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- HWE, Hardy-Weinberg equilibrium
- LSA, long segment aganglionosis
- NT, chromosomes not transmitted
- SNP, single nucleotide polymorphism
- SSA, short segment aganglionosis
- TDT, transmission disequilibrium test
- TR, chromosomes transmitted
Hirschsprung’s disease is a developmental disorder characterised by the absence of ganglion cells in the nerve plexuses of the lower digestive tract. The Hirschsprung phenotype is variable and can be classified into two groups: SSA, or short segment aganglionosis, which includes patients with aganglionosis as far as the rectosigmoid junction; and LSA, or long segment aganglionosis, which includes patients with aganglionosis beyond the rectosigmoid junction. The condition presents in the neonatal period as a failure to pass meconium, chronic severe constipation, colonic distension, secondary electrolyte disturbances, and sometimes enterocolitis and bowel perforation.
The estimated population incidence is 1/5000 live births, although this is a representative value. The highest incidence is in Asian populations (2.8 per 10 000 life births) and the lowest in Hispanics (1 per 10 000 life births).1 The male to female (M:F) ratio is approximately 4:1 for SSA patients and approximately 1:1 for LSA patients.1 Approximately 20% of cases are familial. The recurrence risks for siblings of SSA variant probands ranges between 1.5% and 3.3%, while the risks for those of LSA variant probands varies from 2.9% to 17.6%.1 Hirschsprung’s disease is often associated with chromosomal abnormalities, with other neurodevelopmental disorders such as Waardenburg syndrome type 4, and with a variety of additional isolated anomalies and syndromes.1,2
The disease has a complex genetic aetiology, and many studies indicate the receptor tyrosine kinase gene (RET) as the major susceptibility gene for Hirschsprung’s disease.1–14RET mutations are also associated with multiple endocrine neoplasia type 2 (MEN2),15 and medullary thyroid carcinoma.16 Papillary thyroid carcinoma is associated with RET somatic rearrangements.17
Mutations in the RET gene account for up to 50% of the familial cases and anywhere between 7% and 35% of the sporadic cases, and they lack genotype–phenotype correlation.5– …