Cranioectodermal Dysplasia

Excerpt

Clinical characteristics: 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.

Diagnosis/testing: 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: IFT43, IFT52, IFT122, IFT140, WDR19, or WDR35.

Management: Treatment of manifestations: As needed, surgery to correct sagittal craniosynostosis usually before age one year. Surgical correction may be needed for polydactyly of the hands and feet. Orthopedic care for hip dysplasia. Human growth hormone therapy could be considered in those who meet standard treatment criteria. Standard treatment for dental anomalies, nephronophthisis, liver disease, cardiac anomalies, and/or inguinal and umbilical hernias. For those with progressive visual impairment: low-vision aids and appropriate educational programs. Mechanical ventilation may be required in newborns with pulmonary hypoplasia. For those with developmental delay, speech and physical therapy and appropriate educational programs.

Surveillance: In infancy and childhood: monitor tooth development; morning urine osmolarity testing, urine collection assay for polyuria, blood pressure, serum creatinine and blood urea assessment, and renal ultrasound as recommended by nephrologist; hepatic transaminases and measurement of synthetic liver function as recommended by hepatologist. Annual ophthalmologic examinations starting at age four years to detect early signs of retinal degeneration. Cardiac examinations, EKG, and echocardiography per cardiologist. Review of developmental progress at each primary care visit, and formal evaluation with neuropsychological testing if delays noted.

Genetic counseling: 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.