Familial associations in medullary thyroid carcinoma with Hirschsprung disease: the role of the RET-C620 "Janus" genetic variation.
BACKGROUND
Hirschsprung disease (HSCR) is associated with the later development of multiple endocrine neoplasia (MEN2), because RET gene variations are associated with both conditions. Specifically, HSCR-MEN2 cosegregation mostly relates to the cysteine-rich area at the RET-620 (the "Janus gene").


OBJECTIVE
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.


CONCLUSIONS
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.
Moore
Sam W
SW
Division of Paediatric Surgery, Faculty of Health Sciences, University of Stellenbosch, PO Box 19063, Tygerberg 7505, South Africa. swm@sun.ac.za
Zaahl
Monique
M
D000368:Aged; D018276:Carcinoma, Medullary / Q000453:epidemiology / Q000235:genetics*; D002648:Child; D015897:Comorbidity; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006627:Hirschsprung Disease / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009377:Multiple Endocrine Neoplasia / Q000453:epidemiology / Q000235:genetics*; D018813:Multiple Endocrine Neoplasia Type 2a / Q000453:epidemiology / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D013964:Thyroid Neoplasms / Q000453:epidemiology / Q000235:genetics*
D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human