Genetic testing identifies the potential risk of multiple endocrine neoplasia in a Vietnamese family

Multiple endocrine neoplasia type 2A (MEN2A) is a rare syndrome characterized by the presence of medullary thyroid carcinoma, pheochromocytoma, hyperparathyroidism and sometimes cutaneous lichen amyloidosis. This syndrome is caused by a germline activation mutation in the rearranged during transfection (RET) proto-oncogene transmitted by an autosomal dominant inheritance. In this study, we reported a rare case of a 44-year-old man from Vietnam with medullary thyroid carcinoma and pheochromocytoma as the symptom of MEN2A. Genetic testing indicated a nucleotide substitution located in exon 11 of the RET proto-oncogene (c.1900T>C, p.C634R), which was reported as a known pathogenic mutation of MEN2A. Further genetic tests on the other family members found the same mutation in his daughter (currently 14 years-old) and his son (currently 8 years-old). Although these 2 children do not yet have any manifestations of MEN2A, this data emphasizes their high risks of this disease. Therefore, this case draws attention to the importance of genetic counselling in C634R carriers, as well as rigorous follow-up appointments to reduce incidence and mortality since the mutation is classified as a high-risk group within the medullary thyroid carcinoma guidelines.

Elevated basal serum levels of calcitonin and simultaneous surgery of MEN2A-specific tumors

Background Multiple endocrine neoplasia type 2A (MEN2A) is a rare syndrome caused almost by germline RET mutation, and characterized by medullary thyroid carcinoma (MTC), in combination or not with pheochromocytoma (PHEO), hyperparathyroidism (HPTH), cutaneous lichen amyloidosis (CLA) and Hirschsprung’s disease (HD). The basal serum calcitonin (Ctn)/carcinoembryonic antigen (CEA) levels are significantly correlated with MTC stage. Metachronous surgery of MEN2A-specific tumors is a routine procedure. We aimed to explore the clinical significance of pro-gastrin-releasing peptide (proGRP) in MTC with elevated Ctn, and simultaneous surgery of MEN2A-specific tumors. Methods We retrospectively investigated 8 RET mutation carriers of 2 Chinese pedigrees with MEN2A. Clinical profiles, imaging examinations, preoperative and postoperative biochemical data, surgical procedures and follow-up records were evaluated. Results Three patients showed the levels of elevated Ctn, but normal proGRP. Among them, one patient (FAIII-6) in Family A (one for RET C634R mutation), diagnosed with bilateral MTC, left PHEO, bilateral HPTH and CLA, classified as MEN2A-related CLA subtype, underwent successfully simultaneous adrenal-sparing surgery (ASS), total thyroidectomy (TT) and parathyroidectomy, while TT of the other two patients (FBII-3 and FBIII-7) diagnosed with bilateral MTC in Family B (all for RET C618R mutation) were performed. Unexpectedly, absence of neck lymph node MTC metastasis was indicated by histopathological examination. Postoperatively, all had consistently “undetectable” or normal levels of Ctn/CEA during follow-up. Conclusions Patients with normal proGRP, despite high levels of Ctn, might have noregional lymph node MTC metastasis, and neck dissection should be avoided. Moreover, simultaneous surgery for coexistent PHEO, and either MTC or HPTH is an approach of choice to use as an alternative treatment pattern. Recognition of MEN2A-related CLA and subsequently early screening of RET mutation may be favorable for timely management of MEN2A-specific tumors.

MULTIPLE ENDOCRINE NEOPLASIA IN PRACTICE OF PRIMARY CARE AND FAMILY PHYISICIANS

Multiple endocrine neoplasia is characterized with a predisposition to tumors involving two or more endocrine glands. The four main forms of the disease are inherited as an autosomal dominant syndrome or may occur sporadically. In addition to these four forms, six other syndromes are associated with the presence of multiple endocrine and other neoplasms of the organs: hyperparathyroidism − jaw tumors, Carney complex, von Hippel−Lindau disease, neurofibromatosis type 1, Cowden syndrome and McCune − Albright syndrome. The diagnosis of multiple endocrine neoplasia syndrome can be established in humans by one of the three available criteria: clinical features, family history, genetic analysis. Mutation analysis during these syndromes is useful in clinical practice to confirm the clinical diagnosis; identifying family members who tolerate the mutation and need to be screened, and identifying family members who do not tolerate the mutation. Syndrome of multiple endocrine neoplasia (Wermer syndrome) is characterized by the presence of a triad of tumors, including tumors of the parathyroid glands, pheochromocytoma and tumors of the parathyroid gland. It occurs less frequently in combination with Hirschsprung's disease, caused by the absence of vegetative ganglion cells in the intestine terminal parts, that leads to colonic enlargement, severe constipation and obstruction. This syndrome may be associated with cutaneous lichen amyloidosis, the clinical manifestations of which are pruritus and lichenoid lesions, usually located in the upper back. A clinical case of MEN2 syndrome in a 52−year−old patient is presented. It is noted that for such patients, in addition to timely syndromic rather than component diagnosis of this endocrine multipathology, the spread of neoplastic process in medullary thyroid cancer to its capsule and surrounding tissues, as well as the presence of metastases in peripheral lymph nodes are important. As a rule, such patients cannot be timely cured. Key words: multiple endocrine neoplasia, endocrine tumors, genetic analysis, family history.

A primer on the genetics of medullary thyroid cancer

Medullary thyroid cancer is a rare type of neuroendocrine tumour that arises from the parafollicular cells (C cells) of the thyroid gland. It accounts for 3%–5% of thyroid cancer cases. Close to 25% of cases are familial, and 75% are considered sporadic. Familial cases are associated with a germline RET mutation; 43%–65% of sporadic cases harbour a somatic event in the gene. Germline RET mutations are associated with the autosomal-dominant inherited multiple endocrine neoplasia (men) 2a and 2b syndromes and the isolated familial medullary thyroid cancer syndrome. More than 100 RET codon mutations have been reported to date, with genotype–phenotype correlations that include the extent and aggressiveness of the medullary thyroid cancer and the presence of other features of the men2 syndromes. The latter include pheochromocytoma–paraganglioma, hyperparathyroidism, cutaneous lichen amyloidosis, and Hirschsprung disease. In this narrative review, we focus on RET proto-oncogene physiology and pathogenesis induced by germline and somatic RET mutations, the genotype–phenotype correlation, and the management and follow-up of patients with germline-mutated medullary thyroid cancer.

The RET C611Y mutation causes MEN 2A and associated cutaneous lichen amyloidosis

Background Cutaneous lichen amyloidosis (CLA) has been reported in some multiple endocrine neoplasia type 2A (MEN 2A) families affected by specific germline RET mutations C634F/G/R/W/Y or V804M, as a characteristic of the clinical manifestation in ‘MEN 2A with CLA’, one of four variants of MEN 2A, which was strictly located in the scapular region of the upper back. Patient Findings This study reports a large south-eastern Chinese pedigree with 17 individuals carrying the MEN 2A-harboring germline C611Y (c.1832G>A) RET mutation by Sanger sequencing. One individual presented MEN 2A-related clinical features, including typical CLA in the interscapular region; another individual exhibited neurological pruritus and scratching in the upper back but lacked CLA skin lesions. Both subjects presented with CLA or pruritic symptoms several years before the onset of medullary thyroid carcinoma (MTC) and/or pheochromocytoma. The remaining 15 RET mutation carriers did not exhibit CLA; of these, one presented with MTC and pheochromocytoma, nine with MTC only, two with elevated serum calcitonin and three younger subjects with normal serum calcitonin levels. This family’s clinical data revealed a later diagnosis of MTC (mean age, 45.9 (range: 23–73) years), a lower penetrance of pheochromocytoma (2/17, 11.8%) and CLA (1/17, 5.9%). However, no hyperparathyroidism and Hirschsprung disease were reported in this family. Summary and Conclusions This is the first description of a family with MEN 2A-related CLA due to a germline RET C611Y mutation, which might exhibit a novel and diversified genotype–phenotype spectrum in MEN 2A.