Syndromic congenital diarrhea because of the SPINT2 mutation showing enterocyte tufting and unique electron microscopy findings Mordechai A. Slae a , Michael Saginur a , Rabin Persad a , Jason Yap a , Atilano Lacson b , Julie Salomon c,d , Danielle Canioni e and Hien Q. Huynh a Clinical Dysmorphology 2013, 22:118–120 a Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, b Department of Laboratory Medicine and Pathology, Stollery Children’s Hospital, University of Alberta, Edmonton, Alberta, Canada, Departments of c Genetics, d Pediatric Gastroenterology, Hepatology and Nutrition and e Pathology, Necker-Enfants Malades Hospital, Paris Descartes University, Paris, France Correspondence to Hien Q. Huynh, MBBS, FRACP, FRCPC (Hon), Division of Pediatric Gastroenterology and Nutrition, Stollery Children’s Hospital, University of Alberta, Edmonton Clinic Health Academy (ECHA), 4th Floor, Room 4-579, 11405, 87th Avenue, Edmonton, Alberta, Canada T6G 1C9 Tel: + 1 780 248 5420; fax: + 1 780 248 5628; e-mail: hien.huynh@ualberta.ca Received 9 January 2013 Accepted 27 March 2013 Key features Congenital diarrhea Tufting enteropathy Punctate keratitis Choanal atresia Case presentation The index male patient was the first child born to consanguineous parents at 36 weeks’ gestation with an unremarkable antenatal history. Early respiratory distress led to the diagnosis of choanal atresia and subsequent surgical dilatation. Watery diarrhea began at 2 weeks of age while on full standard enteral nutrition. Diarrhea output of 120 ml/kg/day continued despite cessation of all feeds, thus necessitating total parenteral nutrition. Initial stool and serum sodium levels were normal. However, at 3 weeks of age, the patient developed hyponatremia. Concurrently, the stool sodium increased from normal to 141 mmol/l. Ophthalmology examination indicated superficial punctate keratitis. Multiple upper and lower gastrointestinal endoscopies at 5, 8, and 10 weeks of age were macroscopically normal. The initial hematoxylin and eosin stains of the duodenal biopsies showed villous flattening and inflammatory cell infiltrates, whereas subsequent tissue samples showed prominent enterocyte tufts (Figs 1 and 2). This led to the phenotypic diagnosis of congenital tufting enteropathy (CTE). Further examination of duodenal biopsies by electron microscopy (EM) showed short stubby microvilli with shortened and poorly developed desmosomes (Fig. 3). EM of liver tissue showed hepatocytes with intralysoso- mal cholesterol crystals (Fig. 4). The family history was remarkable for consanguinity, with both parents and maternal grandparents related as second cousins. The mother and her maternal first cousin have sensorineural hearing loss. No causative genetic abnorm- ality was identified for the hearing loss. Genetic studies were carried out to aid in the diagnosis. A homozygous c488A-G (Y163C) mutation was identi- fied in the serine protease inhibitor, Kunitz type, 2 gene (SPINT2) in the index patient, whereas both parents were heterozygous carriers. No known mutation was found in the epithelial cell adhesion molecule gene (EPCAM), consistent with the positive MOC-31 (EPCAM) staining in the small bowel biopsies (Fig. 2). Despite aggressive therapy, the patient developed decompensated intestinal failure-associated-liver disease. At 6 months of age, refractory gastrointestinal bleeding resulted in the patient’s death. Discussion This patient presented with features suggestive of tufting enteropathy (Sherman et al., 2004). The pathogenesis of CTE is currently not well understood. Recently, an associated mutation in the EPCAM gene was described in two consanguineous affected patients (Sivagnanam et al., 2008). This observation was subsequently validated in other patients with CTE, albeit different mutations in the EPCAM gene. Notably, EPCAM mutations were not universally present in all patients with tufting enteropathy as described by Sivagnanam et al. (2010b). Our patient had other clinical features such as punctate keratitis and choanal atresia described previously in a syndromic form of CTE that was associated with the SPINT2 c488A-G (Y163C) missense mutation (Sivagnanam et al. , 2010a). This same specific SPINT2 mutation had been associated with another congenital enteropathy – a syndromic form of congenital sodium diarrhea, in which no histological evidence of enterocyte tufting nor injury was present (Heinz- Erian et al. , 2009). In fact, these two cases are probably the same condition, with the SPINT2 gene mutation causing syndromic congenital diarrhea, where tufts may be seen (like the case of Sivagnanam and the case reported in the present manuscript) or tufts may be absent (like the cases of Heinz-Erian). It is therefore suggested that rather than considering enterocyte tufting as a finding that defines a 118 Short case report 0962-8827  c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/MCD.0b013e328361d42f Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.