The Hirschsprung's–multiple endocrine neoplasia connection

Abstract

The risk of patients with Hirschsprung's disease later developing multiple endocrine neoplasia remains a matter of concern. The multiple endocrine neoplasia 2–Hirschsprung's disease association has been shown to cosegregate in Hirschsprung's disease patients with both short- and long-segment aganglionosis, although patients with long-segment aganglionosis a to carry the greatest risk. The Hirschsprung's disease–medullary thyroid carcinoma relationship also appears to be bi-directional, and activation or suppression of the rearranged during transfection gene appeared to vary over succeeding generations within the same family. Rearranged during transfection gene variations are associated with both conditions. The cosegregation of Hirschsprung's disease and multiple endocrine neoplasia 2 is particularly interesting as it involves both “switch off” and “switch on” of the rearranged during transfection proto-oncogene in the same patient. This cosegregation mostly relates to the cysteine-rich area on RET-620 (the “Janus gene”). The mechanism whereby rearranged during transfection influences gene activation in multiple endocrine neoplasia 2 is complex, but genetic variations impair the rearranged during transfection tyrosine kinase response to tyrosine kinase activation, thus appearing to dictate downstream signaling cascade responses. Better understanding of the RET-620 relationship allows for a more cost-effective method of identifying those at risk by focusing rearranged during transfection gene testing to this specific area as a “hot spot”. The clinical awareness of possible medullary thyroid carcinoma has led to timely intervention and early treatment of this chemo- and radioresistant tumor with poor prognosis. Establishment of “risk” by genetic testing has become a classic model of molecular medicine being integrated into patient care and offering rearranged during transfection-directed prophylactic surgical management. In addition, novel approaches to treatment based on this genetic knowledge have already shown early promise in randomized clinical trials.

Natural Selection Equally Supports the Human Tendencies in Subordination and Domination: A Genome-Wide Study With in silico Confirmation and in vivo Validation in Mice

“…In addition, both overexpression (Ishii et al, 2013) and underexpression (Zhan et al, 1999) of the RET gene can contribute to the pathogenesis of Hirschsprung disease. Finally, both increased (Huang et al, 2003) and decreased (Moore and Zaahl, 2012) levels of this proto-oncogene are often seen in pheochromocytoma. Thus, the above publications additionally validate our results (Figure 3D,E) as italicized in Supplementary Table S3.…”

Twenty years of lesson learning: how does the RET genetic screening test impact the clinical management of medullary thyroid cancer?

“…The germline RET mutations harboured by these patients were the C609R and C609Y mutations in exon 10. The association between these two distinct diseases has already been reported to involve RET germline mutations that are mainly related to cysteine mutations in codon 620 and to a lesser extent in codons 609, 611 and 618 . Patients with these double‐functioning mutations, which are called ‘Janus mutations’ for their ability to be simultaneously activating and inactivating mutations, should be continuously monitored for HD development.…”

A review of diagnostic approaches to medullary thyroid carcinoma

“…Hirschsprung's disease (HD) is linked to certain mutations in codon 620 leading to inactivation of the encoded protein. Some activating mutations have been evidenced as precursors of HD [68,69]. The specific clinical features of MEN2A syndrome can be influenced by patient's genetic characteristics.…”