Retinitis Pigmentosa With Or Without Skeletal Anomalies

A number sign (#) is used with this entry because of evidence that retinitis pigmentosa with or without skeletal anomalies (RPSKA) is caused by homozygous or compound heterozygous mutation in the CWC27 gene (617170) on chromosome 5q12.

Clinical Features

Phillips et al. (1981) described a brother and sister with severe retinitis pigmentosa, short stature, and brachydactyly. Ocular examination in the second decade of life showed severely restricted visual fields and reduced or absent responses on electroretinography. Skeletal x-rays in early childhood showed metaphyseal chondrodysplasia of the proximal femoral metaphyses, whereas hip x-rays at ages 14 and 17 years appeared near-normal and normal, respectively. In addition, hand x-rays showed marked shortening of metacarpals and terminal phalanges. The sibs had IQs within the normal range. Both parents were unaffected clinically and radiologically, and there was no family history of a similar disorder.

Lorda-Sanchez et al. (1999) reported a Spanish brother and sister with RP, short stature, brachydactyly, and moderate mental retardation. Both patients developed slowly progressive visual problems after age 10 years, with night blindness and constriction of visual fields; funduscopy showed findings consistent with RP. Both sibs also showed marked brachydactyly of the hands and feet, particularly of the terminal phalanges, and exhibited craniofacial dysmorphism, including macrocephaly, malar hypoplasia, downslanting palpebral fissures, large columella, hypoplastic nares, large low-set ears, micrognathia, and short neck.

Xu et al. (2017) studied 10 patients from 7 unrelated families of diverse ethnicities, including the 2 Spanish sibs reported by Lorda-Sanchez et al. (1999), who had retinal degeneration, brachydactyly, short stature, craniofacial dysmorphism, and neurologic defects. Retinal defects were consistent with RP in most patients, in whom night blindness occurred around 10 years of age, followed by restriction of visual fields; however, 1 patient with more severe retinal defects had been diagnosed with Leber congenital amaurosis (LCA; see 204000). Brachydactyly affected primarily the distal phalanges, and some affected individuals showed hypoplastic nails. Craniofacial anomalies included frontal bossing, downslanting palpebral fissures, large columella, hypoplastic nares, micrognathia, and large low-set ears. Neurologic features included delays in speech, feeding, and walking, as well as intellectual disability. Two of the probands, a 14-year-old Han Chinese boy and a 7-year-old Han Chinese girl, exhibited a retinal phenotype without syndromic features except for mild brachydactyly in the girl.

Molecular Genetics

In 7 families with retinitis pigmentosa with or without skeletal anomalies, Xu et al. (2017) performed whole-exome sequencing and identified homozygosity or compound heterozygosity for protein-truncating mutations in the CWC27 gene (see, e.g. 617170.0001-617170.0004) in all 10 affected individuals. The mutations segregated with disease in the 7 families, and either were not found or occurred only once in heterozygous state in public variant databases. Xu et al. (2017) noted that the 2 Han Chinese patients who exhibited a significantly milder extraocular phenotype shared the most C-terminal mutation (see 617170.0003), suggesting that residual CWC27 function might account for the phenotypic variability.