Asphyxiating thoracic dystrophy-3 is an autosomal recessive skeletal ciliopathy characterized mainly by small thorax due to shortened ribs, brachydactyly, and shortened long bones. Although short stature is present in childhood, most patients achieve normal height by adolescence or ... Asphyxiating thoracic dystrophy-3 is an autosomal recessive skeletal ciliopathy characterized mainly by small thorax due to shortened ribs, brachydactyly, and shortened long bones. Although short stature is present in childhood, most patients achieve normal height by adolescence or adulthood. The thoracic restriction also tends to improve with age. Unlike other forms of ATD, polydactyly is not usually seen, and extraskeletal manifestations, such as retinal, hepatic, renal, and pancreatic, are rare (summary by Schmidts et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of asphyxiating thoracic dystrophy, also known as Jeune syndrome, see 208500.
Through a study to identify the molecular basis of asphyxiating thoracic dystrophy (ATD) and the related but more severe disorder short rib-polydactyly syndrome (see 263530), Dagoneau et al. (2009) identified 3 families with ATD. Criteria for inclusion in ... Through a study to identify the molecular basis of asphyxiating thoracic dystrophy (ATD) and the related but more severe disorder short rib-polydactyly syndrome (see 263530), Dagoneau et al. (2009) identified 3 families with ATD. Criteria for inclusion in the study were short ribs and a restricted thoracic cage; trident acetabular roof; small hands and feet; and shortening of the long bones. The 3 families with ATD were a large consanguineous Moroccan family and 2 small nonconsanguineous families from France. The 3 ATD families included 5 cases. In the first family, one child died of respiratory distress, and pregnancy of her aunt was terminated at 28 weeks' gestation for severe narrowing of the thorax. In the second family, 2 pregnancies were terminated for severe narrowing of the thorax. In the third family the affected child was 19 years old at the time of the report; no eye, liver, or kidney manifestations were detected. Schmidts et al. (2013) reported 29 patients from 19 families with ATD3 confirmed by genetic analysis. The clinical course was dominated by abnormal bone development with a small thorax due to reduced rib length, handlebar clavicles, scoliosis, and shortened long bones, particularly femurs. There was wide variability in rib shortening and a variable degree of respiratory impairment, even within the same family. Some patients had brachydactyly with cone-shaped epiphyses, but none had bilateral polydactyly; only 1 patient had unilateral polydactyly. Short stature with variable shortening of the limbs and some bowing was often found in early childhood, but most patients reached normal height by adolescence or adulthood. Mild renal, retinal, and liver abnormalities were only rarely observed in 1 or 2 patients overall, so extraskeletal manifestations were essentially absent.
Among the genes in the 20.4-Mb critical region for ATD, Dagoneau et al. (2009) considered DYNC2H1 a good candidate gene because it encodes a subunit of a cytoplasmic dynein complex. The authors sequenced all 90 exons of the ... Among the genes in the 20.4-Mb critical region for ATD, Dagoneau et al. (2009) considered DYNC2H1 a good candidate gene because it encodes a subunit of a cytoplasmic dynein complex. The authors sequenced all 90 exons of the DYNC2H1 gene and identified 2 homozygous missense mutations in the 2 affected Moroccan children (M1991L, 603297.0001 and M3762V, 603297.0002). The mutations cosegregated with the disease and were not identified in 210 ethnically matched control chromosomes. Dagoneau et al. (2009) identified 4 other missense and nonsense mutations in compound heterozygosity in 2 other families, both nonconsanguineous, with ATD. Using a combination of SNP mapping, exome sequencing, and Sanger sequencing, Schmidts et al. (2013) identified 34 DYNC2H1 mutations (see, e.g., D3015G, 603297.0004 and I1240T, 603297.0005) in 29 (41%) of 71 patients from 19 (33%) of 57 families with ATD. Most of the mutations were private, occurring in only 1 family. The variants included 13 terminating mutations and 21 missense mutations distributed across the gene, with some clustering of the missense mutations in functional domains. All mutations occurred in homozygous or compound heterozygous state, and no patients had 2 truncating mutations, suggesting that the human phenotype is at least partly hypomorphic. Two patients carried 3 pathogenic mutations in the DYNC2H1 gene. No functional studies were performed. Patient fibroblasts showed defects in retrograde intraflagellar transport (IFT), as demonstrated by accumulation of anterograde proteins IFT57 (606621) and IFT88 (600595) in the ciliary tips. However, the extent of this cellular defect varied significantly among patients. Ciliary length and number were similar to controls. The patients were mainly of northern European or Turkish origin, and the findings indicated that DYNC2H1 mutations are the most frequent overall cause of ATD.