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- What is RET proto-oncogene?
RET (REarranged during Transfection) proto-oncogene is the only gene known
to be associated with MEN2 syndrome. This gene is located on chromosome
10q11.2 and encodes receptor tyrosine kinase family. Constitutive activation of
this receptor and consequent downstream signaling result in unrestricted cell
growth and proliferation. Cells-derived from the neural crest, branchial arch,
and urogenital system express RET proto-oncogene. Gain-of-function muta-
tions of RET proto-oncogene result in tumorigenesis in these organs. Almost all
patients with MEN2A, MEN2B, and FMTC have RET proto- oncogene
germ-line mutations, and approximately 50 % of patients with sporadic MTC
have somatic RET mutations.- Who should undergo genetic testing for RET proto-oncogene?
Genetic testing for RET mutations should be offered to the following
individuals:
(a) Patient with isolated MTC at any age
(b) Patient with two of the following endocrine organ involvement (e.g., MTC,
PHPT, or pheochromocytoma)
(c) Patients with familial MTC
(d) First-degree relatives of patients with MEN 2
(e) Children with phenotype of MEN2B
(f) Patients with cutaneous lichen amyloidosis (CLA) and Hirschsprung
disease (HD)
(g) Patients with intestinal ganglioneuromatosis- How to suspect MEN 2B syndrome?
Early age of onset (infancy) and aggressive disease at presentation are the usual
features of MTC associated with MEN2B. MTC occurs in all patients with
MEN2B. Approximately, three-fourths of patients with MEN2B are sporadic,
while the rest are familial. However, all affected individuals have RET muta-
tions. Pheochromocytomas occur in approximately 50 % of individuals and are
often bilateral, which may be synchronous or metachronous. Parathyroid ade-
noma/hyperplasia virtually does not occur in MEN2B. Nevertheless, the other
characteristic features which help in recognition of MEN2B syndrome during
infancy and early childhood include mucosal neuromas, narrow long facies,
marfanoid habitus, kyphoscoliosis, and slipped capital femoral epiphysis
(Fig. 11.5).11 Multiple Endocrine Neoplasia