DOZ047.32: Infantile hypertrophic pyloric stenosis in patients with esophageal atresia: proposal for a causative seesaw model

Abstract Aim of the Study Patients born with esophageal atresia (EA) appear to have a 30 times higher prevalence of infantile hypertrophic pyloric stenosis (IHPS). This makes sense from a developmental perspective as both the esophagus and the pyloric sphincter are foregut derived structures. We hypothesized that genetic defects, disturbing foregut morphogenesis, are responsible for the specific combination of EA and IHPS. Methods Patients with both EA and IHPS born between 1970 and 2017 and where possible their parents were included. This study was approved by the internal review board of the Erasmus MC. After parental written informed consent, we determined genetic profiles with whole exome sequencing and SNP-array-based copy number variation analysis. We focused on (1) genetic variation in known EA and IHPS disease genes, (2) pathways important for foregut morphogenesis, (3) shared rare genetic variation, and (4) ultrarare variants in variant-intolerant genes, which have a high chance of being de novo. Segregation analysis of possible candidate variants was performed. Results Twenty-seven out of 664 patients (4.1%) born with EA during the study period developed IHPS, of which 15 cases were analyzed. As none of the parents were affected, we considered dominant (de novo) or recessive and X-linked inheritance models. Unfortunately, we could neither identify rare de novo mutations, nor variants fitting a recessive model. We did however identify inherited putative deleterious heterozygous variants in genes either known to be involved in EA or IHPS (e.g., COL7A1, TNXB, WDR11, GDF6) or important in foregut morphogenesis (e.g., GLI3, NKX2.1) in all patients. Moreover, seven genes were affected by rare variation in ≥2 patients (ADAMTSL4, ANKRD26, CNTN2, HSPG2, KCNN3, LDB3, SEC16B) and expressed in the developing foregut, esophagus or pyloric sphincter in mice between E8.25 and E18.5. However, burden analysis did not show a significant difference with unaffected controls. Conclusions Although the presence of genetic variation in likely candidate genes suggests a genetic component, genetic factors alone could not explain the abnormalities seen in these patients. Therefore, we propose a multifactorial model in which the combination of high impact genetic, mechanical, and environmental factors together can shift the balance from normal to abnormal development.

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Models for infantile hypertrophic pyloric stenosis development in patients with esophageal atresia

10.1101/625921 ◽

2019 ◽

Author(s):

Chantal A. ten Kate ◽

Rutger W.W. Brouwer ◽

Yolande van Bever ◽

Vera K. Martens ◽

Tom Brands ◽

...

Keyword(s):

Environmental Factors ◽

Esophageal Atresia ◽

Pyloric Stenosis ◽

De Novo ◽

Hypertrophic Pyloric Stenosis ◽

Genetic Component ◽

Abnormal Development ◽

Infantile Hypertrophic Pyloric Stenosis ◽

Protein Coding ◽

Significant Difference

ABSTRACTPatients born with esophageal atresia (EA) have a 30 times higher prevalence of infantile hypertrophic pyloric stenosis (IHPS). This makes sense from a developmental perspective as both the esophagus and the pyloric sphincter are foregut derived structures. EA and IHPS are variable features in several (monogenetic) syndromes. This, and twin and familial studies, indicates a genetic component for both conditions as single entities. We hypothesized that genetic defects, disturbing foregut morphogenesis, are responsible for this combination of malformations. Non-genetic factors could also contribute, as mice exposed to Adriamycin develop EA and in utero diethylstilbestrol exposure is associated with EA.We investigated the copy number profiles and protein coding variants of 15 patients with both EA and IHPS. As all parents were unaffected, we first considered dominant (de novo) or recessive inheritance models but could not identify putatively deleterious mutations or recessive variants. We did identify inherited variants in genes either known to be involved in EA or IHPS or important in foregut morphogenesis in all patients. Unfortunately, variant burden analysis did not show a significant difference with unaffected controls. However, the IHPS associated risk SNP rs1933683 had a significantly higher incidence (OR 3.29, p=0.009).Although the genetic variation in likely candidate genes as well as the predisposing locus near BARX1 (rs1933683) suggest a genetic component, it does not fully explain the abnormalities seen in these patients. Therefore, we hypothesize that a combination of high impact genetic, mechanical and environmental factors together can shift the balance to abnormal development.Summary statementInstead of one affected gene, the higher incidence of IHPS in EA patients is more likely the result of multiple (epi)genetic and environmental factors together shifting the balance to disease development.

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Infantile hypertrophic pyloric stenosis (IHPS): A study of its pathophysiology utilizing the newborn hph-1 mouse model of the disease

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00221.2014 ◽

2014 ◽

Vol 307 (12) ◽

pp. G1198-G1206 ◽

Cited By ~ 6

Author(s):

Christopher Welsh ◽

Yulia Shifrin ◽

Jingyi Pan ◽

Jaques Belik

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Pyloric Stenosis ◽

Hypertrophic Pyloric Stenosis ◽

Muscle Cells ◽

Pyloric Sphincter ◽

Ros Generation ◽

Infantile Hypertrophic Pyloric Stenosis ◽

Wild Type ◽

Nnos Expression

Infantile hypertrophic pyloric stenosis (IHPS) is a common disease of unknown etiology. The tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia-1 ( hph-1) newborn mouse has a similar phenotype to the human condition. For hph-1 and wild-type control animals, pyloric tissue agonist-induced contractile properties, reactive oxygen species (ROS) generation, cGMP, neuronal nitric oxide synthase (nNOS) content, and Rho-associated protein kinase 2 (ROCK-2) expression and activity were evaluated. Primary pyloric smooth muscle cells from wild-type newborn animals were utilized to evaluate the effect of BH4 deficiency. One-week-old hph-1 mice exhibited a fourfold increase ( P < 0.01) in the pyloric sphincter muscle contraction magnitude but similar relaxation values when compared with wild-type animals. The pyloric tissue nNOS expression and cGMP content were decreased, whereas the rate of nNOS uncoupling increased ( P < 0.01) in 1-wk-old hph-1 mice when compared with wild-type animals. These changes were associated with increased pyloric tissue ROS generation and elevated ROCK-2 expression/activity ( P < 0.05). At 1–3 days of age and during adulthood, the gastric emptying rate of the hph-1 mice was not altered, and there were no genotype differences in pyloric tissue ROS generation, nNOS expression, or ROCK-2 activity. BH4 inhibition in pyloric smooth muscle cells resulted in increased ROS generation ( P < 0.01) and ROCK-2 activity ( P < 0.05). Oxidative stress upregulated ROCK-2 activity in pyloric tissue, but no changes were observed in newborn fundal tissue in vitro. We conclude that ROS-induced upregulation of ROCK-2 expression accounts for the increased pyloric sphincter tone and nNOS downregulation in the newborn hph-1 mice. The role of ROCK-2 activation in the pathogenesis of IHPS warrants further study.

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Infantile hypertrophic pyloric stenosis in patients with esophageal atresia

Birth Defects Research ◽

10.1002/bdr2.1683 ◽

2020 ◽

Vol 112 (9) ◽

pp. 670-687

Author(s):

Chantal A. Kate ◽

Rutger W. W. Brouwer ◽

Yolande Bever ◽

Vera K. Martens ◽

Tom Brands ◽

...

Keyword(s):

Esophageal Atresia ◽

Pyloric Stenosis ◽

Hypertrophic Pyloric Stenosis ◽

Infantile Hypertrophic Pyloric Stenosis

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To Manage Infantile Hypertrophic Pyloric Stenosis by "Double-Y Pyloromyotomy" is a better Surgical Approach

Journal of Paediatric Surgeons of Bangladesh ◽

10.3329/jpsb.v1i2.19532 ◽

2014 ◽

Vol 1 (2) ◽

pp. 143-147

Author(s):

Md. Ansar Ali ◽

Kaniz Hasina ◽

Shahnoor Islam ◽

Md. Ashraf Ul Huq ◽

Md. Mahbub-Ul Alam ◽

...

Keyword(s):

Weight Gain ◽

Pyloric Stenosis ◽

Hypertrophic Pyloric Stenosis ◽

Treatment Modalities ◽

Infantile Hypertrophic Pyloric Stenosis ◽

Postoperative Vomiting ◽

Acid Base ◽

Feeding Regimes ◽

Acid Base Status ◽

Postoperative Feeding

Background: Different treatment modalities and procedures have been tried for the management of infantile hypertrophic pyloric stenosis. But surgery remains the mainstay for management of IHPS. Ramstedts pyloromyotomy was described almost over a hundred years ago and to date remains the surgical technique of choice. An alternative and better technique is the double-Y pyloromyotomy, which offer better results for management of this common condition.Methods: A prospective comparative interventional study of 40 patients with IHPS was carried out over a period of 2 years from July 2008 to July 2010. The patients were divided into 2 equal groups of 20 patients in each. The study was designed that all patients selected for study were optimized preoperatively regarding to hydration, acid-base status and electrolytes imbalance. All surgeries were performed after obtaining informed consent. Standard preoperative preparation and postoperative feeding regimes were used. The patients were operated on an alternate basis, i.e., one patient by Double-Y Pyloromyotomy(DY) and the next by aRamstedts Pyloromyotomy (RP). Data on patient demographics, operative time, anesthesia complications, postoperative complications including vomiting and weight gain were collected. Patients were followed up for a period of 3 months postoperatively. Statistical assessments were done by using t test.Results: From July 2008 through July 2010, fourty patients were finally analyzed for this study. Any statistical differences were observed in patient population regarding age, sex, weight at presentation, symptoms and clinical condition including electrolytes imbalance and acid-base status were recorded. Significant differences were found in postoperative vomiting and weight gain. Data of post operative vomiting and weight gain in both groups were collected. Vomiting in double-Y(DY) pyloromyotomy group (1.21 ± 0.45days) vs Ramstedts pyloromyotomy (RP) group(3.03 ± 0.37days) p= 0.0001.Weight gain after 1st 10 days DY vs RP is ( 298 ± 57.94 gm vs193±19.8 gm p=0.0014), after 1 month (676.67±149.84 gm vs 466.67 ± 127.71 gm, p=0.0001), after 2months (741.33± 278.74 gm vs 490±80.62 gm, p=0.002) and after 3 months (582±36.01gm vs 453.33±51.64 gm, p=0.0001).No long-term complications were reported and no re-do yloromyotomy was needed.Conclusion: The double-Y pyloromyotomy seems to be a better technique for the surgical management of IHPS. It may offer a better functional outcome in term of postoperative vomiting and weight gain.DOI: http://dx.doi.org/10.3329/jpsb.v1i2.19532

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Per-oral Pyloromyotomy for Treating Infantile Hypertrophic Pyloric Stenosis

Case Medical Research ◽

10.31525/ct1-nct04148040 ◽

2019 ◽

Author(s):

Keyword(s):

Pyloric Stenosis ◽

Hypertrophic Pyloric Stenosis ◽

Infantile Hypertrophic Pyloric Stenosis ◽

Per Oral

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Faculty Opinions recommendation of Common variants near MBNL1 and NKX2-5 are associated with infantile hypertrophic pyloric stenosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.14001975.793457612 ◽

2012 ◽

Author(s):

Deborah Gumucio ◽

Aaron Udager

Keyword(s):

Pyloric Stenosis ◽

Hypertrophic Pyloric Stenosis ◽

Infantile Hypertrophic Pyloric Stenosis ◽

Common Variants

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Integrating genetics with newborn metabolomics in infantile hypertrophic pyloric stenosis

Metabolomics ◽

10.1007/s11306-020-01763-2 ◽

2021 ◽

Vol 17 (1) ◽

Author(s):

João Fadista ◽

Line Skotte ◽

Julie Courraud ◽

Frank Geller ◽

Sanne Gørtz ◽

...

Keyword(s):

Pyloric Stenosis ◽

Hypertrophic Pyloric Stenosis ◽

Dried Blood Spots ◽

Population Based ◽

Case Control ◽

Infantile Hypertrophic Pyloric Stenosis ◽

Sphincter Muscle ◽

Feeding Patterns ◽

Matched Case ◽

Selection Of

Abstract Introduction Infantile hypertrophic pyloric stenosis (IHPS) is caused by hypertrophy of the pyloric sphincter muscle. Objectives Since previous reports have implicated lipid metabolism, we aimed to (1) investigate associations between IHPS and a wide array of lipid-related metabolites in newborns, and (2) address whether detected differences in metabolite levels were likely to be driven by genetic differences between IHPS cases and controls or by differences in early life feeding patterns. Methods We used population-based random selection of IHPS cases and controls born in Denmark between 1997 and 2014. We randomly took dried blood spots of newborns from 267 pairs of IHPS cases and controls matched by sex and day of birth. We used a mixed-effects linear regression model to evaluate associations between 148 metabolites and IHPS in a matched case–control design. Results The phosphatidylcholine PC(38:4) showed significantly lower levels in IHPS cases (P = 4.68 × 10−8) as did six other correlated metabolites (four phosphatidylcholines, acylcarnitine AC(2:0), and histidine). Associations were driven by 98 case–control pairs born before 2009, when median age at sampling was 6 days. No association was seen in 169 pairs born in 2009 or later, when median age at sampling was 2 days. More IHPS cases than controls had a diagnosis for neonatal difficulty in feeding at breast (P = 6.15 × 10−3). Genetic variants known to be associated with PC(38:4) levels did not associate with IHPS. Conclusions We detected lower levels of certain metabolites in IHPS, possibly reflecting different feeding patterns in the first days of life.

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