Association Between Hirschsprung’s Disease and Multiple Endocrine Neoplasia

Abstract

A “loss-of-function” mutation of the RET proto-oncogene is the most common genetic aberration implicated in the pathogenesis of Hirschsprung’s disease (HSCR). Some individuals with HSCR harbour RET mutations, which paradoxically also behave as “gain-of-function” mutations and lead to the co-occurrence of HSCR with multiple endocrine neoplasia 2 (MEN 2). The phenomenon appears to primarily occur in those with MEN 2A or familial medullary thyroid carcinoma (FMTC), while those with MEN 2B are susceptible to the development of multiple benign nerve cell tumours, known as ganglioneuromatosis, throughout the gastrointestinal tract.

The most common RET mutation to give rise to the co-occurrence of MEN 2 and HSCR is the C620 mutation, present in about 40% of such cases. C618, C611 and C609 mutations have also been implicated in this association. Long-segment aganglionosis is present in almost two thirds of HSCR patients with one of these mutations, with approximately 40% having total colonic aganglionosis. Such mutations are associated with a less aggressive phenotype of MTC than those with MEN 2A linked to a C634 mutation or in those with MEN 2B. The utility of RET genetic testing in cases of familial HSCR or in those with HSCR and a family history of MTC offers the opportunity to detect such mutations and screen patients and family members appropriately for MEN 2. Patients with MEN 2B almost invariably experience bowel symptoms due to ganglioneuromatosis, for which surgical management is only attempted for symptom management when obstructing lesions are present (approx. 30% of cases), unlike in HSCR where pull-through surgery is undertaken with “curative” intent.