Oculoskeletodental Syndrome

A number sign (#) is used with this entry because of evidence that oculoskeletodental syndrome (OCSKD) is caused by homozygous mutation in the PIK3C2A gene (603601) on chromosome 11p15.

Description

Oculoskeletodental syndrome is characterized by congenital cataract, short stature and various skeletal anomalies, dysmorphic facial features and dental anomalies, developmental delay, and stroke. Other recurrent features include hearing loss, secondary glaucoma, and nephrocalcinosis (Tiosano et al., 2019).

Clinical Features

Tiosano et al. (2019) studied 5 affected individuals, aged 8 to 20 years, from 3 unrelated consanguineous families with oculoskeletodental syndrome. Dysmorphic facial features included coarse facies, low hairline, epicanthal folds, flat and broad nasal bridges, thick columella, thick alae nasi, and retrognathia. Congenital cataract was present in all, and 4 had secondary glaucoma. Three patients showed hearing loss, which was reported as conductive in 1 and sensorineural in 1. Dental anomalies included broad maxillary incisors, narrow mandibular teeth, oligodontia, and enamel defects. Skeletal findings included scoliosis, delayed bone age, diminished ossification of femoral heads, cervical lordosis and thoracic kyphosis, and shortened fifth digits with mild metaphyseal dysplasia and clinodactyly. Hypercalcemia associated with nephrocalcinosis was present in 3 patients, and 1 patient showed hypocalcemia. Four patients had developmental delay or were in special education classes, whereas the fifth exhibited selective mutism. MRI showed evidence of stroke within the first decade of life in 3 patients; MRI abnormalities in the remaining 2 patients included a nodular lesion in the thalamus, dysgenesis of the corpus callosum splenium, and herniation of the gyrus supraorbitalis in 1, and white matter lesions in the other. Three patients who were tested showed elevated urinary mucopolysaccharide levels.

Molecular Genetics

In affected individuals from 3 unrelated consanguineous families with oculoskeletodental syndrome, who had negative results on targeted genetic testing for various metabolic disorders and syndromes with overlapping features, Tiosano et al. (2019) performed whole-exome sequencing and identified homozygosity for 3 different mutations in the PIK3C2A gene: a nonsense mutation in 2 Muslim-Arab Israeli sisters (family I; Y195X, 603601.0001), a large intragenic deletion in 2 Syrian brothers (family II; 603601.0002), and a splicing mutation in a 20-year-old female proband from Tunisia (family III; 603601.0003). Each mutation segregated with disease in the respective family, and none of the mutations were found in homozygosity in the gnomAD database. Analysis of patient-derived fibroblasts from all 3 families revealed alterations suggestive of defective trafficking of ciliary components, and the PIK3C2A-deficient fibroblasts showed reduced proliferative capacity compared to control cells.