Multiple endocrine neoplasia syndromes, children, Hirschsprung’s disease and RET

Abstract

Multiple endocrine neoplasia (MEN) type 2 syndromes are autosomal dominant clinical associations characterized by a common clinical feature, medullary thyroid carcinoma (MTC). The ability to accurately predict the risk by genetic RET proto-oncogene analysis has resulted in the active follow-up of children at risk for developing early metastatic tumours and which can be prevented by prophylactic thyroidectomy. The C634 and M918T mutations (associated with MEN2A and MEN2B, respectively) are particularly associated with early aggressive behavior and distant metastatic spread requiring early intervention. RET is known to be involved in cellular signalling processes during development and controls the survival, proliferation, differentiation and migration of the enteric nervous system (ENS) progenitor cells, as well as the survival and regeneration of sympathetic neural and kidney cells. The centrality of RET in the etiology of both MEN2 and HSCR is now well established with fairly consistent associations existing between RET genotype and phenotype in MEN2. The relationship between Hirschsprung's disease (HSCR) MEN2 syndromes appears to be a highly significant one, sharing a common etiological factor in the RET proto-oncogene. It is now well accepted that most HSCR arises from loss of function, RET mutations, RET haploinsufficiency or RET polymorphisms and haplotypes of the RET promotor region. MEN2 syndromes result from gene up regulation due to germline activating mutations in the RET proto-oncogene (1:500,000). MTC is mostly associated with variations in the 5 cysteine RET radicals and codon-risk management protocols are of considerable value but not infallible. Oncogenic RET mutations may, however, vary between specific population groups. RET analysis in MEN has revolutionized the management of children of MEN2 and allowed surgical prediction and prophylaxis to take place. We discuss the role of genetic testing and possible guidelines for the management of patients from MTC families. The future appears full of promise and the current evaluation of RET-targeting tyrosine kinase and other inhibitors are of considerable interest in the management of these conditions.

RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma

“…[17][18][19][20][21][22][23][24] Mice homozygous for a targeted mutation in RET demonstrate renal agenesis or severe dysgenesis and lack enteric neurons throughout the digestive tract, suggesting that RET is a component of a signaling pathway required for renal organogenesis and enteric neurogenesis. 25,26 Subsequently, inactivating mutations in RET associated with Hirschprung's disease [27][28][29][30][31][32] and renal agenesis were identified.…”

“…68 Particularly early aggressive behavior and metastasis in MEN2A and MEN2B are associated with C634 and M918T mutations, respectively, requiring early intervention. 22 On the other hand, A883F mutation displays a more indolent form of MTC compared with a M918T mutation for MEN2B. 73 In addition, polymorphism at codon 836 is associated with early metastases in patients with hereditary or sporadic MTC.…”

Non-cell-autonomous retinoid signaling is crucial for renal development

“…RA signaling regulates formation of the primary ureteric bud from the Wolffian duct and its branching morphogenesis within the developing kidney via Ret Ret is a gene that, when mutated in humans, can cause renal defects, Hirschsprung's disease and cancer (Dressler, 2008;Moore and Zaahl, 2008;Runeberg-Roos and Saarma, 2007). The majority of Ret mutant mice display renal agenesis due to defects at the first stage of branch formation, whereas a minority display renal hypoplasia due to impaired ureteric bud branching within the kidney (Schuchardt et al, 1996).…”

Achalasia: will genetic studies provide insights?

“…Whereas mutations in GDNF may be causative in rare cases of HSCR (\1%)-termed HSCR3 (MIM 600837) (Amiel and Lyonnet 2001), this is not the case for RET, which is located on chromosome 10q11 and which represents the most important disease gene for HSCR and the MEN 2 cancer syndromes (Amiel and Lyonnet 2001;Moore and Zaahl 2008). Interestingly, achalasia and related symptoms have been observed in some patients with MEN 2B (Carney et al 1976(Carney et al , 1978Carney and Hayles 1977;Cuthbert et al 1978;Demos et al 1983;Ghosh et al 1994;Hirano 1999).…”