Oculodentodigital dysplasia

Oculodentodigital dysplasia is a rare, autosomal dominant disorder with high penetrance and variable expressivity, caused by mutations in the connexin 43 or gap junction protein alpha-1 gene. It has been diagnosed in fewer than 300 people worldwide with an incidence of around 1 in 10 million. It affects many parts of the body, particularly eyes (oculo), teeth (dento), and fingers and/or toes (digital). The common clinical features include facial dysmorphism with thin nose, microphthalmia, syndactyly, tooth anomalies such as enamel hypoplasia, anodontia, microdontia, early tooth loss and conductive deafness. Other less common features are abnormalities of the skin and its appendages, such as brittle nails, sparse hair, and neurological abnormalities. To prevent this syndrome from being overlooked, awareness of possible symptoms is necessary. Early recognition can prevent blindness, dental problems and learning disabilities. Described here is the case of a 21-year-old male who presented to the ophthalmology outpatient department with a complaint of bilateral progressive loss of vision since childhood.     

Mutations in the fourth β‐propeller domain of LRP4 are associated with isolated syndactyly with fusion of the third and fourth fingers

Isolated hand syndactyly is a common limb malformation with limited known genetic etiology. We used exome sequencing to discover two novel variants, chr11 g.46896373C>G; p.D1403H and chr11 g.46893078G>T; p.Q1564K, in LRP4 in a child with isolated bilateral syndactyly of the third and fourth fingers. Each variant was inherited from a different parent and neither parent was affected. Variants in LRP4 have been previously associated with syndactyly in Cenani‐Lenz syndactyly syndrome and Sclerosteosis 2, but have not been reported in individuals with isolated syndactyly. LRP4 inhibits LRP6/LRP5‐mediated activation of canonical Wnt signaling and mediates sclerostin‐dependent inhibition of bone formation. p.D1403H and p.Q1564K are located within the fourth β‐propeller of the extracellular protein domain that has yet to be associated with human disease. Functional analyses of p.D1403H and p.Q1564K show that they significantly decrease LRP4's inhibition of Wnt signaling. These results suggest that variants in the fourth β‐propeller of the extracellular protein domain may cause a phenotype distinct from previously characterized LRP4 variants.