Multiple endocrine neoplasia-IIb with RET gene mutation p.M918T： A case report / 中南大学学报(医学版)

Multiple endocrine neoplasia-IIb (MEN-IIb) is a rare hereditary autosomal dominant syndrome caused by mutations in the RET proto-oncogene. It's characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), mucosal neuromas, and Marfanoid habitus. Because of the rarity of MEN-IIb and finiteness of clinical cognition, the majority of the patients suffer a delayed diagnosis. A MEN-IIb patient with the lingual mucosal neuromas since childhood was admitted in the Third Xiangya Hospital of Central South University in November, 2018. He had surgical history of mitral valve prolapse and spinal deformity. He was diagnosed with MTC and PHEO at the age of 22 and 28, respectively, and received surgical treatments. Sequencing of RET gene revealed a de novo heterozygous p.M918T mutation in the patient. Being aware of the unique clinical phenotype and screening of RET gene mutation may lead to the early diagnosis and better long-term outcome for MEN-IIb.

brief review on the molecular basis of medullary thyroid carcinoma

Approximately 5-10% of all thyroid cancers are medullary thyroid carcinomas [MTC]. MTC is mainly sporadic in nature, but 20-30% of cases are hereditary. Genetic testing for hereditary MTC is very important for the patient and his family, but the patients must be receiving appropriate genetic counseling. About 98% of patients with hereditary MTC have germline mutations in exons 10, 11, 13, 14, 15, 16 and intron 16 of the REarrangement during transfection [RET] proto-oncogene, but the etiology of the more frequent sporadic form of MTC [sMTC] is not well understood. Recently, it has been reported that apparently sporadic MTC may involve point mutations in BRAF and RAS genes, with an overall prevalence of almost 10%. Also alteration and abnormal expression of miRNA has been described in MTC. In this review, we attempted to mention some mutations and molecular changes in sporadic and hereditary MTC pathogenesis

A RET C634R mutation in a Thai female with multiple endocrine neoplasia type 2A.

Multiple endocrine neoplasia type 2A (MEN 2A) is an autosomal dominant disorder characterized by medullary thyroid carcinoma, pheochromocytoma and primary hyperparathyroidism. The first tumor is usually a medullary thyroid carcinoma. MEN 2A is caused by mutations in the RET proto-oncogene. The detection of mutations in the gene has important diagnostic and therapeutic impacts. Genetic testing of at-risk family members allows one to identify individuals carrying the mutant alleles with very high specificity and sensitivity. Subsequently, total thyroidectomy, recommended at 5 years of age, can be performed in a prophylactic attempt. The authors performed a molecular analysis to identify a mutation in a Thai woman with MEN 2A. She was found to be heterozygous for 1900T>C (C634R). The patient had two daughters who were not found to carry the mutation. The newly available genetic test for patients with MEN 2A in Thailand makes possible accurate DNA-based diagnosis of their at-risk family members before development of the disease, which has important therapeutic impacts for them.

Diagnostico precoz de neoplasia endocrina multiple tipo 2 (MEN 2) por la deteccion de portadores de mutaciones en el proto-oncogen RET / Early diagnosis of multiple endocrine neoplasia type 2 by detection of matated RET proto-oncogene carriers

El MEN 2 es un síndrome hereditario autosómico dominante, en el cual mutaciones del RET dan origen a tres fenotipos diferentes: carcinoma medular de tiroides familiar (CMTF), MEN 2A y MEN 2B. La identificación de mutaciones en el proto-oncogen RET predice el desarrollo de la enfermedad antes de las evidencias clínicas y bioquímicas. En este trabajo se identificaron portadores del RET por caracterización de mutaciones en pacientes y sus familiares. Se estudiaron 21 familias con CMTF (5 y 6 miembros), 4 con MEN 2A (dos de 5, una de 4 y otra de 3 miembros) y 2 con MEN 2B (5 y 1 miembros). Se obtuvieron muestras de ADN de sangre, en todos los casos y de tejido de feocromocitoma y/o tejido tiroideo en los operados. Se utilizó PCR para amplificar los exones 10, 11 y 16 con oligonucleótidos específicos, realizándose secuenciación directa de los fragmentos. En las familias con CMTF y con MEN 2A se encontraron mutaciones en el codón 634 del exón 11 en 16 sujetos, dectándose 9 casos con la mutación TGC r CGC (cisteína a arginina), 3 con TGC r TAC (cisteína a tirosina) y 4 con TGC r TTC (cisteína a fenilalanina). En los pacientes con MEN 2 B se encontró una mutación en el codón 918 del exón 16 ATG r ACG (meitonina a treonina). En tejido tumoral se detectó la misma mutación que en sangre periférica. El diagnóstico de MEN 2 fue confirmado en los 8 pacientes y detectado en 10 familiares. En los 5 portadores tiroidectomizados se encontró hiperplasia de células C o microcarcinoma in situ en 2 niños (9 y 12 años) y CMT en 3 adultos. La detección temprana de mutaciones del RET, especialmente en familiares seguida por tiroidectomía total, podría prevenir el desarrollo de CMT, modificado el desenlace fatal que ocurre cuando es diagnosticado tardíamente.