Volume 155, Issue 6, Pages 1681-1684 (December 2018) Even When You Know Everything, There Is Still More to Learn About Hirschsprung Disease  Robert O. Heuckeroth  Gastroenterology  Volume 155, Issue 6, Pages 1681-1684 (December 2018) DOI: 10.1053/j.gastro.2018.11.006 Copyright © 2018 AGA Institute Terms and Conditions

Figure 1 Hirschsprung disease genetics is complicated because enteric nervous system (ENS) development is complicated. (A) The ENS is formed from enteric neural crest-derived precursor cells (ENCDC). While many ENS precursors come from the vagal neural crest region (shown), ENS precursors also come from cervical “sympatho-enteric” crest, sacral crest, and from Schwann cell precursors that travel along mesenteric and pelvic nerves.7 Everyone with Hirschsprung disease has a region at the end of the colon (ie, rectum) where the ENS is absent. In 80% of Hirschsprung cases only rectosigmoid is missing neurons, so slightly increased bowel colonization by precursors would have prevented disease. This type of “short-segment” Hirschsprung disease is the focus of the paper by Tang and colleagues who identified many genetic variants that affect Hirschsprung disease occurrence. (B) The major risk alleles identified via whole genome analysis of Hirschsprung disease and control samples include receptors on the surface of migrating ENS precursors (RET, EDNRB, ERBB2), ligands for these receptors (GDNF, EDN3, NRG1), molecules that impact interactions with the extracellular matrix (IGGB4, PTK2), and BACE2 (a protease that prevents accumulation of Aβ peptide which accumulates in people with Alzheimer disease). Gastroenterology 2018 155, 1681-1684DOI: (10.1053/j.gastro.2018.11.006) Copyright © 2018 AGA Institute Terms and Conditions