Causes and consequences: development and pathophysiology of Hirschsprung disease

Hirschsprung disease (HSCR) is a congenital enteric neuropathy in which the enteric nervous system (ENS) fails to develop along variable lengths of the distal gastrointestinal (GI) tract. This aganglionosis results in a functional bowel obstruction and requires surgical resection of the aganglionic segment. Despite surgery, however, long-term bowel dysfunction affects many patients. Understanding the embryologic causes and pathophysiologic consequences of HSCR is critical to improving its diagnosis and treatment. During normal gut development, the ENS arises from neural crest cells (NCCs) that delaminate from the neural tube to populate the entire GI tract with enteric neurons and glia. This process requires NCCs to undergo proliferation, migration and differentiation to form the complex neuroglial network that regulates gut motility and other intestinal functions. This review discusses the cellular and molecular processes that control normal ENS formation and what goes awry to give rise to HSCR. The complex pathophysiologic consequences of aganglionosis are discussed, including recent observations that describe novel aspects of HSCR beyond the absence of ganglion cells. This review aims to expand the understanding of HSCR and to stimulate new ideas on how to improve current management of the disease.