Clinical Information

Variants in the RET proto-oncogene are associated with two distinct and, in rare cases, overlapping clinical syndromes: multiple endocrine neoplasia type 2 (MEN2) and Hirschsprung disease (HSCR).(1)

MEN2:

MEN2 is an autosomal dominant cancer syndrome, which has classically been divided into 3 subtypes: MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). The characteristic features of MEN2A include medullary thyroid carcinoma (MTC), pheochromocytoma, and primary hyperparathyroidism.(1-3) MEN2B is characterized by early-onset MTC, pheochromocytoma, mucosal neuromas, and distinctive facies with enlarged lips. Other features of MEN2B include enlarged nerves of the gastrointestinal tract (ganglioneuromatosis), marfanoid habitus, hypotonia, and corneal nerve thickening.(1-3) FMTC has traditionally been diagnosed in families of MTC in the absence of pheochromocytoma or parathyroid involvement. All MEN2 subtypes are inherited in an autosomal dominant inheritance pattern. The National Comprehensive Cancer Network and the American Thyroid Association provide recommendations regarding the medical management of individuals with MEN2 syndrome.(1,4)

HSCR:

HSCR, also known as aganglionic megacolon, is a congenital disorder of impaired intestinal motility.(1,5,6) Variable lengths of the colon may be affected, resulting in either total aganglionosis, long-segment HSCR, or short-segment HSCR. HSCR affects approximately 1 in 5000 live births and is resolved via surgical intervention.(1,5,6) HSCR can result from chromosome abnormalities, single gene disorders (both syndromic and non-syndromic), a combination of variants in multiple genes, and unknown causes.(1,5,6) However, disease-causing RET variants are considered the most common cause of HSCR cases, particularly in families with multiple cases of HSCR and long-segment disease.(1,5,6) It has been reported that up to 50% of familial cases of HSCR and up to 33% of sporadic HSCR cases are due to RET germline variants.(1,5,6)

While gain-of-function variants in RET are typically associated with MEN2, loss-of-function variants have been reported in patients with HSCR including full or partial RET gene deletions.(1) In addition to clearly disease-causing RET variants that cause HSCR, additional benign variants in RET (which may not be causative in themselves) confer increased susceptibility to HSCR.(1)