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Recent improvement in our understanding of the pathology and genetics of HSCR and relevant animal models indicates highly variable expressivity. The spectrum of intestinal neuropathology includes patients with very short-segment aganglionosis, limited to the distal 1 to 2\u2009cm of the rectum, and possibly patients with no true aganglionic segment, but nonphysiological transition zone pathology in their distal rectums. The presence or absence of submucosal ganglion cells in a rectal biopsy is not sufficient to exclude these patients, in whom submucosal nerve hypertrophy and\/or abnormal cholinergic mucosal innervation may be the only diagnostic clues. In addition, diagnosis or exclusion of HSCR by rectal biopsy now relies in part on mucosal patterns of calretinin immunohistochemistry, with less emphasis on submucosal tissue adequacy and assessment of cholinergic innervation. These recent trends in the surgical pathology approach to rectal biopsies may miss patients at the phenotypically milder end of the malformation spectrum, with profound implications for subsequent management, prognosis, and genetic counseling.<\/jats:p>","DOI":"10.1177\/1093526619889434","type":"journal-article","created":{"date-parts":[[2019,11,21]],"date-time":"2019-11-21T00:44:01Z","timestamp":1574297041000},"page":"60-71","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":13,"title":["Are We Underdiagnosing Hirschsprung Disease?"],"prefix":"10.1177","volume":"23","author":[{"given":"Raj P","family":"Kapur","sequence":"first","affiliation":[{"name":"Department of Pathology, Seattle Children\u2019s Hospital and the University of Washington, Seattle, Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lusine","family":"Ambartsumyan","sequence":"additional","affiliation":[{"name":"Department of 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