Hirschsprung’s disease: clinical dysmorphology, genes, micro-RNAs, and future perspectives

On the occasion of the 100th anniversary of Dr. Harald Hirschsprung’s death, there is a worldwide significant research effort toward identifying and understanding the role of genes and biochemical pathways involved in the pathogenesis as well as the use of new therapies for the disease harboring his name (Hirschsprung disease, HSCR). HSCR (aganglionic megacolon) is a frequent diagnostic and clinical challenge in perinatology and pediatric surgery, and a major cause of neonatal intestinal obstruction. HSCR is characterized by the absence of ganglia of the enteric nervous system, mostly in the distal gastrointestinal tract. This review focuses on current understanding of genes and pathways associated with HSCR and summarizes recent knowledge related to micro RNAs (miRNAs) and HSCR pathogenesis. While commonly sporadic, Mendelian patterns of inheritance have been described in syndromic cases with HSCR. Although only half of the patients with HSCR have mutations in specific genes related to early embryonic development, recent pathway-based analysis suggests that gene modules with common functions may be associated with HSCR in different populations. This comprehensive profile of functional gene modules may serve as a useful resource for future developmental, biochemical, and genetic studies providing insights into the complex nature of HSCR.