Abstract
Hirschsprung's disease (HSCR) is a congenital developmental disease of enteric nervous system. The cause is the congenital primary loss of intramural innervation of certain bowel segment.
The affected part of bowel is permanently contracted and the healthy bowel above is dilatated and it leads to the development of megacolon. Several variants of HSCR are distinguished by different length of affected colon.
It is occurred alone or syndromic, sporadic (80%) or familial form (20%) of HSCR. Genetic cause of HSCR is complex, 12 causative genes are known to be involved in different signal cascades.
The major gene is the RET proto-oncogene, where causative inactivating mutations or predisposing variants in coding or non-coding part of gene are found. The other genes are involved in RET/GDNF or EDNRB/ENT3 cascades and transcription factors modulating activities of these cascades.
These cascades and factors are in connection and influence themselves. Beside causative genes several modifying genes are known that can influence phenotype of HSCR.
Due to the recognition of genetic cause of HSCR it is possible to find the cause of development of HSCR, distinguish the inheritance and the penetrance of each mutation. Because mutations in the RET proto-oncogene are known to be the cause of development of medullary thyroid carcinoma (MTC), patients with HSCR are in higher risk of MTC and all patients should be recommended to genetic screening.