Developmental Delay With Short Stature, Dysmorphic Facial Features, And Sparse Hair

A number sign (#) is used with this entry because of evidence that developmental delay with short stature, dysmorphic facial features, and sparse hair (DEDSSH) is caused by homozygous mutation in the DPH1 gene (603527) on chromosome 17p13.

Clinical Features

Alazami et al. (2015) reported 4 patients from a consanguineous Saudi family (10DG0934) with syndromic intellectual disability. Loucks et al. (2015) provided more clinical details of these patients. The patients had delayed psychomotor development and an unusual skull shape, mainly scaphocephaly with or without craniosynostosis. Other features included short stature, hypertelorism, downslanting palpebral fissures, epicanthal folds, low-set ears, depressed nasal bridge, and micrognathia, as well as sparse hair of the scalp, eyelashes, and eyebrows. Brain imaging showed posterior malformations, including Dandy-Walker malformation, cerebellar vermis hypoplasia, and posterior fossa cyst. Three patients had a ventricular septal defect and 3 had a renal anomaly. Three patients died between 8 months and 4 years of age.

Loucks et al. (2015) reported 4 children, including 2 sibs, from a North American genetic isolate with a neurodevelopmental syndrome. The patients presented in the neonatal period with dysmorphic features and thereafter showed developmental delay and short stature. Dysmorphic features included scaphocephaly, prominent forehead, and sparse eyebrows and hair and hypoplastic toenails, reminiscent of an ectodermal dysplasia. Other more variable features included epicanthal folds, downslanting palpebral fissures, and dental anomalies. One patient had recurrent hematuria and proteinuria associated with mild focal interstitial nephritis on biopsy, but renal function was normal. Brain CT scan of 1 patient was essentially normal. Two sibs, ages 23 and 18, had moderate cognitive impairment and could not live independently.

Inheritance

The transmission pattern of DEDSSH in the families reported by Loucks et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 affected individuals from a consanguineous Saudi family with DEDSSH, Alazami et al. (2015) identified a homozygous missense mutation in the DPH1 gene (L234P; 603527.0001). The family was part of a large cohort of 143 multiplex consanguineous families with various neurodevelopmental disorders who underwent whole-exome sequencing. Functional studies of the variant were not performed.

In 4 patients from a North American genetic isolate with DEDSSH, Loucks et al. (2015) identified a homozygous missense mutation in the DPH1 gene (M6K; 603527.0002). The mutation was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing. The carrier frequency of the variant was 0.46% in this population, consistent with a founder effect. Functional studies of the variant and studies of patient cells were not performed.