Exclusion of the Ellis–van Creveld region on chromosome 4p16 in some families with asphyxiating thoracic dystrophy and short-rib polydactyly syndromes

Abstract

Ellis-van Creveld syndrome (EVC) is a relatively rare, usually non-lethal, autosomal recessive skeletal dysplasia characterized by short stature, polydactyly, cardiac and renal anomalies. Linkage analysis has localized the disease gene to chromosome 4p16, with the markers at loci D4S827 and D4S3135 defining the centromeric and telomeric limits of the linked interval, respectively. There has been long-term speculation that asphyxiating thoracic dystrophy (ATD) and the short-rib polydactyly syndromes (SRP) represent the severe end of the EVC disease spectrum. We performed linkage analysis using markers from the EVC region in seven families manifesting either ATD or SRP type III. In two of the families, one segregating ATD and one SRP kindred, linkage of the phenotype to the EVC region was excluded. In the other five families linkage of the phenotype to the EVC region could not be excluded, but the families were too small for linkage to the region to be established. The exclusion of the EVC region in ATD and SRP III families suggests that locus heterogeneity exists within the short-rib dysplasia (with and without polydactyly) group of disorders.

Clinical insights gained from eight new cases and review of reported cases with Jeune syndrome (asphyxiating thoracic dystrophy)

“…When it is present, the postaxial polydactyly occurs most frequently in the distribution of bilateral hands and feet. The frequency of hepatic problems occurs in <30% of reported cases, and it is difficult to predict risk of developing liver disease based upon the presence of skeletal findings [Karjoo et al, 1973;Friedman et al, 1975;Oberklaid et al, 1977;Shah, 1980;Turkel et al, 1985;Hudgins et al, 1990;Labrune et al, 1999;Krakow et al, 2000;Kajantie et al, 2001;Ö zçay et al, 2001;Morgan et al, 2003;Yerian et al, 2003;Tuysuz et al, 2009;De Vries et al, 2010;Lehman et al, 2010]. In addition, from review of the literature, most cases with hepatic structural changes are identified at autopsy, but are usually clinically mild, stable, or resolve with therapy.…”

“…Further both SRPS III and a mild form Jeune syndrome were reported in a consanguineous family [Ho et al, 2000]. Because of suggestion that Jeune syndrome and SRPS type III may represent a spectrum of disorders with EvC syndrome, Krakow et al [2000] performed and showed no linkage with markers from 4p in seven families having ATD or SRPS III. Rinaldi et al [1990] reported two sisters with cystinuria and Jeune syndrome suggesting there may be linkage between the two genes causing these conditions.…”

Targeted next-generation sequencing identifies novel compound heterozygous mutations of DYNC2H1 in a fetus with short rib-polydactyly syndrome, type III

“…SRPS III is phenotypically related to asphyxiating thoracic dystrophy (ATD [MIM 208500]) and Ellis-van Crefeld syndrome (EVC [MIM 225500]). Indeed, all three disorders share similar radiological features, including short ribs and polydactyly [8,9]. However, SRPS III is more severe and is associated with early prenatal expression, severely shortened tubular bones with round metaphyseal ends bearing lateral spikes, and lethality.…”

Mutations in the EVC1 gene are not a common finding in the Ellis‐van Creveld and short rib‐polydactyly type III syndromes

“…Patients with SRP could have mutations in the EVC2 gene. However, we excluded linkage to the EvC region on chromosome 4p in one family with SRP III [Krakow et al, 2000]. With our unbiased sample, we conclude that mutations in the coding region of EVC1 do not account for the majority of cases of EvC, and SRP III is probably due to a defect in a gene other than EVC1 or EVC2.…”

“…Radiographically and histologically, SRP III most resembles some forms of EvC [Yang et al, 1987]. The question of SRP being due to disruption of a gene in the 4p16 region where EvC maps was raised [Urioste et al, 1994], but we were able to exclude it in one family with SRP III by linkage analysis [Krakow et al, 2000]. It remained possible that some SRP III cases could have mutations in the EVC1 gene.…”