The PTEN hamartoma tumor syndromes (PHTSs) are a collection of disorders caused by germline mutations of the tumor suppressor gene PTEN. Eosinophilic gastrointestinal disorders (EGIDs) are rare diseases characterized by food-induced, eosinophil-dominant inflammation in various segments of the gastrointestinal tract. On the basis of our clinical observations of several patients with EGID-PHTS, we investigated whether there is an association between these 2 disorders.
The Cincinnati Children's Hospital Medical Center (CCHMC) Informatics for Integrating Biology and the Bedside (i2b2) warehouse was queried for the years 2007 to 2012 using International Classification of Diseases-9 codes for PTEN-related diseases; the results were cross-referenced with participants enrolled in the Cincinnati Center for Eosinophilic Disorder's EGID database to identify patients with both disorders. In an effort to replicate our findings, the Cleveland Clinic Genomic Medicine Institute PTEN database was queried for cases between 2005 and 2012. Inclusion criteria were age ≤18 years, history of PHTS, and an esophagogastroduodenoscopy (EGD) and/or colonoscopy with at least 1 histologic EGID diagnosis confirmed by a CCHMC pathologist. The Pearson χ2 test was used to determine the odds of EGID enrichment in PHTS.
Of the 1,058,260 CCHMC distinct patients identified by the i2b2 search, 53 had clinical diagnoses suggestive of PHTS. Thirteen of the 53 had PTEN mutations, with 8 of 13 (62%) having had an EGD and/or colonoscopy. Five of the 8 had confirmed EGID. At the Cleveland Clinic, 3 of 75 patients (3/4 who had EGD and/or colonoscopy) with PHTS had confirmed EGID. CCHMC i2b2 query data showed a substantial enrichment of EGIDs in PHTSs (odds ratio 272; confidence interval 89–831, P < 0.0001). An EGID prevalence estimate from the i2b2 query supported a marked enrichment of EGIDs in PHTSs in the Cleveland Clinic database (P < 0.0001). Among the 8 subjects with EGIDs and PHTSs, the age at EGID and PHTS diagnosis was 7.6 ± 3.2 and 7.9 ± 5.8 years, respectively. Patients with EGID-PHTS had excess eosinophils in biopsies of the esophagus (75%), stomach (38%), and colon (13%), with a notable presence of eosinophil-rich gastrointestinal polyposis (88%).
EGID is a previously unrecognized comorbid disease in pediatric patients with PHTS. These data suggest a potential role of PTEN in contributing to EGID susceptibility.
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*Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati
†Genomic Medicine Institute, Cleveland Clinic, Cleveland
‡Division of Pathology
§Division of Biostatistics and Division of Human Genetics
||Division of Gastroenterology, Hepatology and Nutrition
¶Division of Biomedical Informatics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Address correspondence and reprint requests to Marc E. Rothenberg, MD, PhD, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, ML 7028, Cincinnati, OH 45229 (e-mail: Rothenberg@cchmc.org).
Received 11 July, 2013
Accepted 15 November, 2013
Supplemental digital content is available for the present article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of the present article on the journal's Web site (www.jpgn.org).
The present work was funded in part by PHS grants DK078392, AI083450, AI045898, DK076893, and CA124570 (to M.E.R. and C.E.), the Buckeye Foundation, the Food Allergy Research & Education Foundation, the Campaign Urging Research for Eosinophilic Disease Foundation (http://www.curedfoundation.org), the National Institutes of Health UL1 TR000077 (to K.M.), and the Breast Cancer Research Foundation (to C.E.). J.N. is an Ambrose Monell Foundation Cancer Genomic Medicine Clinical Fellow and was partially funded by SingHealth and NMRC (Singapore) Fellowships. C.E. is the Sondra J. and Stephen R. Hardis Endowed Chair of Cancer Genomic Medicine at the Cleveland Clinic Genomic Medicine Institute and is an American Cancer Society Clinical Research Professor.
The authors report no conflicts of interest.