Alternative titles; symbols
SNOMEDCT: 48644003; ICD10CM: Q40.0; ICD9CM: 750.5; DO: 12638;
Cytogenetic location: 12q Genomic coordinates (GRCh38): 12:35,500,001-133,275,309
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q | Pyloric stenosis, infantile hypertrophic 1 | 179010 | Autosomal dominant; Multifactorial | 2 |
Infantile pyloric stenosis is the most common condition requiring surgical intervention in the first year of life. It typically presents in infants 2 to 6 weeks after birth. Clinically the disorder is characterized by projectile vomiting, visible gastric peristalsis, and a palpable pyloric tumor (summary by Everett et al., 2008). Mortality was high until successful treatment by pyloromyotomy was developed by Ramstedt (1912).
Genetic Heterogeneity of Infantile Hypertrophic Pyloric Stenosis
Multiple susceptibility loci have been implicated in IHPS including IHPS1 on chromosome 12q, IHPS2 (610260) on chromosome 16p13-p12, IHPS3 (612017) on chromosome 11q14-q22, IHPS4 (300711) on chromosome Xq23, and IHPS5 (612525) on chromosome 16q24.
Genetic predisposition to IHPS was well established in the classic studies of Carter and Powell (1954) and Carter (1961), who defined the disease as a paradigm for the multifactorial sex-modified threshold model of inheritance, with affected males outnumbering females in a 4:1 ratio.
Carter (1961) estimated that the recurrence risk was 10% for males born after an affected child and 1.5 to 2% for females.
Finsen (1979) described a multigenerational family consistent with autosomal dominant transmission of infantile hypertrophic pyloric stenosis. Fried et al. (1981) reported an unusual family that appeared to represent autosomal dominant inheritance through 4 generations.
Segregation analysis yields results best explained by a multifactorial sex-modified threshold model of inheritance (Carter and Evans, 1969; Lalouel et al., 1977), but the findings are also compatible with a single major dominant gene of low penetrance with a multifactorial background. Because pyloric stenosis was reported to occur in 4 of 7 cases of duplication of 9q11-q33 (Yamamoto et al., 1988), Chung et al. (1993) did a linkage study of this candidate region, searching for a gene predisposing to pyloric stenosis. The results of linkage studies in 20 families were negative.
Mitchell and Risch (1993) reanalyzed several published family studies and concluded that the recurrence pattern was inconsistent with generalized single major locus inheritance. It was, however, considered compatible with multifactorial threshold inheritance or the effects of multiple interacting loci. Under a model of multiple interacting loci, no single locus could account for more than a 5-fold increase in the risk of first-degree relatives. In contrast to several earlier reports, this analysis did not support the existence of a maternal factor that contributed to the risk of infantile hypertrophic pyloric stenosis in the offspring of affected females.
Krogh et al. (2010) performed a population-based study of pyloric stenosis among 1,999,738 children born in Denmark between 1977 and 2008 and followed up for the first year of life. Surgery for pyloric stenosis occurred in 3,362 children, of which 2,741 (81.5%) were boys, resulting in a male-to-female ratio of 4.4:1. The incidence rate per 1,000 person-years was 1.8 for singletons and 3.1 for twins. The rate ratios of pyloric stenosis were 182 for monozygotic twins, 29.4 for dizygotic twins, 18.5 for sibs, 4.99 for half sibs, 3.06 for cousins, and 1.60 for half cousins. There were no differences in rate ratios for maternal and paternal relatives of children with pyloric stenosis, and no difference according to sex of cohort member or sex of relative. Overall, the findings indicated that pyloric stenosis in Danish children shows strong familial aggregation with a heritability of about 87%. However, the condition does not follow classic mendelian inheritance.
The incidence of infantile pyloric stenosis was estimated to be between 1 and 5 per 1,000 live births in Britain (Davison, 1946; Dodge, 1975).
There is a striking variation in incidence between population groups, with the cumulative incidence in American infants being 1.9 per 1,000 live births in whites, 1.8 in Hispanics, 0.7 in blacks, and 0.6 in Asians (Schechter et al., 1997).
Vanderwinden et al. (1992) concluded that lack of neuronal NOS1 in pyloric tissue is responsible for pylorospasm in IHPS. In biopsy specimens, NADPH-diaphorase (NDP) staining is absent in the neurons that innervate the circular muscle of the pylorus, and the nerve fibers themselves appear grossly abnormal and tortuous. (NDP, a histochemical enzymatic activity that reduces tetrazolium dyes in the presence of NADPH but not NADH, is due to neuronal NOS.) Support for the Vanderwinden hypothesis was provided by the demonstration by Huang et al. (1993) that in mice in whom targeted disruption of the neuronal NOS gene had been achieved by homologous recombination, grossly enlarged stomach with hypertrophy of the pyloric sphincter and the circular muscle layer was the most striking feature.
The etiologic role of the NOS1 gene (163731) on chromosome 12q in infantile pyloric stenosis was investigated by analysis of 2 intragenic polymorphisms, NOS1a and NOS1b, in 27 families by Chung et al. (1996). They found significant overall transmission disequilibrium between pyloric stenosis and NOS1a (P = 0.006). Consideration of each allele independently revealed a significant tendency for preferential transmission of allele 7 (210 bp) to the affected offspring (P = 0.006). Chung et al. (1996) suggested that NOS1 is a susceptibility locus for pyloric stenosis. Findings leading to a contradictory conclusion were reported by Soderhall and Nordenskjold (1998), who could find no linkage between infantile hypertrophic pyloric stenosis and NOS1 in 3 Swedish families with multiple affected members. For these studies they used the AAT motif repeat in the first intron of the NOS1 gene.
Saur et al. (2004) studied molecular mechanisms by which NOS1 gene expression is altered in pyloric tissues of 16 German infants with IHPS and 9 German controls. In IHPS patients, a significantly decreased expression of total NOS1 mRNA was found by quantitative RT-PCR; the decrease affected predominantly exon 1c, with a reduction of 88% compared with controls. Expression of exon 1f was increased significantly, indicating a compensatory upregulation of this NOS1 mRNA variant. Studying DNA samples of the 16 IHPS patients and 81 controls for mutations and SNPs in the NOS1 exon 1c promoter, Saur et al. (2004) found that carriers of the A allele of the exon 1c promoter -84G-A SNP (163731.0001) had increased risk of development of IHPS (odds ratio, 8.0). In contrast, Lagerstedt-Robinson et al. (2009) found no association between rs41279104 and infantile hypertrophic pyloric stenosis among 82 Swedish patients and 80 controls. The frequency of the A allele in the control group was 29%.
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Lagerstedt-Robinson, K., Svenningsson, A., Nordenskjold, A. No association between a promoter NOS1 polymorphism (rs41279104) and infantile hypertrophic pyloric stenosis. J. Hum. Genet. 54: 706-708, 2009. [PubMed: 19851341] [Full Text: https://doi.org/10.1038/jhg.2009.101]
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Saur, D., Vanderwinden, J.-M., Seidler, B., Schmid, R. M., De Laet, M.-H., Allescher, H.-D. Single-nucleotide promoter polymorphism alters transcription of neuronal nitric oxide synthase exon 1c in infantile hypertrophic pyloric stenosis. Proc. Nat. Acad. Sci. 101: 1662-1667, 2004. [PubMed: 14757827] [Full Text: https://doi.org/10.1073/pnas.0305473101]
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Soderhall, C., Nordenskjold, A. Neuronal nitric oxide synthase, nNOS, is not linked to infantile hypertrophic pyloric stenosis in three families. (Letter) Clin. Genet. 53: 421-422, 1998. [PubMed: 9660065] [Full Text: https://doi.org/10.1111/j.1399-0004.1998.tb02758.x]
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