title: Increased prevalence of eosinophilic gastrointestinal disorders in pediatric PTEN hamartoma tumor syndromes.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 χ(2) test was used to determine the odds of EGID enrichment in PHTS.
  
  
  RESULTS
  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%).
  
  
  CONCLUSIONS
  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.
authors.affiliation: *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.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Henderson
authors.forename: Joanne
authors.initials: J
authors.lastname: Ngeow
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Collins
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Martin
authors.forename: Philip E
authors.initials: PE
authors.lastname: Putnam
authors.forename: Juan P
authors.initials: JP
authors.lastname: Abonia
authors.forename: Keith
authors.initials: K
authors.lastname: Marsolo
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
mesh_terms: D000293:Adolescent; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D003106:Colon / Q000473:pathology; D004751:Enteritis / Q000453:epidemiology / Q000209:etiology* / Q000473:pathology; D004802:Eosinophilia / Q000453:epidemiology / Q000209:etiology* / Q000473:pathology; D004804:Eosinophils / Q000473:pathology; D004947:Esophagus / Q000473:pathology; D005260:Female; D005756:Gastritis / Q000453:epidemiology / Q000209:etiology* / Q000473:pathology; D041981:Gastrointestinal Tract / Q000473:pathology; D018095:Germ-Line Mutation; D006223:Hamartoma Syndrome, Multiple / Q000150:complications* / Q000235:genetics; D006801:Humans; D007223:Infant; D007417:Intestinal Polyps / Q000473:pathology; D008297:Male; D009820:Ohio; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D013270:Stomach / Q000473:pathology
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human