Hirschsprung Disease, Susceptibility To, 2
A number sign (#) is used with this entry because of evidence that susceptibility to Hirschsprung disease-2 (HSCR2) is conferred by variation in the gene encoding the endothelin-B receptor (EDNRB; 131244) on chromosome 13q22.
DescriptionThe disorder described by Hirschsprung (1888) and known as Hirschsprung disease or aganglionic megacolon is characterized by congenital absence of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses of the gastrointestinal tract. Patients are diagnosed with the short-segment form (S-HSCR, approximately 80% of cases) when the aganglionic segment does not extend beyond the upper sigmoid, and with the long-segment form (L-HSCR) when aganglionosis extends proximal to the sigmoid. Total colonic aganglionosis and total intestinal HSCR also occur (Amiel et al., 2008).
Isolated HSCR appears to be of complex nonmendelian inheritance with low sex-dependent penetrance and variable expression according to the length of the aganglionic segment, suggestive of the involvement of one or more genes with low penetrance (Amiel et al., 2008).
For a general description and a discussion of genetic heterogeneity of Hirschsprung disease (HSCR), see 142623.
Clinical FeaturesPuffenberger et al. (1992) found a high frequency of Hirschsprung disease in an extended inbred Mennonite kindred. In 49 nuclear families, 56 affected persons were found. In one of these individuals, one or more of the following characteristics was found: white forelock, hearing deficit, and heterochromia iridis. However, further studies suggested that this triad of traits segregated independently of Hirschsprung disease in several of the families within the kindred. A couple who immigrated to the United States about 1717 was ancestral to both parents of all affected individuals. Segregation analysis yielded a segregation ratio of 12.0% for males and 6.2% for females.
CytogeneticsLamont et al. (1989) described 3 cases of interstitial deletion of chromosome 13 involving the common segment 13q22.1-q32.1. In addition to the recognized clinical features of this deletion, such as prominent upper incisors, 2 had short segment Hirschsprung disease with aganglionosis confirmed histologically. Bottani et al. (1991) also described an interstitial deletion of 13q in approximately the same region in a boy who, in addition to having Hirschsprung disease, was mentally retarded and autistic. They concluded that the 13q33.1 band was missing in all cells. Sparkes et al. (1984) and Kiss and Osztovics (1989) had also reported Hirschsprung disease in association with deletions of 13q.
Shanske et al. (2001) reviewed 10 case reports of patients with 13q deletions and Hirschsprung disease or other intestinal anomalies, and added an eleventh case.
MappingIn further studies of the large and extensively affected Mennonite kindred, Puffenberger et al. (1994) found that segregation analysis indicated a segregation ratio of 10.67% for males and 5.45% for females. They searched for locations of the genes responsible for HSCR in this kindred by genotyping 3 small multicase families and locating genomic regions demonstrating identity by descent followed by linkage disequilibrium analysis of 28 additional nuclear families. Based on this novel strategy, Puffenberger et al. (1994) identified a new locus for HSCR on 13q22. They genotyped 9 microsatellite markers spanning 10 cM in this region on 31 nuclear families. Significant nonrandom association was detected with alleles at 4 markers.
Puffenberger et al. (1994) reported association studies indicating that 36% of homozygotes for a 235-basepair allele at locus D13S160 were affected and 27% of heterozygotes were affected, giving an overall penetrance of 31%, which accords well with the 33% value estimated by Badner et al. (1990). In studies of 2 patients with HSCR and interstitial deletions of chromosome 13 analyzed with microsatellite markers, they found that the 13q22 region was included and was bounded distally by D13S160.
InheritanceCohen and Gadd (1982) had suggested a dominant inheritance pattern for HSCR in the Mennonite kindred. However, by genotype analysis of patients in the Mennonite pedigree, Puffenberger et al. (1994) demonstrated multigenic inheritance.
Molecular GeneticsIn affected members of a large Mennonite kindred with Hirschsprung disease mapping to chromosome 13q22, Puffenberger et al. (1994) identified a missense mutation in the endothelin-B receptor gene (W276C; 131244.0001). The mutation was dosage sensitive, with W276C homozygotes and heterozygotes having a 74% and a 21% risk, respectively, of developing HSCR.
Animal ModelThe 'piebald lethal' (s-l) mouse phenotype is located on chromosome 14, in a region that is homologous to the chromosome 13 locus for Hirschsprung disease. Hosoda et al. (1994) demonstrated that this mouse phenotype is allelic to the Ednrb knockout mouse and harbors a mutation in Ednrb.
Hultgren (1982) described ileocolonic aganglionosis in the horse. The lethal white foal syndrome (LWFS) is a congenital abnormality of overo spotted horses which appears to be a model for human aganglionic megacolon. Affected foals are all white or nearly all white and succumb to intestinal obstruction in the first few days of life. The designation 'overo' comes from the Spanish for 'egg-colored' or 'speckled.' Yang et al. (1998) demonstrated that mutation in the equine Ednrb gene results in LWFS. When homozygous, a dinucleotide mutation that which changed isoleucine to lysine in the predicted first transmembrane domain of the Ednrb protein, was found as the basis of LWFS; the heterozygous state resulted in the 'overo' phenotype. It had been known that LWFS is produced most often by mating horses with the overo color pattern. One mutant allele produces the coat color change, but the presence of at least 1 normal allele appears to protect against the development of aganglionosis.
Metallinos et al. (1998) also showed that an ile118-to-lys missense mutation in EDNRB is responsible for lethal white foal syndrome. Breedings between particular spotted horses, generally described as frame overo, produce some foals that, in contrast to their parents, are all white or nearly all white and die shortly after birth of severe intestinal blockage. These foals have aganglionosis characterized by a lack of submucosal and myenteric ganglia from the distal small intestine to the large intestine, similar to human Hirschsprung disease. Metallinos et al. (1998) found that lethal white foal syndrome occurred in homozygotes; heterozygotes showed the frame overo pattern. Horses with tobiano markings included some carriers, indicating that tobiano is epistatic to frame overo. In addition, some horses identified as carriers had no recognized overo coat pattern phenotype, demonstrating the incomplete penetrance of the mutation. Santschi et al. (1998) likewise studied the ile118-to-lys change in the overo lethal white syndrome in foals born to American Paint Horse parents of the overo coat pattern lineage.