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.

Figure 1

Characteristic phenotype of MEN 2B including thickened lips with bumps.

Figure 2

Multiple pseudo-polyps and bumps on the tongue. The lesions are mucous ganglioneurofibromas and ganglioneuromas.

Figure 3

The first toe is longer than the others and there is a wide space between the first and second toe.

Figure 4

Enzymo-histochemical studies of MEN 2B intestinal innervation performed by acetylcholinesterase on suction rectal biopsies: giant ganglioneurofibroma. SM = submucous layer; AChE = acetylcholinesterase.

Figure 5

Enzymo-histochemical studies of MEN 2B intestinal innervation performed by acetylcholinesterase on suction rectal biopsies: multiple ganglioneuromas and ganglioneurofibromas are brown stained. SM = submucous layer.

Figure 6

Total thyroidectomy for a MEN 2B patient 3 years old. Macroscopic evidence of carcinoma in the right lobe. Homolateral lymphadectomy together with central compartment lymphadectomy has to be performed during thyroidectomy.