Short-Rib Thoracic Dysplasia 19 With Or Without Polydactyly

A number sign (#) is used with this entry because of evidence that short-rib thoracic dysplasia-19 with or without polydactyly (SRTD19) is caused by compound heterozygous mutation in the IFT81 gene (605489) on chromosome 12q24.

Description

Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013).

There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330).

For a discussion of genetic heterogeneity of short-rib thoracic dysplasia with or without polydactyly, see SRTD1 (208500).

Clinical Features

Duran et al. (2016) studied 2 unrelated infants with short-rib thoracic dysplasia. The first patient (R98-443) was an African American boy who had dolichocephaly with prominent occiput, midface hypoplasia, handlebar clavicles, short ribs, and short curved appendicular bones, with the upper limbs particularly abnormally shaped. He developed respiratory distress soon after birth which worsened over time, and he died at 19 months of age. The second patient (R13-147A) was a male infant delivered at 35 weeks who died a few minutes after birth from respiratory failure due to severely hypoplastic lungs. Postnatal radiographs showed dolichocephaly with prominent occiput, midface hypoplasia, very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses, and marked hypoplasia of the radii, ulnae, tibiae, and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. Although at birth the genitalia appeared phenotypically female, karyotype analysis showed 46,XY. The authors stated that the features of the first patient were consistent with asphyxiating thoracic dystrophy, whereas the clinical findings in the second patient supported short-rib polydactyly syndrome type II (Mohr-Majewski syndrome; see 263520).

Molecular Genetics

In 2 unrelated male patients with SRTD, Duran et al. (2016) performed exome sequencing and identified compound heterozygosity for mutations in the IFT81 gene (605489.0003-605489.0006). One of the patients (R98-443), an African American boy, was also heterozygous for a known variant (R867H; rs76726265) in the SRTD-associated gene TTC21B (612014), but RT-PCR and Western blot analysis showed no differences in mRNA or protein levels between patient and control chondrocytes, and the mutation appeared to be a polymorphism in the African American population, with an ethnicity-specific allele frequency of 0.006 in the ExAC database (February 2018).