Spondyloepimetaphyseal Dysplasia, Shohat Type

A number sign (#) is used with this entry because of evidence that Shohat-type spondyloepimetaphyseal dysplasia (SEMDSH) is caused by homozygous mutation in the DDRGK1 gene (616177) on chromosome 20p13.

Description

Shohat-type spondyloepimetaphyseal dysplasia (SEMDSH) is a chondrodysplasia characterized by vertebral, epiphyseal, and metaphyseal abnormalities, including scoliosis with vertebral compression fractures, flattened vertebral bodies, and hypomineralization of long bones. Affected individuals may exhibit a small trunk, short neck, small limbs, joint laxity, bowlegs, and/or abdominal distention with hepatosplenomegaly (summary by Egunsola et al., 2017).

Clinical Features

Shohat et al. (1993) described 3 patients, 2 brothers and a son of their male cousin, with spondyloepimetaphyseal dysplasia (SEMD). All 3 boys had severe short stature, short neck, small chest, distended abdomen, lumbar lordosis, and marked genu varum. Radiologic manifestations during the first months of life were similar to those in achondroplasia (100800). After 1 year of age, significant metaphyseal changes (widened flared metaphyses with irregularity and ossification defects) and delayed ossification of epiphyses were evident. Other forms of SEMD (see 184250, 271640) were excluded. Egunsola et al. (2017) provided follow-up on this family. At age 18 years, the cousin's son (patient 1) required a lifesaving tracheostomy during orthopedic surgery due to a narrowed trachea, and 1 of the 2 brothers (patient 3) died due to this surgical complication. At age 26, patient 1 had hoarseness due to his severely narrowed larynx and bronchi, as well as joint pain.

Figuera et al. (1994), who reported a Mexican boy with the same type of SEMD, proposed the name 'spondyloepimetaphyseal dysplasia, Shohat type.'

Egunsola et al. (2017) studied 4 Jewish families of Iraqi descent with SEMDSH, including the family originally described by Shohat et al. (1993) (family 1). The 4 affected individuals in the 3 new families were diagnosed with very short limbs in utero, and at birth showed vertebral and long-bone defects similar to those observed in family 1. In 1 of the families (family 4), an affected female (patient 5) had severe scoliosis, vertebral compression fractures, platyspondyly, broadened hypomineralized metaphyses, and hypomineralized epiphyses, as well as a narrow trachea and severe upper airway obstruction requiring a tracheostomy and continuous positive airway pressure (CPAP) therapy while sleeping. Her affected brother (patient 4) died during a surgical procedure due to a narrowed trachea.

Inheritance

Shohat et al. (1993) suggested that spondyloepimetaphyseal dysplasia in the family they reported had autosomal recessive inheritance.

Molecular Genetics

In 2 Jewish families of Iraqi descent with SEMDSH (families 1 and 2), one of which was the family originally reported by Shohat et al. (1993), Egunsola et al. (2017) performed whole-exome sequencing and identified homozygosity for a splice site mutation in the DDRGK1 gene (616177.0001) that segregated fully with disease in both families. Sanger sequencing in 2 more Jewish families of Iraqi descent with SEMDSH revealed homozygosity for the same DDRGK1 splice site mutation in 2 affected individuals, suggesting that this variant represents a founder mutation.