The contribution of associated congenital anomalies in understanding Hirschsprung's disease
Date
2006
Authors
Moore S.W.
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Abstract
Hirschsprung's disease (HSCR) is a complex congenital disorder which, from a molecular perspective, appears to result due to disruption of normal signalling during development of enteric nerve cells, resulting in aganglionosis of the distal bowel. Associated congenital anomalies occur in at least 5-32% (mean 21%) of patients and certain syndromic phenotypes have been linked to distinct genetic sites, indicating underlying genetic associations of the disease and probable gene-gene interaction in its pathogenesis. Clear-cut associations with HSCR include Down's syndrome, dominant sensorineural deafness, Waardenburg syndrome, neurofibromatosis, neuroblastoma, phaeochromocytoma, the MEN type IIB syndrome and other abnormalities. Individual anomalies vary from 2.97% to 8%, the most frequent being the gastrointestinal tract (GIT) (8.05%), the central nervous system (CNS) and sensorineural anomalies (6.79%) and the genito-urinary tract (6.05%). Other associated systems include the musculoskeletal (5.12%), cardiovascular systems (4.99%), craniofacial and eye abnormalities (3%) and less frequently the skin and integumentary system (ectodermal dysplasia) and syndromes related to cholesterol and fat metabolism. In addition to associations with neuroblastoma and tumours related to MEN2B, HSCR may also be associated with tumours of neural origin such as ganglioneuroma, ganglioneuroblastoma, retinoblastoma and tumours associated with neurofibromatosis and other autonomic nervous system disturbances. The contribution of the major susceptibility genes on chromosome 10 (RET) and chromosome 13 (EDNRB) is well established in the phenotypic expression of HSCR. Whereas major RET mutations may result in HSCR by haploinsufficiency in 20-25% of cases, the etiology of the majority of sporadic HSCR is not as clear, appearing to arise from the combined cumulative effects of susceptibility loci at critical genes controlling the mechanisms of cell proliferation, differentiation and maturation. In addition, potential "modifying" associations exist with chromosome 2, 9, 20, 21 and 22, and we explore the importance of certain flanking genes of critical areas in the final phenotypic expression of HSCR. © Springer-Verlag 2006.
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Keywords
anorectal malformation, cardiovascular malformation, cell differentiation, cell maturation, cell proliferation, central nervous system malformation, cholesterol metabolism, chromosome 10, chromosome 13, chromosome 2, chromosome 20, chromosome 21, chromosome 22, chromosome 9, congenital malformation, craniofacial malformation, disease association, Down syndrome, ectodermal dysplasia, EDNRB gene, eye malformation, ganglioneuroma, gastrointestinal malformation, gene, gene mutation, genetic association, genetic susceptibility, Hirschsprung disease, human, intestine atresia, intestine innervation, intestine malformation, lipid metabolism, musculoskeletal system malformation, neuroblastoma, neurofibromatosis, oncogene ret, perception deafness, phenotype, pheochromocytoma, priority journal, retinoblastoma, review, syndrome, trisomy 21, urogenital tract malformation, Waardenburg syndrome, Abnormalities, Animals, Comorbidity, Genetic Predisposition to Disease, Hirschsprung Disease, Humans, Incidence, Mice
Citation
Pediatric Surgery International
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