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and further molecular analysis. Follow-up at 4 years showed a normal psychomotor, social and intellectual development, scoliosis of the thoracic part of the backbone, and no facial or hand and feet dysmorphism. Using the comparative genomic hybridization technique we revealed deletions of 7q11.1–7q11.2, 16p11.2–16p13.2, 16p13.3, 16q11.2–16q12.2 and 19p13.1–19p13.3 chromosomal regions in the esophagus (Figure 1) and no chromosomal aberrations in blood (Figure 2) in the same patient resulting in somatic mosaicism. No other tissues were analyzed. We validated 19p13 deletion using quantitative real-time PCR and MLPA. Recent scientific reports suggest that in the process of cell differentiation genome rearrangements may occur (5–7). This somatic cell mosaicism can be formed after fertilization in the early stages of embryonic development, being one of the mechanisms for the differentiation of various tissues (8). More and more reports in the literature describe somatic mosaicism as well as the cause of various diseases (9). The chromosome deletions described by us in this paper are large DNA losses and may be pathogenic alterations with significance in the etiology of this developmental defect. We suspect that 7q11.1–7q11.2, 16p11.2– 16p13.2, 16p13.3, 16q11.2–16q12.2 and 19p13.1–19p13.3 chromosomal regions may contain key genes, regulatory sequences, or other genetic elements playing an important role in esophagus development. For example, the 19p13 chromosomal region contains the LDLR gene, which is involved in cholesterol metabolism. Cholesterol acts in the proper functioning of the Sonic Hedgehog signaling pathway, which is instrumental in patterning of the early embryo and is essential to foregut development (10). We hypothesize that genetic mosaicism may be the cause of the EA and this readily explains the difficulty in identifying pathogenic mutations in patients with isolated EA. ACKNOWLEDGMENTS This study was accepted by the Bioethical Committee of Wroclaw Medical University and was supported by the National Science Center, Poland (grant number 5349/B/ P01/2011/40). The American Journal of GASTROENTEROLOGY

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CONFLICT OF INTEREST The authors declare no conflict of interest. REFERENCES 1. Pedersen RN, Calzolari E, Husby S et al. Oesophageal atresia: prevalence, prenatal diagnosis and associated anomalies in 23 European regions. Arch Dis Child 2012;97: 227–32. 2. Bednarczyk D, Sasiadek MM, Smigiel R. Chromosome aberrations and gene mutations in patients with esophageal atresia. J Pediatr Gastroenterol Nutr 2013;57:688–93. 3. Smigiel R, Lebioda A, Blaszczynski M et al. Alternations in genes expression of pathway signaling in esophageal tissue with atresia: results of expression microarray profiling. Dis Esophagus, advance online publication, 27 January 2014; doi: 10.1111/dote.12173 (e-pub ahead of print). 4. Bednarczyk D, Smigiel R, Sasiadek MM. The role of genetic and environmental factors in the etiology of esophageal atresia and tracheoesophageal fistula. Postepy Hig Med Dosw (Online) 2014;68:238–46. 5. Rodríguez-Santiago B, Malats N, Rothman N et al. Mosaic uniparental disomies and aneuploidies as large structural variants of the human genome. Am J Hum Genet 2010;87:129–38. 6. Astolfi PA, Salamini F, Sgaramella V. Are we genomic mosaics? Variations of the genome of somatic cells can contribute to diversify our phenotypes. Curr Genomics 2010;11:379–86. 7. Mkrtchyan H, Gross M, Hinreiner S et al. The human genome puzzle - the role of copy number variation in somatic mosaicism. Curr Genomics 2010;11:426–31. 8. Mkrtchyan H, Gross M, Hinreiner S et al. Early embryonic chromosome instability results in stable mosaic pattern in human tissues. PLoS One 2010;5:e9591. 9. Poduri A, Evrony GD, Cai X et al. Somatic mutation, genomic variation, and neurological disease. Science 2013;341:1237758. 10. Litingtung Y, Lei L, Westphal H et al. Sonic hedgehog is essential to foregut development. Nat Genet 1998;20:58–61. 1

Department of Genetics, Wroclaw Medical University, Wroclaw, Poland; 2Department of Social Paediatrics, Wroclaw Medical University, Wroclaw, Poland. Correspondence: Damian Bednarczyk, MSc, Department of Genetics, Wroclaw Medical University, Marcinkowskiego 1, 50-368 Wroclaw, Poland. E-mail: [email protected]

Diverticulitis after Fecal Microbiota Transplant for C. difficile Infection Amar Mandalia, MD1, Colleen S. Kraft, MD2 and Tanvi Dhere, MD3 doi:10.1038/ajg.2014.350

To the Editor: Fecal microbiota transplantation (FMT) has become a cornerstone of the management of recurrent and refractory Clostridium difficile infection (CDI) (1). Although it is safe and tolerable, adverse events have been reported with FMT via colonoscopy (1–5). Here we report the first case of diverticulitis occurring after an FMT for the treatment of recurrent CDI. The patient was a 78-year-old Caucasian woman with a history of recurrent diverticulitis who had at least four episodes of recurrent CDI and had been treated with metronidazole and vancomcyin. She also had a history of coronary atherosclerotic heart disease, insulin-dependent diabetes, and hypertension. She had a partial colectomy over 10 years ago for self-reported Crohn’s disease that had since been in remission. Because of the history of recurrent CDI, an FMT via colonoscopy was performed. One hundred grams of donor stool diluted in 250 ml of sterile saline, as previously described, was infused into the most proximal colon (6). The colonoscopy revealed moderate diverticular disease in the left colon, and no macroscopic evidence of Crohn’s disease. The FMT procedure was performed without difficulty, and the patient was discharged from the endoscopy suite with no complaints. On her ride home 2 to 3 hours after the procedure, the patient developed severe diffuse abdominal pain. She went to a local emergency department (ED) and was found to be febrile to 40°C. A CT scan performed at that ED visit confirmed uncomplicated left-sided diverticulitis (Figure 1). She was admitted to the hospital and placed on antibiotics, to which she responded well and was discharged home uneventfully. In the past 3 months post FMT, the patient has not had a recurrence of CDI despite being treated with antibiotics after the FMT. Diverticulitis as a complication of FMT has never been reported in the literature. The pathogenesis of diverticulitis is not fully understood; however, the literature does highlight the role of dysbiosis as a plausible mechanism (7). Fecal material may collect in a diverticulum, leading to obstruction followed by distention and flora overgrowth. Aerobic and anaeroVOLUME 109 | DECEMBER 2014 www.amjgastro.com

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Figure 1. Focal segmental sigmoid wall thickening with surrounding inflammatory changes superimposed upon the background of sigmoid diverticulosis consistent with sigmoid diverticulitis.

bic microbes implicated in diverticulitis include Escherichia coli, Streptococcus spp., Bacteroides spp., Peptostreptococcus, Clostridium, and Fusobacterium (8). Our patient developed diverticulitis subsequent to FMT, which begs the question whether FMT can be an iatrogenic cause of dysbiosis through alterations of gut microbiome and subsequent inflammation. Dysbiosis is also associated with inflammatory bowel disease (IBD). Case reports of worsening of IBD are reported after FMT, which may be related to attempts at realtering the gut microbiome (9). In recurrent CDI, FMT disrupts and typically restores the gut microbiome with commensal organisms that prevent it. Studies have shown increases in Bacteroides, Lachnospiraceae, Peptostreptococcaceae, and Ruminococcaceae in post-FMT stool samples, and abundances of Streptococcus, Veillonella, and Enterococcus; Klebsiella was significantly reduced in post-FMT stool samples (10–12). No differences in the relative abundance of a specific genus were seen when samples were compared by the time period of collection (12). This suggests that changes to gut microbiome occur relatively quickly after FMT and may be permanent. The above studies demonstrate a rise in the number of gut microbiome post FMT that could be involved in the pathogenesis of diverticulitis. FMT © 2014 by the American College of Gastroenterology

may be a source of diverticulitis by the induction of an inflammatory response to the altered microbiome generated after FMT. Rare reports of diverticulitis after colonoscopy have also been reported; therefore, it may not be possible to determine cause and effect with regard to FMT and diverticulitis without additional reporting by others (13). FMT is a safe method to treat recurrent and refractory CDI; however, complications are known to arise, and diverticulitis should be considered as a potential complication. CONFLICT OF INTEREST The author declares no conflict of interest. REFERENCES 1. Kassam Z, Lee CH, Yuan Y et al. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol 2013;108:500–8. 2. Gough E, Shaikh H, Manges AR. Systemic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis 2011;53:994–1002. 3. Youngster I, Sauk J, Pindar C et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unreleated donors: a randomized, openlabel, controlled pilot study. Clin Infect Dis 2014;58:1515–22. 4. Quera R, Espinoza R, Estay C et al. Bacteremia as an adverse event of fecal microbiota transplantation in a patient with Crohn’s disease and recurrent Clostridium difficile infection. J Crohns Colitis 2014;8:252–3.

5. Schwartz M, Gluck M, Koon S. Norovirus gastroenteritis after fecal microbiota transplantation for treatment of Clostridium difficile infection despite asymptomatic donors and lack of sick contacts. Am J Gastroenterology 2013;108:1367. 6. Moraco-Friedman RJ, Mehta AK, Lyon GM et al. Fecal microbiota transplantation for refractory Clostridium difficile colitis in solid organ transplant recipients. Am J Transplant 2014;14:477–80. 7. Slate LL, Modi R, Cohen E et al. Diverticular disease as a chronic illness: evolving epidemiologic and clinical insights. Am J Gastroenterol 2012;107:1486–93. 8. Brook I, Frazier EH. Aerobic and anaerobic microbiology in intra-abdominal infections associated with diverticulitis. J Med Microbiol 2000;49:827–30. 9. De Leon LM, Watson JB, Kelly CR. Transient flare of ulcerative colitis after fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin Gastroenterol Hepatol 2013;11:1036–8. 10. Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhea in six patients. Lancet 1989;1:1156–60. 11. Khoruts A, Dicksved J, Jansson JK et al. Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea. J Clin Gastroenterol 2010;44: 354–60. 12. Song Y, Garg S, Girotra M et al. Microbiota dynamics in patients treated with fecal microbiota transplantation for recurrent Clostridium difficile infection. PLoS one 2013;8:e81330. 13. Ko CW, Dominitz JA. Complications of colonoscopy: magnitude and management. Gastrointest Endosc Clin N Am 2010;20: 659–71.

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Department of Medicine, Emory University, Atlanta, Georgia, USA; 2Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA; 3Division of Digestive Diseases, Emory University, Atlanta, Georgia, USA. Correspondence: Tanvi Dhere, MD, Division of Digestive Diseases, Emory University, Atlanta, Georgia, USA. E-mail: [email protected]

Far-infrared Therapy as a Novel Treatment for Encapsulating Peritoneal Sclerosis Shuo-Ming Ou, MD1, 2, 3, Fen-Hsiang Hu, MD4, Wu-Chang Yang, MD1, 2 and Chih-Ching Lin, MD, PhD1, 2 doi:10.1038/ajg.2014.352

The American Journal of GASTROENTEROLOGY

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Diverticulitis after fecal microbiota transplant for C. difficile infection.

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