Hirschsprung disease, associated syndromes and genetics: a review

  title={Hirschsprung disease, associated syndromes and genetics: a review},
  author={Jeanne Amiel and E Sproat-Emison and Maria-Merc{\`e} Garcia-Barcelo and Francesca Lantieri and Grzegorz M. Burzynski and Salud Borrego and Anna Pelet and Stacey Arnold and Xiaoping Miao and Paola Griseri and Alice Brooks and Guillermo Anti{\~n}olo and Loïc De Pontual and Mathieu Cl{\'e}ment-Ziza and Arnold Munnich and Carl S. Kashuk and Kristen West and K. K. Y. Wong and Stanislas Lyonnet and Aravinda Chakravarti and Paul Kwong-Hang Tam and Isabella Ceccherini and Robert M.W. Hofstra and Raquel M. Fern{\'a}ndez},
  journal={Journal of Medical Genetics},
  pages={1 - 14}
Hirschsprung disease (HSCR, aganglionic megacolon) represents the main genetic cause of functional intestinal obstruction with an incidence of 1/5000 live births. This developmental disorder is a neurocristopathy and is characterised by the absence of the enteric ganglia along a variable length of the intestine. In the last decades, the development of surgical approaches has importantly decreased mortality and morbidity which allowed the emergence of familial cases. Isolated HSCR appears to be… 
The developmental genetics of Hirschsprung's disease
The objective of this review is to provide an overview of the pathophysiology and genetics of HSCR within the context of the current knowledge of NCC development, sex chromosome genetics and laboratory models.
Gastrointestinal Tract: Molecular Genetics of Hirschsprung Disease
Nine genes and three signal pathways have been identified in relation to the aetiology of this group of disorders, and Hirschsprung disease is currently the best understood multifactorial, nonMendelian genetic disorder.
Comprehensive Analysis of NRG1 Common and Rare Variants in Hirschsprung Patients
A comprehensive analysis of the NRG1 gene in the context of the disease is presented, by both mutational screening of its coding sequence and evaluation of 3 common tag SNPs as low penetrance susceptibility factors, finding some potentially damaging variants which are functionally characterized.
Hirschsprung’s disease and associated syndrome and malformation: A case series of four cases
Hirschsprung’s disease is a genetic disorder with a multigenic pattern of inheritance characterized by aganglionosis of the intestine extending up to a variable length and malformation and neoplasm can be seen.
Hirschsprung’s disease: clinical dysmorphology, genes, micro-RNAs, and future perspectives
A 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.
Analysis of the RET Gene in Subjects with Sporadic Hirschsprung's Disease
Genetic basis of Hirschsprung’s disease
This review will focus on the genes known to be involved in HSCR pathology, how they interact, and on how technology advances are being employed to uncover the pathological processes underlying this disease.
Advances in understanding the association between Down syndrome and Hirschsprung disease (DS–HSCR)
  • S. Moore
  • Medicine
    Pediatric Surgery International
  • 2018
Evidence of both germline and somatic gene mutations suggesting causation of Down syndrome patients with Hirschsprung disease are provided, and potential role of other facilitatory influence of other susceptibility genes as well as potential other chromosome 21 gene actions and the microenvironment on the Down syndrome gastro-intestinal tract are explored.
Molecular Genetic Anatomy and Risk Profile of Hirschsprung's Disease
Among the patients in this study, Hirschsprung's disease arose from common noncoding variants, rare coding variants, and copy‐number variants affecting genes involved in enteric neural‐crest cell fate that exacerbate the widespread genetic susceptibility associated with RET.


Hirschsprung disease and L1CAM: is the disturbed sex ratio caused by L1CAM mutations?
HSCR is a congenital disorder characterised by an absence of enteric ganglia over various lengths of the bowel and proliferation of nerve fibres in the distal bowel and genetic analysis of HSCR has confirmed the heterogeneity.
Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease
S segregation analysis suggested an incompletely penetrant dominant inheritance in HSCR families with agan-glionosis extending beyond the sigmoid colon, and mutations of the gene encoding GDNF could either cause or modulate the H SCR phenotype in some cases.
Hirschsprung Disease in an Infant with a Contiguous Gene Syndrome of Chromosome 13
Congenital anomalies associated with deletions of the distal long arm of chromosome 13 are sufficiently consistent to suggest a clinical syndrome, suggesting the existence of a contiguous gene syndrome involving developmental genes necessary for the normal growth of the neural crest derivatives of the eye, inner ear, and colon.
Endothelin-3 Gene Mutations in Isolated and Syndromic Hirschsprung Disease
The present data give further support to the role of the endothelin-signaling pathway in the development of neural crest-derived enteric neurons and suggest the possibility that either recessive or weakly penetrant dominant alleles could occur at the EDN3 locus, depending on the nature of the mutation.
Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease.
The low penetrance of the mutant gene, the lack of genotype-phenotype correlation, the sex-dependent effect of RET mutations and the variable clinical expression of the disease support the existence of one or more modifier genes in familial HSCR.
Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease.
The data suggest that the overall frequency of RET mutations in HSCR patients is low and therefore, other genetic and/or environmental determinants contribute to the majority of HscR susceptibility, and at present, there is no obvious relationship between RET genotype and H SCR phenotype.
Hydrocephalus and intestinal aganglionosis: is L1CAM a modifier gene in Hirschsprung disease?
It is hypothesized that L1CAM-mediated cell adhesion may be important for the ability of ganglion cell precursors to populate the gut, and that L 1CAM may modify the effects of a Hirschsprung disease-associated gene to cause intestinal aganglionosis.
PMX2B, a new candidate gene for Hirschsprung's disease
The present observation suggests that PMX2B haploinsuffciency might predispose to HSCR, a congenital intestinal malformation of the enteric nervous system.
Novel mutations of the endothelin-B receptor gene in isolated patients with Hirschsprung's disease.
Observations indicate that dysfunction or loss of function of endothelin-B receptor may be involved in the aetiology of some isolated patients with HSCR.
Frequency of RET mutations in long‐ and short‐segment Hirschsprung disease
The approach of single‐strand conformational polymorphism analysis established for all the 20 exons of the RET proto‐oncogene, and previously used to screen for point mutations in Hirschsprung patients, allowed us to identify seven additional mutations among 39 sporadic and familial cases of HirschSprung disease.