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Less than 300 cases have been described worldwide, predominantly in Caucasian families. There are some reports in the Asian population.

Oculodentodigital dysplasia (ODDD) is characterized by great phenotypic variability. Typical craniofacial anomalies include thin nose with hypoplastic alae nasi, small anteverted nares and a prominent columella, mandibular overgrowth, cleft palate, and microcephaly. Limb malformations include syndactyly type 3 (involving the fourth and fifth fingers) and/or syndactyly of second to fourth toes, camptodactyly, and clinodactyly due to hypoplasia or aplasia of the middle phalanges. Cranial hyperostosis and broad tubular bones can occur. Ophthalmological anomalies include decreased visual acuity, microphthalmia, microcornea, cataracts, glaucoma, iris abnormalities and optic atrophy. Less often, nystagmus, palpebral fissure hypoplasia, epicanthal folds and convergent strabismus are found. Most patients have abnormal primary and permanent dentition with microdontia, partial anodontia, enamel hypoplasia, multiple caries and early tooth loss. Frequent neurological manifestations vary 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 global development delay has been described. Brain magnetic resonance imaging 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.

ODDD is caused by mutations in the GJA1 gene (6q22-q23), encoding Cx43 protein. Around 70 causative mutations have been identified, resulting in variable ODDD phenotypes. Most missense variants are located in the connexin domain.

Diagnosis is based on clinical findings. Careful phenotype evaluation of facial dysmorphism and digital anomalies, ophthalmological and dental examination, and hand X-ray are required. Neurological symptoms might also be present. The clinical diagnosis can be confirmed by molecular analysis of GJA1 gene.

Differential diagnosis includes syndromes presenting with skeletal, ocular, dental and neurological features. Syndactyly type 3 is also linked with GJA1 mutations.

Genetic prenatal diagnosis is theoretically possible if GJA1 mutation has been identified in the family.

Inheritance is mostly autosomal dominant (AD) with high penetrance and variable expression. Genetic counselling should be offered to affected individuals and their families. For AD variants, the risk for each pregnancy is 50 %. GJA1 variants may occur de novo. Advanced paternal age has been noted in sporadic cases. A few families with autosomal recessive inheritance have been reported in the recent years.

Management is multidisciplinary. Early recognition is crucial to prevent and treat the variety of clinical manifestations. Follow-up should include a complete eye, neurological, hearing and dental evaluation. As blindness due to glaucoma can occur, patients at risk should receive anti-glaucoma treatment. Neurological symptoms may be subtle or appear only late in life. Instrumental tests can detect structural anomalies if no symptoms are present. Cardiac arrhythmias have been associated with ODDD and may require cardiologist monitoring. Plastic or orthopedic surgery is indicated for severe limb malformations.

Prognosis varies based on the severity. Functional, social and psychological care help to lessen the impact on the everyday life. Life expectancy depends on other system (neurological and cardiac) involvement. In cases of cardiac involvement, there is a risk of progressive heart failure. However, further understanding of cardiac anomalies in ODDD is needed.