The contribution of associated congenital anomalies in understanding Hirschsprung's disease

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dc.contributor.authorMoore S.W.
dc.date.accessioned2011-05-15T16:03:45Z
dc.date.available2011-05-15T16:03:45Z
dc.date.issued2006
dc.description.abstractHirschsprung'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.
dc.description.versionReview
dc.identifier.citationPediatric Surgery International
dc.identifier.citation22
dc.identifier.citation4
dc.identifier.issn1790358
dc.identifier.other10.1007/s00383-006-1655-2
dc.identifier.urihttp://hdl.handle.net/10019.1/12770
dc.subjectanorectal malformation
dc.subjectcardiovascular malformation
dc.subjectcell differentiation
dc.subjectcell maturation
dc.subjectcell proliferation
dc.subjectcentral nervous system malformation
dc.subjectcholesterol metabolism
dc.subjectchromosome 10
dc.subjectchromosome 13
dc.subjectchromosome 2
dc.subjectchromosome 20
dc.subjectchromosome 21
dc.subjectchromosome 22
dc.subjectchromosome 9
dc.subjectcongenital malformation
dc.subjectcraniofacial malformation
dc.subjectdisease association
dc.subjectDown syndrome
dc.subjectectodermal dysplasia
dc.subjectEDNRB gene
dc.subjecteye malformation
dc.subjectganglioneuroma
dc.subjectgastrointestinal malformation
dc.subjectgene
dc.subjectgene mutation
dc.subjectgenetic association
dc.subjectgenetic susceptibility
dc.subjectHirschsprung disease
dc.subjecthuman
dc.subjectintestine atresia
dc.subjectintestine innervation
dc.subjectintestine malformation
dc.subjectlipid metabolism
dc.subjectmusculoskeletal system malformation
dc.subjectneuroblastoma
dc.subjectneurofibromatosis
dc.subjectoncogene ret
dc.subjectperception deafness
dc.subjectphenotype
dc.subjectpheochromocytoma
dc.subjectpriority journal
dc.subjectretinoblastoma
dc.subjectreview
dc.subjectsyndrome
dc.subjecttrisomy 21
dc.subjecturogenital tract malformation
dc.subjectWaardenburg syndrome
dc.subjectAbnormalities
dc.subjectAnimals
dc.subjectComorbidity
dc.subjectGenetic Predisposition to Disease
dc.subjectHirschsprung Disease
dc.subjectHumans
dc.subjectIncidence
dc.subjectMice
dc.titleThe contribution of associated congenital anomalies in understanding Hirschsprung's disease
dc.typeReview
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