Short-Rib Thoracic Dysplasia 17 With Or Without Polydactyly

A number sign (#) is used with this entry because of evidence that short-rib thoracic dysplasia-17 with or without polydactyly (SRTD17) is caused by homozygous or compound heterozygous mutation in the TCTEX1D2 gene (617353) on chromosome 3q29.

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

Schmidts et al. (2015) studied 5 affected children from 3 unrelated families with a clinical diagnosis of Jeune asphyxiating thoracic dysplasia based on clinical and radiologic findings including short ribs with small or narrow thorax, small ilia with trident acetabulum and spurs, handlebar clavicles, and brachydactyly. Polydactyly was also present in 4 of the 5 patients. None exhibited renal, hepatic, or ocular features, although Schmidts et al. (2015) noted that such features might emerge with age.

Molecular Genetics

By whole-exome sequencing in 69 patients from 60 families clinically diagnosed with Jeune asphyxiating thoracic dysplasia, Schmidts et al. (2015) identified homozygosity for a splice site mutation in the TCTEX1D2 gene (617353.0001) in the proband from a consanguineous Turkish family (UCL82). Analysis of an additional 154 exomes from SRTD patients and Sanger sequencing of TCTEX1D2 in another 69 SRTD cases that previously had been excluded for mutations in known SRTD-associated genes revealed compound heterozygosity for a nonsense mutation (R88X; 617353.0002) and a deletion/insertion frameshift mutation (617353.0003) in the proband from a nonconsanguineous French family (INS). The mutations segregated with disease in each family and were not found in public variant databases. In a consanguineous Yemeni family (UCL4), exome copy number variant analysis revealed homozygosity for a more than 10-kb deletion removing the start codon and exons 1 and 2 of the TCTEX1D2 gene in an affected brother and sister, who were negative for mutation in known SRTD-associated or other ciliary-component genes. The deletion also removed exons 2 to 5 of a neighboring pancreatic development-associated gene, TM4SF19, which the authors stated was unlikely to be involved in SRTD. RT-PCR on RNA from patient blood lymphocytes detected no TCTEX1D2 transcript, indicating likely nonsense-mediated decay of the mutant transcript. In this family, the homozygous deletion was also found in an affected male sib who died at age 2 months of respiratory failure, as well as in an older brother and sister who exhibited only short stature, with mild brachydactyly and slight shortening of lower limb distal segments. The older sister was also reported to have had pectus carinatum in childhood. Noting that brachydactyly and short stature can occur in SRTD but are not specific for the condition, Schmidts et al. (2015) suggested that the SRTD phenotype was not fully penetrant in the Yemeni family.