Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10

Abstract

Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical-risk profiles. Presentation, age-dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4-86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon-associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609→620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected.

Advances in risk-oriented surgery for multiple endocrine neoplasia type 2

“…Children with complication after total thyroidectomy, n (%) Age at thyroidectomy, year (17) 0 of 21 (0) 2 of 43 (5) 4 of 55 (7) 6 of 98 (6 40s for mutations in cysteine codons 609-620/630, and 2.6% by the age of 56.5 years for mutations in non-cysteine codons 768-891 (Asari et al 2006, Frank-Raue et al 2011, Machens et al 2013a. Three-quarters of these pheochromocytomas were unilateral only.…”

“…That level of detail is rarely available for ATA risk categories. Exceptions include moderate-risk mutations in exon 10 (ATA category MOD; mutations in cysteine codons 609-620), in which the penetrance of pheochromocytoma was 0% by age 10 years; 0.8% by age 20 years; 5.1% by age 30 years, 12.0% by age 40 years; 23.1% by age 50 years and 33.2% by age 60 years (Frank-Raue et al 2011). …”

“…• Moderate-risk mutations (ATA category MOD; atypical MEN2A) infrequently go along with primary hyperparathyroidism (Asari et al 2006, Frank-Raue et al 2011, Machens et al 2013a. Current estimates range from 1.3% by the age of 54.5 years (mutations in non-cysteine codons 768-891) to 2.7% by the age of 46 years (mutations in cysteine codons 609-620 in exon 10).…”

“…Current estimates range from 1.3% by the age of 54.5 years (mutations in non-cysteine codons 768-891) to 2.7% by the age of 46 years (mutations in cysteine codons 609-620 in exon 10). The penetrance of primary hyperparathyroidism, pooling data of 27 centers from 15 countries, was estimated at 0% by age 20 years; 0.5% by age 30 years, 1.8% by age 40 years; 3.9% by age 50 years and 3.9% by age 60 years (Frank-Raue et al 2011). …”

A comprehensive review on MEN2B

“…Finally, the underlying RET mutation also determines the extra-thyroidal features of MEN2, likely imparting a different susceptibility of adrenal or parathyroid cells to a given mutant receptor; this might explain the lack of primary hyperparathyroidism in MEN2B or, for example, the difference in the prevalence of pheochromocytoma in M918T patients compared with patients who harbor exon 10 germline RET mutations , Frank-Raue et al 2011. Of note, the M918T RET mutation has also been identified somatically in a high percentage of sporadic MTC (Marsh et al 1996, Eng & Mulligan 1997.…”