Multiple endocrine neoplasias type 2B and RET proto-oncogene

Abstract

Multiple Endocrine Neoplasia type 2B (MEN 2B) is an autosomal dominant complex oncologic neurocristopathy including medullary thyroid carcinoma, pheochromocytoma, gastrointestinal disorders, marphanoid face, and mucosal multiple ganglioneuromas. Medullary thyroid carcinoma is the major cause of mortality in MEN 2B syndrome, and it often appears during the first years of life. RET proto-oncogene germline activating mutations are causative for MEN 2B. The 95% of MEN 2B patients are associated with a point mutation in exon 16 (M918/T). A second point mutation at codon 883 has been found in 2%-3% of MEN 2B cases. RET proto-oncogene is also involved in different neoplastic and not neoplastic neurocristopathies. Other RET mutations cause MEN 2A syndrome, familial medullary thyroid carcinoma, or Hirschsprung's disease. RET gene expression is also involved in Neuroblastoma. The main diagnosis standards are the acetylcholinesterase study of rectal mucosa and the molecular analysis of RET. In our protocol the rectal biopsy is, therefore, the first approach. RET mutation detection offers the possibility to diagnose MEN 2B predisposition at a pre-clinical stage in familial cases, and to perform an early total prophylactic thyroidectomy. The surgical treatment of MEN 2B is total thyroidectomy with cervical limphadenectomy of the central compartment of the neck. When possible, this intervention should be performed with prophylactic aim before 1 year of age in patients with molecular genetic diagnosis. Recent advances into the mechanisms of RET proto-oncogene signaling and pathways of RET signal transduction in the development of MEN 2 and MTC will allow new treatment possibilities.

Presence of the RET Cys634Tyr mutation and Gly691Ser functional polymorphism in Iranian families with multiple endocrine neoplasia type 2A

“…2,10,11 Genetic analysis of the RET proto-oncogene can be performed in those families affected by MEN2A and MEN2B, in cases of sporadic MTC or HSCR, and allows exact molecular diagnosis of the disease. 12 To the best of our knowledge, this study is the first report of genetic screening of families of the Eastern region of Iran for identification of MEN2A families. We checked all mutation hotspots of the RET proto-oncogene in exons 11, 10, 13, and 8 by direct sequencing to produce reliable results.…”

A comprehensive review on MEN2B

“…Other signs: Other associations have also been reported in MEN2B, including coarse facies, tooth malposition, abnormal feet with a long first toe and an increased space between the 1st and the 2nd toe (Martucciello et al 2012). Underweight, chronic pain and asthenia and delayed puberty can also be seen.…”

Neural crest cells: From developmental biology to clinical interventions

“…Forty years ago, Bolande () divided neurocristopathies to simple and complex ones including those with syndromic features. A modification presented by Martucciello et al () adds the possible neoplastic component to both categories. Examples of simple neurocristopathies include albinism and Hirschsprung's disease, whereas neuroblastoma and pheochromocytoma represent examples of simple neurocristopathies with a neoplastic component.…”

“…Examples of simple neurocristopathies include albinism and Hirschsprung's disease, whereas neuroblastoma and pheochromocytoma represent examples of simple neurocristopathies with a neoplastic component. Complex neurocristopathies include entities such as neurofibromatosis and multiple endocrine neoplasias 2 and 3 (Martucciello et al ). However, the above classifications do not include craniofacial syndromes of neural crest origin; neural crest‐derived tissues and cells are also frequently affected in Down syndrome, and in animal studies ethanol has been shown to affect cranial neural crest cells with a possible link to human fetal alcohol syndrome (Cartwright and Smith, ).…”