Short rib-polydactyly syndrome, type III (SRPS3)

Short rib-polydactyly syndrome, type III, short rib-polydactyly syndrome, type V and asphyxiating thoracic dystrophy 2 and 3

Short rib-polydactyly syndrome, type III (SRPS3; MIM 263510), short rib-polydactyly syndrome, type V (SRPS5; MIM 614091) and asphyxiating thoracic dystrophy 2 and 3 (ATD2; MIM 611263 and ATD3; MIM 613091) are autosomal recessive osteochondrodysplasias that display similar clinical, radiological and histological features.  All of these disorders are ciliopathies and are characterized by short ribs with a narrow thorax, short long bones and polydactyly.  The short-rib polydactyly syndromes and ATD are among the most common autosomal recessive osteochondrodysplasias.

Short rib-polydactyly syndrome

SRPS3, or Verma-Naumoff syndrome, is considered to be more severe than ATD and is characterized by a very narrow thorax and neonatal asphyxia.  SRPS3 may also be characterized by a distinct corticomedullary demarcation of the long bones, metaphyseal spikes, ambiguous genitalia, cystic renal disease, and various cranial, gastrointestinal and brain abnormalities. Mutations in the cytoplasmic dynein 2 heavy chain 1 gene (DYNC2H1) have been reported in both SRPS3 and ATD3 (see below). The DYNC2H1 gene codes for a component of the cytoplasmic dynein complex.  Specifically, it codes for the “motor” responsible for retrograde intraflagellar transport from the cilia tip to basal body.

SRPS5 is similar to SRPS3 but with novel features of acromesomelic hypomineralization and campomelia.  Mutations have been described in the WDR35 gene. WDR35 encodes a molecule implicated in intraflagellar transport.  Mutations result in the abrogation or interruption of retrograde transport.   SRPS5 is allelic to cranioectodermal dysplasia 2 (MIM 613610), also known as Sensenbrenner syndrome 2, a less severe osteochondrodysplasia.

Asphyxiating thoracic dystrophy

Although ATD2 and ATD3 are typically fatal during the first year of life, some patients have survived to adulthood.  Additional findings in patients with ATD2/ATD3 may include trident shaped acetabular roofs, retinal degeneration, cystic renal disease and occasional liver involvement.

Mutations in the intraflagellar transport protein 80 homolog (IFT80) gene have been described in patients with ATD2.  IFT80 is a component of the intraflagellar transport complex B, which is essential for the development and maintenance of motile and sensory cilia.

Mutations in the cytoplasmic dynein 2 heavy chain 1 gene (DYNC2H1) have been described in some cases of SRPS3 and ATD3.  The DYNC2H1 gene codes for a component of the cytoplasmic dynein complex. Specifically, it codes for the “motor” responsible for retrograde intraflagellar transport form the cilia tip to the basal body.