Clinical characteristics: CTDP1-related congenital cataracts, facial dysmorphism, and neuropathy (CTDP1-CCFDN) is characterized by abnormalities of the eye (bilateral congenital cataracts, microcornea, microphthalmia, micropupils), mildly dysmorphic facial features apparent in late childhood, and a hypo-/demyelinating, symmetric, distal peripheral neuropathy. The neuropathy is predominantly motor at the onset and results in delays in early motor development, progressing to severe disability by the third decade of life. Secondary foot deformities and scoliosis are common. Sensory neuropathy develops after age ten years. Most affected individuals have a mild nonprogressive intellectual deficit and cerebellar involvement including ataxia, nystagmus, intention tremor, and dysmetria. All have short stature and most have subnormal weight. Adults have hypogonadotropic hypogonadism. Parainfectious rhabdomyolysis (profound muscle weakness, myoglobinuria, and excessively elevated serum concentration of creatine kinase usually following a viral infection) is a potentially life-threatening complication. To date all affected individuals and carriers identified have been from the Romani population.
Diagnosis/testing: The diagnosis of CTDP1-CCFDN is established in a proband by identification of biallelic pathogenic variants in CTDP1 on molecular genetic testing.
Management: Treatment of manifestations: Cataracts are treated surgically; exaggerated inflammatory response and foreign-body reaction to contact lenses and intraocular lenses warrant close postoperative follow up. Peripheral neuropathy is managed symptomatically in the usual manner. Secondary spine and foot deformities may require surgical intervention. Developmental services and educational support as needed. Management of cerebellar manifestations per physical medicine / rehabilitation / physical and occupational therapists. Close postoperative monitoring for risk of anesthetic complications. Hormone replacement therapy for hypogonadotropic hypogonadism may help prevent osteoporosis in females. Awareness of rhabdomyolysis as a potential complication following febrile infections in order to seek medical attention with the first recognizable symptoms and to provide oral corticosteroid treatment (for 2-3 weeks for optimal recovery).
Surveillance: Annual examinations for possible ophthalmologic, neurologic, and endocrine manifestations. Developmental assessments throughout childhood.
Evaluation of relatives at risk: It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from early initiation of treatment of ophthalmologic, neurologic, and endocrine manifestations.
Genetic counseling: CTDP1-CCFDN is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CTDP1 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 CTDP1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal/preimplantation genetic testing are possible.
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