MEN 2

MEN 2A and MEN 2B

Introduction of MEN 2A and MEN 2B
In MEN 2A, virtually all patients have MTC, 50% pheochromocytoma, and approximately 15% HPT. Variants include MEN 2A with cutaneous lichen amyloidosis, and MEN 2A with Hirschsprung´s disease.

The MEN-2B syndrome is rare, consists of MTC, pheochromocytoma in approximately 50%, and developmental abnormalities with Marfanoid habitus, tall slender body and long extremities, thick lips, and mucosal neuromas. Characteristic mucosal neuromas cover the anterior tongue, lips, buccal mucosa, conjunctiva and eyelids. Gastrointestinal complaints due to intestinal ganglioneuromatosis with obstipation and megacolon are common.
The MTC is aggressive in MEN 2B, often develops already during the first years of life, with mean age at diagnosis of around 16 years. Extensive local spread and metastases from the thyroid carcinoma have been the common cause of death. Most patients represent de novo mutations where no other cases in the family can be recognized.
The MEN-2 genetic syndrome also comprises cases with only familial MTC (FMTC) without evidence of other endocrinopathies.

Genetics of MEN 2A and MEN 2B
MEN-2 patients have germ-line mutations in the RET protooncogene, located on chromosome 10q11.2, encoding a tyrosine kinase receptor, with important role for growth differentiation. RET with 21 exons, has six “hot-spot” exons in the extracellular or the intracellular domains, where mutations occur in more than 97% of MEN-2 patients.

Extracellular mutations: Mutations in codon 634, exon 10 of RET account for 75-85% of all mutations in MEN 2 and hereditaryMTC, and is most commonly associated with the classical MEN 2A. (MEN 2A and cutaneous lichen amyloidosis occurs with the 634 mutation). Mutations of codon 609, 611, 618 and 620 constitute an additional ~10% of mutations in MEN 2A. Mutations of these codons and codon 630 will most commonly cause FMTC, but may also lead to MEN 2A. MEN 2A and Hirschsprung´s disease has occurred with 609, 618 and 620 mutations.

Intracellular mutations: The most common intracellular mutation is codon 918 of exon 16 in the thyrosine kinase domain, found in more than 95% of patients with MEN 2B. A smaller proportion of MEN-2B patients have codon 883 mutations. Mutations at codon 790 and 804 of the intracellular domain have been associated with MEN 2A.

In hereditary MTC, the specific mutated codon of RET correlates with the familial pattern of disease and the aggressiveness of the MTC. On basis of reported age of disease onset and its aggressiveness, recommendations have been made regarding the optimal age for thyroidectomy.

Level 1 – least high risk:
RET codons 768, 790, 791, 804, 891. Usually grows more slowly, develops at later age, can have nodal metastases, be fatal (except 790, 791), total thyroidectomy is recommended at age 5-10 years.

Level 2 – high risk of MTC
RET codons 609, 611, 618, 620, 630, 634. Total thyroidecomy ± central node dissection is recommended by age 5 years.

Level 3 – highest risk/aggressive MTC:
RET codons 883, 918, 922. Thyroidectomy is recommended within 1-6 months of life, metastases have been documented during first year of life.