Penetrance and Clinical Manifestations of Non-Hotspot Germline RET Mutation, C630R, in a Family with Medullary Thyroid Carcinoma

Abstract

Germline mutations in specific hot spot-codons of the RET proto-oncogene are associated with multiple endocrine neoplasia type 2 (MEN 2). Clinical RET gene testing has been routine for the last 10 years in some countries. In Argentina, RET testing excluding MEN 2B was always reported with a mutation at codon 634, with one exception: we described a novel mutation T > C transition at codon 630 (C630R), the family to which we extend the study in the present report. This family comprised 29 members in four generations including 6 individuals affected with medullary thyroid cancer (MTC), positive for the C630R mutation and normal adrenaline/ noradrenaline and ionized calcium/parathyroid hormone levels. Two asymptomatic mutation carriers aged 5 and 11 years underwent total thyroidectomy. The histopathologic examination showed C-cell hyperplasia and microcarcinoma foci, while preoperative basal calcitonins were normal for both. Our report emphasizes the importance of testing for non-hot spot RET mutations in apparently mutation negative MEN 2 families. Furthermore, it would appear that C630R mirrors C634R in penetrance (100% in this family) and in early age of onset of MTC, although paradoxically, no pheochromocytomas and hyperparathyroidism have developed. In addition to recommending RET testing before 5 years of age; we also can postulate that codon 630 may be the key point along the extracellular domain, important in the tissue-specific penetrance.

Familial medullary carcinoma prevention, risk evaluation, and RET in children of families with MEN2

“…Although generally true that the risk is codon specific, the age of onset of MTC does not always appear to be constant and there appear to be exceptions to the rule. For example, CCH and microcarcinoma have been described as early as 5 and 11 years in association with a C630R mutation [26]. On the other hand, the affected parent in our series who developed MTC as a result of a 620 mutation probably developed MTC in her early 30s as it was present without metastases at 37 years of age.…”

A Family of Multiple Endocrine Neoplasia Type 2A (MEN 2A) with Cys630Tyr RET Germline Mutation: Report of a Case

“…The risk category of the consensus guidelines [9] does not include cases with a RET mutation in codon 630. To our knowledge, except for two reports [5,6], there are no reports concerning prophylactic thyroidectomy in the literature. Machens et al [6] reported three patients of a family with Cys630Arg RET genotype, all of whom had MTC including a 1-year-old one.…”

“…They recommended early prophylactic thyroidectomy before 5 years old. Dourisboure et al [5] reported 10 patients of one family. They all had MTC including a 5-year-old child.…”

“…Only limited clinical information is available about penetration, onset, and prognosis in Cys630 RET genotype [5,6]. Most of the previous papers, as shown in Table 2, reported that MTC with codon 630 mutation clinically appeared as familial medullary thyroid carcinoma.…”

“…The mutations at codon 634, 620 and 618 make up about 95% of MEN 2A family members [1][2][3]. MEN 2A patients with Cys630 RET genotype mutations are exceedingly rare [4], and to our knowledge, only six families [2,[5][6][7][8] are described in the literature. Little is known about the clinical manifestation of this rare RET germline mutation, including penetration, onset, and prognosis of MEN 2A.…”