Spondyloepimetaphyseal Dysplasia, Faden-Alkuraya Type

A number sign (#) is used with this entry because of evidence that spondyloepimetaphyseal dysplasia of the Faden-Alkuraya type (SEMDFA) is caused by homozygous mutation in the RSPRY1 gene (616585) on chromosome 16q13.

Clinical Features

Faden et al. (2015) studied a consanguineous Bedouin Saudi family in which 4 sibs had progressive spondyloepimetaphyseal dysplasia, short stature, facial dysmorphism, short fourth metatarsals, and intellectual disability. The proband was a 13-year-old girl with a history of delayed motor milestones in infancy, who was walking at 5 years of age but progressively lost the ability to walk and was wheelchair-bound. She could follow simple commands but expressive language was severely limited. Examination revealed poor weight gain, severe short stature, microcephaly, dysmorphic facial features, small low-set ears, and short neck. Musculoskeletal examination showed generalized hypotonia with reduced muscle power, short hands, rocker-bottom feet with overriding toes, knocked knees, and mild scoliosis. Skeletal survey revealed generalized osteopenia, delayed bone age, copper-beaten appearance of the skull with premature closure of sutures, short metacarpals, platyspondyly, anterior wedging and posterior scalloping of lower thoracic vertebrae, and mild to moderate thoracolumbar scoliosis. In addition, she had narrow pelvis, bilateral coxa vara, short and slender long bones, small epiphyses, cupping and fraying of the metaphyses of the tibia and fibula, slipped capital femoral epiphyses, short femoral neck, and mild distal femoral bowing. The overriding toes were found to be secondary to marked shortening of the fourth metatarsal bilaterally. She had 2 affected older sisters and 1 affected younger brother, who all showed strikingly similar clinical and radiographic findings. The severity of the skeletal dysplasia appeared to correlate with age, as the findings in the 18-year-old sister were more severe than those of the 9-year-old brother. Brain CT in the proband showed asymmetry of the cerebral hemispheres, lateral ventricle, orbits, and skull, as well as evidence of premature closure of the right coronal suture. Faden et al. (2015) also studied a Peruvian boy with a similar phenotype, who was born of parents from a small isolated region and presented with significant speech delay; he was diagnosed with autism spectrum disorder at 5 years of age. At age 8 years, he exhibited short stature, dysmorphic facial features, low-set ears, short trunk with hyperlordosis, varus and valgus knee deformities, and overriding toes. Skeletal survey showed delayed epiphyseal maturation, flattening of femoral heads, thoracic platyspondyly, and short fourth metatarsals.

Mapping

Faden et al. (2015) performed autozygosity mapping in a consanguineous Bedouin Saudi family with a progressive form of spondyloepimetaphyseal dysplasia and identified 2 autozygous blocks shared only by affected family members, both on chromosome 16.

Molecular Genetics

In the proband of a consanguineous Bedouin Saudi family with a progressive form of spondyloepimetaphyseal dysplasia mapping to chromosome 16, Faden et al. (2015) performed whole-exome sequencing and identified homozygosity for a 1-bp duplication in the RSPRY1 gene (616585.0001). The mutation segregated fully with disease in the family and was not found in 650 Saudi control exomes or in the ExAC database. Using a gene-centric 'matchmaking' system, Faden et al. (2015) identified a Peruvian boy with a homozygous missense mutation in RSPRY1 (G41C; 616585.0002) who exhibited a similar phenotype.