Multiple endocrine neoplasia type 2: achievements and current challenges

Abstract

Incremental advances in medical technology, such as the development of sensitive hormonal assays for routine clinical care, are the drivers of medical progress. This principle is exemplified by the creation of the concept of multiple endocrine neoplasia type 2, encompassing medullary thyroid cancer, pheochromocytoma, and primary hyperparathyroidism, which did not emerge before the early 1960s.This review sets out to highlight key achievements, such as joint biochemical and DNA-based screening of individuals at risk of developing multiple endocrine neoplasia type 2, before casting a spotlight on current challenges which include: (i) ill-defined upper limits of calcitonin assays for infants and young children, rendering it difficult to implement the biochemical part of the integrated DNA-based/biochemical concept; (ii) our increasingly mobile society in which different service providers are caring for one individual at various stages in the disease process. With familial relationships disintegrating as a result of geographic dispersion, information about the history of the origin family may become sketchy or just unavailable. This is when DNA-based gene tests come into play, confirming or excluding an individual's genetic predisposition to multiple endocrine neoplasia type 2 even before there is any biochemical or clinical evidence of the disease.However, the unrivaled molecular genetic progress in multiple endocrine neoplasia type 2 does not come without a price. Screening may uncover unknown gene sequence variants representing either harmless polymorphisms or pathogenic mutations. In this setting, functional characterization of mutant cells in vitro may generate helpful ancillary evidence with regard to the pathogenicity of gene variants in comparison with established mutations.

A rare missense variant in RET exon 8 in a Portuguese family with atypical multiple endocrine neoplasia type 2A

“…9 Moreover, in contrast to cysteines encoded in exons 10 and 11, which are commonly mutated in hereditary MEN2, cysteine 531 is less conserved throughout evolution. 34 Taken together, these observations suggest that mutation of cysteine 531 can activate the RET receptor but has mild oncogenic potential.…”

“…8 Patients with germline RET mutations may undergo risk assessment and may be offered thyroidectomy prior to developing clinically evident MTC. 9,10 However, due to the varying clinical effects of RET mutations, establishing precise genotype-phenotype correlations remains challenging. The RET gene is located on chromosome 10 (10q11.2) and comprises 21 exons that encode for a transmembrane tyrosine kinase receptor involved in growth and differentiation of neural crest-derived tissues.…”

Bilateral Medullary Thyroid Carcinoma in a 3-Year-Old Female Patient with Multiple Endocrine Neoplasia 2A Syndrome Undergoing Prophylactic Thyroidectomy: Should Current Guidelines Be Revised?

“…In addition, patients’ probability for cure from MTC has been found to be associated with lymph node status, ranging from 95% when no lymph nodes are involved, 31–57% when 1–10 lymph nodes are involved, and 0–4% when more than 10 lymph nodes are involved with MTC [12-14]. Previous publications have demonstrated the possibility of lymph node involvement regardless of the size of the tumor and even in micro-medullary carcinomas of less than 0.5 cm in diameter [15].…”

Ophthalmic manifestations of endocrine disorders—endocrinology and the eye

“…Most patients with either type of MEN are diagnosed in adulthood, although there are reports of medullary thyroid carcinoma associated with MEN2 presenting in infancy (62). Given the autosomal dominant inheritance pattern of MEN, an extended family history and additional testing may be indicated when the index of suspicion for MEN is high.…”