Hirschsprung's disease (HSCR) is a fairly frequent cause of intestinal 
obstruction in children. It is characterized as a sex-linked heterogonous 
disorder with variable severity and incomplete penetrance giving rise to a 
variable pattern of inheritance. Although Hirschsprung's disease occurs as an 
isolated phenotype in at least 70% of cases, it is not infrequently associated 
with a number of congenital abnormalities and associated syndromes, 
demonstrating a spectrum of congenital anomalies. Certain of these syndromic 
phenotypes have been linked to distinct genetic sites, indicating underlying 
genetic associations of the disease and probable gene-gene interaction, in its 
pathogenesis. These associations with HSCR include Down's syndrome and other 
chromosomal anomalies, Waardenburg syndrome and other Dominant sensorineural 
deafness, the Congenital Central Hypoventilation and Mowat-Wilson and other 
brain-related syndromes, as well as the MEN2 and other tumour associations. A 
number of other autosomal recessive syndromes include the Shah-Waardenburg, the 
Bardet-Biedl and Cartilage-hair hypoplasia, Goldberg-Shprintzen syndromes and 
other syndromes related to cholesterol and fat metabolism among others. The 
genetics of Hirschsprung's disease are highly complex with the majority of known 
genetic sites relating to the main susceptibility pathways (RET an EDNRB). 
Non-syndromic non-familial, short-segment HSCR appears to represent a 
non-Mendelian condition with variable expression and sex-dependent penetrance. 
Syndromic and familial forms, on the other hand, have complex patterns of 
inheritance and being reported as autosomal dominant, recessive and polygenic 
patterns of inheritance. The phenotypic variability and incomplete penetrance 
observed in Hirschsprung's disease could also be explained by the involvement of 
modifier genes, especially in its syndromic forms. In this review, we look at 
the chromosomal and Mendelian associations and their underlying signalling 
pathways, to obtain a better understanding of the pathogenetic mechanisms 
involved in developing aganglionosis of the distal bowel.