13. Tanno S, Nakano Y, Sugiyama Y, et al. Incidence of synchronous and metachronous pancreatic carcinoma in 168 patients with branch duct intraductal papillary mucinous neoplasm. Pancreatology 2010;10:173–178. 14. Ideno N, Ohtsuka T, Matsunaga T, et al. Clinical signifi- cance of GNAS mutation in intraductal papillary mucinous neoplasm of the pancreas with concomitant pancreatic ductal adenocarcinoma. Pancreas 2015;44:311–320. 15. Ideno N, Ohtsuka T, Kono H, et al. Intraductal papillary mucinous neoplasms of the pancreas with distinct pancreatic ductal adenocarcinomas are frequently of gastric subtype. Ann Surg 2013;258:141–151. 16. Kamata K, Kitano M, Kudo M, et al. Value of EUS in early detection of pancreatic ductal adenocarcinomas in patients with intraductal papillary mucinous neoplasms. Endoscopy 2014;46:22–29. Reprint requests Address requests for reprints to: Masao Tanaka, MD, PhD, FACS, Department of Surgery, Shimonoseki City Hospital, 1-13-1 Koyo-cho, Shimonoseki 750-8520, Japan. e-mail: masaotan@med.kyushu-u.ac.jp. Conflicts of interest The author discloses no conflicts. Most current article © 2018 by the AGA Institute 0016-5085/$36.00 https://doi.org/10.1053/j.gastro.2018.01.014 Development of the Enteric Nervous System: A Genetic Guide to the Perplexed See “Transcription and signaling regulators in developing neuronal subtypes of mouse and human enteric nervous system,” by Memic F, Knoflach V, Morarach K, et al, on page 624. T he critical and obvious role that the bowel plays in the life of an organism is to be the site where digestion and absorption of ingested food occurs. These functions, however, are not simply accomplished, but require enteric motility and management by the nervous system. In addition to its well-known roles in controlling gastrointestinal motility and secretion, the nervous system regulates mucosal epithelial growth, 1,2 as well as gastrointestinal manifestations of immunity and inflammation. 3,4 Although the gut has long been known to be able to function independently of input from the central nervous system (CNS), 5 it cannot function independently of input from its intrinsic enteric nervous system (ENS); a lethal pseudo-obstruction occurs when even a small segment of bowel is aganglionic. Such an aganglionosis may be acquired, as it is, for example, in Chagas disease, 6 which occurs as a consequence of infection with the protist, Trypansoma cruzi, or as a result of enteric zoster, 7 which occurs when varicella zoster virus reactivates from latency in enteric neurons. Aganglionoses may also be congenital. Congenital aganglionoses are, despite heterogeneity, referred to collectively as Hirschsprung disease (congenital megacolon), which is a multigenic disorder with variable penetrance that may involve short or long segments of bowel. 8–10 Whether an aganglionic region is long or short, acquired or congenital, survival requires that the aganglionic bowel be removed surgically. The results of the surgical excision of an aganglionic region of gut, although life saving, are often disappointing in that dysmotility, enterocolitis, and soiling may persist despite the complete removal of aganglionic tissue. 8 Better therapy, such as stem cell transplantation, awaits advances in knowledge of ENS development, which is advanced by resources included in the article “Transcription and Signaling Regulators in Developing Neuronal Subtypes of Mouse and Human Enteric Nervous System” in the current issue of Gastroenterology (Figure 1). Hirschsprung disease has attracted a great deal of investigative attention because aganglionosis is an obvious lesion. With the exception of surgeons who recognize that it is dangerous to leave behind portions of the hypoplastic transition zone when surgery is done to excise aganglionic intestine, 8 physicians have tended to think of the ENS in binary terms, as there or not there. There has been relatively little investigation of the effects of ENS hypoplasia or hyperplasia in the human intestine, although both are functionally deleterious when either is genetically induced in mice. 2,4,11–15 Hyperplasia and hypoplasia of the human ENS, moreover, are known to occur and both are associated with dysmotility. Examples of ENS hyperplasia are intestinal ganglioneuromatosis, which occurs in association with neurofibromatosis type 1 and multiple endocrine neoplasia 2B, 16–18 and intestinal neuronal dysplasia type B, which involves hyperplastic ganglia in the submucosa. 18,19 Diffuse ENS hypoplasia also occurs. 18 Given that ENS development is very complicated and that its formation involves the coordinated action of many genes, 10 it seems reasonable to expect that defects will arise during development that are not sufficient to cause an aganglionosis but that, nevertheless, are sufficient to cause functional abnormalities of the ENS. These defects could involve the number of enteric neurons, the relative proportions of the various neuronal phenotypes, or their interconnections. The state of neuropathologic examination of the human intestine is such that abnormalities of this sort would probably go undetected. EDITORIALS 478