventful pregnancy remain at risk for AFLP in subsequent pregnancies with an affected fetus. In any pregnancies that follow identification of a child with CPT1A deficiency, it is recommended that liver function testing be performed at each prenatal visit during the first two trimesters and more frequently during the third trimester, when the risk for AFLP is greatest. Management by a team comprising a maternal-fetal medicine specialist and a medical/biochemical geneticist is highly recommended.
## Therapies Under Investigation
Search
## Genetic Counseling
Carnitine palmitoyltransferase 1A (CPT1A) deficiency is inherited in an autosomal recessive manner.
The parents of an affected individual are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are not at risk for CPT1A deficiency. Although published data is limited, pregnant female carriers may be at risk of developing acute fatty liver of pregnancy if the fetus has CPT1A deficiency.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are not at risk for CPT1A deficiency. Pregnant female carriers may be at risk of developing acute fatty liver of pregnancy if the fetus has CPT1A deficiency.
Unless an affected individual's reproductive partner also has CPT1A deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that the reproductive partner of the proband may be affected or a carrier. Thus, the risk to offspring is most accurately determined after molecular genetic testing of the proband's reproductive partner.
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of individuals affected with CPT1A deficiency and individuals known to be carriers of CPT1A deficiency, particularly if consanguinity is likely and/or both partners are of the same ancestral background (see
Although data are limited, it is prudent to counsel unaffected females who are heterozygous for a
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are not at risk for CPT1A deficiency. Although published data is limited, pregnant female carriers may be at risk of developing acute fatty liver of pregnancy if the fetus has CPT1A deficiency.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are not at risk for CPT1A deficiency. Pregnant female carriers may be at risk of developing acute fatty liver of pregnancy if the fetus has CPT1A deficiency.
• Unless an affected individual's reproductive partner also has CPT1A deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
• In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that the reproductive partner of the proband may be affected or a carrier. Thus, the risk to offspring is most accurately determined after molecular genetic testing of the proband's reproductive partner.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals affected with CPT1A deficiency and individuals known to be carriers of CPT1A deficiency, particularly if consanguinity is likely and/or both partners are of the same ancestral background (see
• Although data are limited, it is prudent to counsel unaffected females who are heterozygous for a
## Mode of Inheritance
Carnitine palmitoyltransferase 1A (CPT1A) deficiency is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are not at risk for CPT1A deficiency. Although published data is limited, pregnant female carriers may be at risk of developing acute fatty liver of pregnancy if the fetus has CPT1A deficiency.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are not at risk for CPT1A deficiency. Pregnant female carriers may be at risk of developing acute fatty liver of pregnancy if the fetus has CPT1A deficiency.
Unless an affected individual's reproductive partner also has CPT1A deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that the reproductive partner of the proband may be affected or a carrier. Thus, the risk to offspring is most accurately determined after molecular genetic testing of the proband's reproductive partner.
• The parents of an affected individual are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are not at risk for CPT1A deficiency. Although published data is limited, pregnant female carriers may be at risk of developing acute fatty liver of pregnancy if the fetus has CPT1A deficiency.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are not at risk for CPT1A deficiency. Pregnant female carriers may be at risk of developing acute fatty liver of pregnancy if the fetus has CPT1A deficiency.
• Unless an affected individual's reproductive partner also has CPT1A deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
• In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that the reproductive partner of the proband may be affected or a carrier. Thus, the risk to offspring is most accurately determined after molecular genetic testing of the proband's reproductive partner.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of individuals affected with CPT1A deficiency and individuals known to be carriers of CPT1A deficiency, particularly if consanguinity is likely and/or both partners are of the same ancestral background (see
Although data are limited, it is prudent to counsel unaffected females who are heterozygous for a
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals affected with CPT1A deficiency and individuals known to be carriers of CPT1A deficiency, particularly if consanguinity is likely and/or both partners are of the same ancestral background (see
• Although data are limited, it is prudent to counsel unaffected females who are heterozygous for a
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
TEMPLE (Tools Enabling Metabolic Parents LEarning)
United Kingdom
United Kingdom
Health Resources & Services Administration
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• TEMPLE (Tools Enabling Metabolic Parents LEarning)
• United Kingdom
•
•
•
•
•
•
•
•
•
•
• United Kingdom
•
•
• Health Resources & Services Administration
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•
•
## Molecular Genetics
Carnitine Palmitoyltransferase 1A Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Carnitine Palmitoyltransferase 1A Deficiency (
Carnitine palmitoyltransferase 1A (CPT1A) deficiency is caused by a defect in the initial step of the carnitine shuttle (
There are three isoforms of carnitine palmitoyltransferase 1 (CPT1). CPT1A is expressed in liver, kidney, lymphocytes, and skin fibroblasts. Pathogenic variants in
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Carnitine palmitoyltransferase 1A (CPT1A) deficiency is caused by a defect in the initial step of the carnitine shuttle (
There are three isoforms of carnitine palmitoyltransferase 1 (CPT1). CPT1A is expressed in liver, kidney, lymphocytes, and skin fibroblasts. Pathogenic variants in
Variants listed in the table have been provided by the authors.
## Chapter Notes
Note: Authors Kristen Lee and Amanda Pritchard contributed equally to this work.
Kristen Lee, MD (
Amanda Pritchard, MD (
Ayesha Ahmad, MD (
The authors would be happy to communicate with persons who have any questions regarding the diagnosis of CPT1A deficiency or other considerations.
Ayesha Ahmad, MD (2025-present)Michael J Bennett, PhD, FRCPath, DABCC; Children's Hospital of Philadelphia (2005-2025)Kristen Lee, MD (2025-present)Srinivas B Narayan, PhD, DABCC; Children's Hospital of Philadelphia (2005-2013)Amanda Pritchard, MD (2025-present)Avni B Santani, PhD, FACMG; Children's Hospital of Philadelphia (2005-2025)
20 February 2025 (gf/sw) Comprehensive update posted live
17 March 2016 (ma) Comprehensive update posted live
7 September 2010 (me) Comprehensive update posted live
24 September 2007 (me) Comprehensive update posted live
27 July 2005 (ca) Review posted live
14 January 2005 (mb) Original submission
• 20 February 2025 (gf/sw) Comprehensive update posted live
• 17 March 2016 (ma) Comprehensive update posted live
• 7 September 2010 (me) Comprehensive update posted live
• 24 September 2007 (me) Comprehensive update posted live
• 27 July 2005 (ca) Review posted live
• 14 January 2005 (mb) Original submission
## Author Notes
Note: Authors Kristen Lee and Amanda Pritchard contributed equally to this work.
Kristen Lee, MD (
Amanda Pritchard, MD (
Ayesha Ahmad, MD (
The authors would be happy to communicate with persons who have any questions regarding the diagnosis of CPT1A deficiency or other considerations.
## Author History
Ayesha Ahmad, MD (2025-present)Michael J Bennett, PhD, FRCPath, DABCC; Children's Hospital of Philadelphia (2005-2025)Kristen Lee, MD (2025-present)Srinivas B Narayan, PhD, DABCC; Children's Hospital of Philadelphia (2005-2013)Amanda Pritchard, MD (2025-present)Avni B Santani, PhD, FACMG; Children's Hospital of Philadelphia (2005-2025)
## Revision History
20 February 2025 (gf/sw) Comprehensive update posted live
17 March 2016 (ma) Comprehensive update posted live
7 September 2010 (me) Comprehensive update posted live
24 September 2007 (me) Comprehensive update posted live
27 July 2005 (ca) Review posted live
14 January 2005 (mb) Original submission
• 20 February 2025 (gf/sw) Comprehensive update posted live
• 17 March 2016 (ma) Comprehensive update posted live
• 7 September 2010 (me) Comprehensive update posted live
• 24 September 2007 (me) Comprehensive update posted live
• 27 July 2005 (ca) Review posted live
• 14 January 2005 (mb) Original submission
## Key Sections in This
## References
## Literature Cited
The carnitine shuttle
Acyl-coenzyme A (coA) enzymes are converted to acylcarnitines by carnitine palmitoyltransferase 1, translocated into the mitochondrial matrix by carnitine:acylcarnitine translocase, and reconverted to acyl-CoAs and free carnitine by carnitine palmitoyltransferase 2.
|
[] |
27/7/2005
|
20/2/2025
|
24/3/2009
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
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