Short-Rib Thoracic Dysplasia 8 With Or Without Polydactyly

A number sign (#) is used with this entry because of evidence that short-rib thoracic dysplasia-8 with or without polydactyly (SRTD8) is caused by compound heterozygous mutation in the WDR60 gene (615462) on chromosome 7q36.

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, see SRTD1 (208500).

Clinical Features

McInerney-Leo et al. (2013) studied a nonconsanguineous Australian family of British and Maori descent in which the healthy parents had 2 offspring with short-rib polydactyly syndrome, clinically classified as SRPS type III (SRTD3; 613091). The first child presented with short long bones on ultrasound at 6 weeks' gestation. Follow-up ultrasound at 31 weeks' showed polyhydramnios, severe shortening of long bones with bowed femurs, macrocephaly, short ribs, and ambiguous genitalia. Born at 32 weeks' gestation, the baby died at 2 hours of life. Autopsy confirmed the above findings and in addition revealed postaxial polydactyly of both hands, syndactyly of some fingers and toes, acetabular spurs, pancreatic fibrosis, mild dilation of renal tubules, and enlarged liver with ductal plate malformation. A second pregnancy was terminated at 17 weeks' gestation after ultrasound showed short ribs and short bowed limbs. Autopsy further revealed brachydactyly (not polydactyly), conical epiphyses, hypoplastic trabecular bone, depressed nasal bridge, ventricular septal defect (VSD), focal cystic changes in the kidneys, prominent bile ducts, and early evidence of pulmonary hypoplasia.

Molecular Genetics

In the deceased proband from a nonconsanguineous Australian family of British and Maori descent segregating autosomal recessive short rib-polydactyly syndrome, McInerney-Leo et al. (2013) performed whole-exome sequencing and identified compound heterozygosity for a nonsense (Q631X; 615462.0001) and a missense (T749M; 615462.0002) mutation in the WDR60 gene. An affected fetus in the family was also compound heterozygous for the mutations, whereas the unaffected parents were each heterozygous for 1 of the mutations. The authors reviewed exome sequencing data from 1,985 unrelated individuals but found no compound heterozygotes carrying WDR60 mutations. However, a review of exome sequencing data from 54 patients with skeletal ciliopathies revealed a 5-year-old Spanish boy, originally diagnosed with Jeune syndrome (see 208500), who was compound heterozygous for mutations in WDR60: the T749M missense mutation and a splice site mutation (615462.0003). In the Spanish boy, prenatal ultrasound had shown short femurs, and at birth he was noted to have narrow chest, preaxial polydactyly on the right hand, and a clinically insignificant VSD. At 1 year of age, he showed signs of failure to thrive, and at 5.25 years of age, his height and weight were below the 5th centile for age. X-rays showed mildly narrowed thorax, 'handlebar' clavicles, and acetabular spurs. He had no evidence of renal, hepatic, retinal, neurologic, or developmental problems. Haplotype analysis excluded a common founder for the shared missense mutation.