Short-Rib Thoracic Dysplasia 11 With Or Without Polydactyly

A number sign (#) is used with this entry because of evidence that short-rib thoracic dysplasia-11 with or without polydactyly (SRTD11) is caused by homozygous or compound heterozygous mutation in the WDR34 gene (613363) on chromosome 9q34.

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 (see CED1, 218330).

For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).

Clinical Features

Tuysuz et al. (2009) reported 13 patients with a clinical diagnosis of Jeune syndrome from 11 families and emphasized the phenotypic variability of the disorder, particularly regarding prognosis. The diagnosis was established in the prenatal period in 4 patients, infancy in 6 patients, and childhood in 3 patients. Two affected fetuses were terminated. The living patients all had small thorax deformity, classified as bell-shaped or long narrow, varying degrees of mesomelic shortness, and mild to severe brachydactyly. Tuysuz et al. (2009) classified them into 3 groups according to clinical features: 7 with severe pulmonary involvement; 1 with renal failure; and 2 with a milder form of the disorder. The degree of respiratory distress varied from negligible to fatal and improved with age. Short stature was sometimes present at birth but also developed in the postnatal period. Patients with severe pulmonary involvement had a bell-shaped thorax and mild brachydactyly; the patient with renal involvement had a long narrow thorax and severe brachydactyly, whereas those with mild involvement presented with polydactyly and moderate to severe brachydactyly. Important radiologic findings included metaphyseal widening and trident appearance of the acetabular margin, which improved with age in 2 older patients. Other radiologic features included high handlebar clavicles, shortness of the metacarpals and second and distal phalanges, and hypoplastic ileum. In the follow-up period, 8 had respiratory distress, which was lethal in 6 before age 2 years, and 1 died of chronic renal failure at age 13. None had ocular involvement, ectodermal dysplasia, or cardiac or urogenital anomalies.

Huber et al. (2013) studied a consanguineous Algerian family in which 3 sibs had short-rib thoracic dysplasia. The proband was diagnosed with SRPS type III, or severe ATD, by ultrasound at 23 weeks of gestation due to the findings of micromelia, curved femurs, and short thorax. The proband died on day 7 of life from respiratory insufficiency, and abnormal skeletal findings were confirmed by postnatal radiographs that showed long narrow thorax with short ribs, shortened tubular bones, round metaphyseal ends with lateral spike, and trident appearance of the acetabular roof. The second case was a suspected recurrence and the pregnancy was terminated at 26 weeks of gestation. The third case was diagnosed at 20 weeks of gestation and was stillborn at 42 weeks of gestation.

Mapping

In a consanguineous Algerian family in which 3 sibs had short-rib thoracic dysplasia, Huber et al. (2013) performed genomewide homozygosity mapping and identified a single region of homozygosity shared by the 3 sibs on chromosome 9, obtaining a lod score of 2.4 (theta = 0) between markers D9S1819 and D9S1847. Analysis of SNP genotypes narrowed the critical region to a 3.6-Mb interval bounded by rs2798429 and rs10114591 at 9q34.11.

Molecular Genetics

In 3 affected individuals from a consanguineous Algerian family with short-rib thoracic dysplasia mapping to chromosome 9q34.11, in whom mutation in the IFT80 (611177) and DYNC2H1 (603297) genes had been excluded, Huber et al. (2013) identified homozygosity for a missense mutation in the candidate gene WDR34 (613363.0001). Whole-exome analysis in 1 of the affected individuals confirmed that the WDR34 variant was the only homozygous variant in the chromosome 9 region. Sequencing of WDR34 combined with whole-exome analysis in 30 independent patients with short-rib thoracic dysplasia in the ATD/SRPS III phenotype spectrum revealed another 2 patients with homozygous missense mutations in WDR34 (613363.0002; 613363.0003) and 1 who was compound heterozygous for a missense mutation (613363.0004) and a splice site mutation (613363.0005). The mutations cosegregated with disease in each family and were not found in controls. Only 1 of the 6 patients with WDR34 mutations exhibited polydactyly; there were no visceral anomalies apart from hypotrophic lungs in 1 patient, and none had cleft lip/palate.

Schmidts et al. (2013) performed whole-exome sequencing in 61 unrelated individuals diagnosed with Jeune syndrome based on classic clinical and radiologic findings, primarily short ribs with a small or narrow thorax and small ilia with acetabular spurs. Biallelic mutations in the WDR34 gene (see, e.g., 613363.0003 and 613363.0006-613363.0007) were identified in 6 of the probands, 1 of whom had previously been reported by Tuysuz et al. (2009). Screening of 52 more patients with a clinical diagnosis of Jeune/ATD revealed 4 patients from 3 families with biallelic variants in WDR34 (see, e.g., 613363.0008-613363.0009). Schmidts et al. (2013) stated that because most patients did not survive beyond the neonatal period due to a severe respiratory phenotype, it was difficult to predict the degree of renal, hepatic, or retinal involvement associated with WDR34 mutations; however, 1 patient who was alive at 8 years of age had been diagnosed with rod-cone dystrophy, indicating that retinal degeneration may occur. In addition, the authors noted that in this study, mutations in WDR34 accounted for approximately 10% of all cases of ATD, making it the most commonly mutated gene after DYNC2H1 in this disease.