Short-Rib Thoracic Dysplasia 18 With Polydactyly

A number sign (#) is used with this entry because of evidence that short-rib thoracic dysplasia-18 with polydactyly (SRTD18) is caused by homozygous mutation in the IFT43 gene (614068) on chromosome 14q24.

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. (2017) reported a family (R06-303) in which a fetus from a dizygotic twin pregnancy showed features of short-rib polydactyly syndrome. Delivery occurred at 30 weeks' gestation and the affected newborn (R06-303A) died the following day. Significant findings included short long bones with reverse campomelia of the humeri, bending of the bones of the mesomelic segments, long narrow chest with bent ribs, postaxial polydactyly of all extremities, and brain, liver, pancreas, and kidney abnormalities. A second pregnancy (R06-303E) with similar findings was interrupted at 18 weeks' gestation. The authors noted that the features were consistent with SRPS type II, except for the unusual finding of bending of the ribs and mesomelic segments of the appendicular skeleton. Duran et al. (2017) studied another family (R03-121) in which prenatal ultrasound at 18 weeks' gestation showed cystic hygroma, micromelia, poorly calcified calvarium, and postaxial polydactyly of both hands and both feet. The pregnancy was terminated and radiographic and autopsy examination confirmed the SRPS diagnosis, with some unusual radiographic features including short irregularly bent ribs, short campomelic long bones, hypoplastic and bent mesomelic bones, and lack of ossification of the calvarium, hands, and feet. Additional findings included hydrocephalus, malrotation of the intestines, and polycystic kidneys. By history, similar findings had been present in a previous fetus but no postmortem information or material was available.

Molecular Genetics

In 3 affected individuals with SRTD from 2 unrelated families, Duran et al. (2017) performed exome sequencing and identified homozygosity for missense mutations in the IFT143 gene, M1K (614068.0002) and W179R (614068.0003), respectively. Their unaffected parents were heterozygous for the mutations, which were not found in public variant databases.