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Infantile hypertrophic pyloric stenosis in patients with esophageal atresia
Author(s) -
Kate Chantal A.,
Brouwer Rutger W. W.,
Bever Yolande,
Martens Vera K.,
Brands Tom,
Beelen Nicole W. G.,
Brooks Alice S.,
Huigh Daphne,
Helm Robert M.,
Eussen Bert H. F. M. M.,
IJcken Wilfred F. J.,
IJsselstijn Hanneke,
Tibboel Dick,
Wijnen Rene M. H.,
Klein Annelies,
Hofstra Robert M. W.,
Brosens Erwin
Publication year - 2020
Publication title -
birth defects research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.845
H-Index - 17
ISSN - 2472-1727
DOI - 10.1002/bdr2.1683
Subject(s) - foregut , hypertrophic pyloric stenosis , biology , atresia , morphogenesis , genetics , exome sequencing , phenotype , ciliogenesis , pathology , anatomy , cilium , medicine , gene
Abstract Background Patients born with esophageal atresia (EA) have a higher incidence of infantile hypertrophic pyloric stenosis (IHPS), suggestive of a relationship. A shared etiology makes sense from a developmental perspective as both affected structures are foregut derived. A genetic component has been described for both conditions as single entities and EA and IHPS are variable components in several monogenetic syndromes. We hypothesized that defects disturbing foregut morphogenesis are responsible for this combination of malformations. Methods We investigated the genetic variation of 15 patients with both EA and IHPS with unaffected parents using exome sequencing and SNP array‐based genotyping, and compared the results to mouse transcriptome data of the developing foregut. Results We did not identify putatively deleterious de novo mutations or recessive variants. However, we detected rare inherited variants in EA or IHPS disease genes or in genes important in foregut morphogenesis, expressed at the proper developmental time‐points. Two pathways were significantly enriched ( p < 1 × 10 −5 ): proliferation and differentiation of smooth muscle cells and self‐renewal of satellite cells. Conclusions None of our findings could fully explain the combination of abnormalities on its own, which makes complex inheritance the most plausible genetic explanation, most likely in combination with mechanical and/or environmental factors. As we did not find one defining monogenetic cause for the EA/IHPS phenotype, the impact of the corrective surgery could should be further investigated.