Familial associations in medullary thyroid carcinoma with Hirschsprung disease: the role of the RET-C620 "Janus" genetic variation

Introduction: Hirschsprung disease (HSCR) is associated with the later development of multiple endocrine neoplasia (MEN2), because RET gene variations are associated with both conditions. Specifically, HSCRMEN2 cosegregation mostly relates to the cysteine-rich area at the RET-620 (the "Janus gene"). Aim: The aim of this study was to explore the clinical and genetic associations of HSCR-MEN2 in a cohort of HSCR patients. Methods: RET gene variation was evaluated by heteroduplex single-strand conformational polymorphism analysis and validated with automated sequencing techniques in HSCR patients (including 18 kindreds). Those with RET C620 variations were subjected to familial evaluation for coexisting HSCR-MEN2. Results: A cohort of 118 patients with HSCR(n = 89) or medullary thyroid carcinoma (n = 29) were studied, including 3 families where a RET-620 point mutation was identified. No C618, C609, or C611 variations were detected. In 1 remarkable 6-generational family (family 3), HSCR in early generations seemed to be later replaced by MEN2A. In the other 2 families with total colonic aganglionosis, a relative with a medullary thyroid carcinoma was identified. Conclusion: Gene mutation in the RET-620 position carries significant risk and may be part of a targeted investigation of high-risk areas in HSCR. We propose an alternative hypothesis of endoplasmic reticulum control to explain the changing phenotypic expression. (C) 2010 Elsevier Inc. All rights reserved.