Oculodentodigital dysplasia (ODDD) is characterized by craniofacial, neurologic, limb and ocular abnormalities. To date, approximately 250 cases have been described worldwide (the majority of whom were white individuals). The disease is characterized by wide intra- and interfamilial phenotypic variability. The typical craniofacial anomalies include a thin nose with hypoplastic alae nasi, small anteverted nares and a prominent columella, mandibular overgrowth, cleft palate, and microcephaly. Skeletal manifestations consist of syndactyly (involving the 4th and 5th fingers and/or 2nd to 4th toes), camptodactyly, and clinodactyly due to hypoplasia or aplasia of the middle phalanges. Cranial hyperostosis and broad tubular bones may be present. Ophthalmic anomalies include decreased visual acuity, microphthalmia, microcornea, cataracts, glaucoma, iris abnormalities and optic atrophy. Less frequent ocular findings are nystagmus, palpebral fissure hypoplasia, epicanthal folds and convergent strabismus. The majority of patients with ODDD have abnormal primary and permanent dentition with microdontia, partial anodontia, enamel hypoplasia, multiple caries and early tooth loss. Neurologic symptoms are inconsistent but frequent and include dysarthria, neurogenic bladder disturbances, spastic paraparesis, ataxia, anterior tibial muscle weakness, and seizures. Some patients have dysplastic ears and conductive hearing loss. Mild psychomotor delay has been described. Brain magnetic resonance imaging (MRI) may show white matter abnormalities. Brittle nails and hair abnormalities (hypotrichosis and slow growth) may be present. Cardiac anomalies, including arrhythmias or congenital malformations (ventricular septal defect) have been described but are not frequent. Umbilical hernia, congenital optociliary veins, and recurrent ketotic hypoglycemia in early childhood have been reported in a single case. ODDD is caused by heterozygous mutations in the GJA1 gene (6q22-q23), which encodes the gap junction protein connexin 43 (Cx43). Over 40 causative mutations have been identified. Mutations of the GJA1 gene have also been observed in syndactyly type 3 (see this term), suggesting that both syndromes are part of the same spectrum. In the majority of cases, ODDD is inherited in an autosomal dominant manner with high penetrance and variable expression. Advanced paternal age has been noted in sporadic ODDD cases. Five families with apparently autosomal recessive inheritance have been reported, but this remains to be confirmed. Diagnosis is based on clinical findings and can be confirmed by molecular studies. Differential diagnosis includes a wide number of syndromes that present with skeletal, ocular, dental and neurological manifestations. Genetic counseling should be offered to all ODDD patients. In familial cases, the recurrence risk is elevated and prenatal mutational analysis may be considered. Management is multidisciplinary. Regular follow-up should include a complete eye examination, and neurological, hearing and dental evaluation. As blindness due to glaucoma can occur, patients at risk should receive anti-glaucoma treatment. Plastic or orthopedic surgery is indicated for severe limb malformations. Early recognition of the syndrome is of crucial importance in prevention and treatment of the wide variety of clinical manifestations.
Last update: October 2010
- Dr Nicole MORICHON-DELVALLEZ