Causes and consequences: development and pathophysiology of Hirschsprung disease

Area of Science:

• Developmental biology
• Gastroenterology
• Pediatric surgery

Background:

• Hirschsprung disease (HSCR) is a congenital enteric neuropathy characterized by aganglionosis in the distal gastrointestinal tract.
• This developmental defect leads to functional bowel obstruction, necessitating surgical intervention.
• Despite treatment, many patients experience persistent long-term bowel dysfunction.

Purpose of the Study:

• To review the cellular and molecular mechanisms underlying normal enteric nervous system (ENS) formation.
• To elucidate the developmental origins and pathophysiologic consequences of HSCR.
• To explore novel aspects of HSCR beyond aganglionosis and stimulate improved management strategies.

Main Methods:

• Review of existing literature on ENS development and Hirschsprung disease.
• Discussion of cellular processes including neural crest cell (NCC) proliferation, migration, and differentiation.
• Analysis of molecular pathways involved in enteric nervous system formation.

Main Results:

• Normal ENS development relies on NCCs populating the GI tract to form a neuroglial network regulating gut function.
• HSCR arises from disruptions in these critical NCC processes.
• Emerging research reveals HSCR complexities extending beyond the absence of ganglion cells.

Conclusions:

• A comprehensive understanding of HSCR embryology and pathophysiology is crucial for advancing diagnostic and therapeutic approaches.
• Further research into novel HSCR aspects may lead to improved clinical outcomes.
• This review aims to foster new ideas for enhancing the current management of Hirschsprung disease.