Multiple endocrine neoplasia type 2 (MEN2)

2001-01-01 Sophie Giraud Affiliation

Laboratoire de Génétique, Hôpital E. Herriot, 69437 Lyon cedex 03, France

Identity

Name

Alias

Sipple syndrome , Gorlin syndrome (not to be confused with the Gorlin-Goltz\/naevoid basal cell carcinoma syndrome)

Note

Multiple Endocrine Neoplasia type 2 (MEN2) is defined by the association of C-cell tumors of the thyroid ( medullar thyroid carcinoma), tumors of the adrenal medulla ( pheochromocytoma) and parathyroid hyperplasia or adenoma in a single patient or in close relatives

Inheritance

MEN2 is an autosomal dominant disorder with a high penetrance. Expressivity is variable but phenotype-genotype correlations have been described. Incidence is estimated at 0.1\/10^{5\/year. It is generally assumed that 20 to 25% of medullar thyroid carcinomas (MTC) are heritabl}

Omim

171400

Mesh

D018813

Orphanet

653 Multiple endocrine neoplasia type 2

Umls

Clinics

Phenotype and clinics

Three subtypes have been described:

MEN2A (Sipple syndrome) is the most frequent form, characterized by MTC in 95% of cases, phaeochromocytoma in 50% and parathyroid hperplasia or adenoma in 25%.

In familial MTC (FMTC), MTC is the only clinical manifestation.

MEN2B (Gorlin syndrome) is the least frequent variant defined by predisposition to MTC and phaechromocytoma and marfanoid habitus, mucosal neuromas and ganglioneuromatosis of the gastrointestinal tract.
C-cells secrete the hormon calcitonin which is a valuable marker for early diagnosis and for following the later course of the disease. There is no obvious syndrome of calcitonin overproduction.
Pheochromocytoma secrete adrenaline and noradrenaline which are responsible of hypertension but could be undetected and lead to fatal hypertensive episodes.
Parathyroid hyperplasia or adenoma lead to hyperparathyroidism; they are often clinically silent but could be revealed by symptomatic hypercalcemia or renal stones.

Neoplastic risk

MTC is a malignant tumor, metastasizing at first locally within the neck and then to distant sites. Usually pheochromocytoma is non malignant; parathyroid hyperplasia or adenoma are benign

Treatment

Total thyroidectomy with bilateral radical lymph node dissection is the treatment of MTC. Thyroidectomy is recommended for carriers of mutations, in the first years of life in MEN2A and MEN2B families, as soon as elevation CT during pentagastrin test in FMTC families.
Pheochromocytoma, hyperplasic parathyroid or adenoma should be surgically removed.

Prognosis

Pheochromocytoma could be letal by hypertension episodes but prognosis is essentially dependant from MTC.

Genes involved and Proteins

Description

21 exons; genomic sequence of 55kb

Expression

RET is expressed predominantly in the developing central and peripheral nervous system, the excretory system and the migratory neural-crest cells during embryogenesis.

Function

Receptor tyrosine kinase

Germinal

In MEN2A and FMTC, mutations are located in the sequence encoding the juxtamembrane cystein-rich domain and involved aminoacids C609, C611, C618, C620, C630, D631 and C634. Most of these mutations result in the substitution of the cystein for a different amino acid. MEN2A is predominantly associated with a mutation of C634, highly predictive for the development of pheochromocytoma and hyperparathyroidism. Until today three duplications in the cystein-rich domain have been published.

MEN2B is caused by germline mutations of the tyrosin kinase domain: substitution M918T in more than 95% of cases, A883F in less than 4% of those. Rare mutations at aminoacids 912, 922 and an association of V804M\/Y806C have been described.

Other mutations of the tyrosin kinase domain have been identified in FMTC families and unusually in MEN2A patients: E768D, L790F, Y791F, V804M, V804L and S891A.

Some families with MEN2 and Hirschsprung disease have been described: each of them has a mutation in either C618 or C620. Families with Hirschsprung disease alone have mutations overspread in all the coding region of RET.

To be noted

Hgmd

120346

Databases

http:\/\/sf-endocrino.net\/pathologies\/cancer\/articles\/contedevolx1.html NEM2 - SFE

Article Bibliography

Pubmed ID	Last Year	Title	Authors
7356828	1980	Clinical characteristics distinguishing hereditary from sporadic medullary thyroid carcinoma. Treatment implications.	Block MA et al
8918855	1996	The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis.	Eng C et al
9067749	1997	Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours, and hirschsprung disease.	Eng C et al
9452064	1998	Duplication of 9 base pairs in the critical cysteine-rich domain of the RET proto-oncogene causes multiple endocrine neoplasia type 2A.	Höppner W et al
7906866	1994	A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma.	Hofstra RM et al
9230192	1997	Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype.	Ito S et al
10679286	2000	A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations.	Iwashita T et al
9660211	1998	Prophylactic thyroidectomy for medullary thyroid carcinoma in gene carriers of MEN2 syndrome.	Lallier M et al
9096393	1997	Development of medullary thyroid carcinoma in transgenic mice expressing the RET protooncogene altered by a multiple endocrine neoplasia type 2A mutation.	Michiels FM et al
8099202	1993	Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.	Mulligan LM et al
7491519	1995	Early treatment of hereditary medullary thyroid carcinoma after attribution of multiple endocrine neoplasia type 2 gene carrier status by screening for ret gene mutations.	Pacini F et al
10323403	1999	A novel 9-base pair duplication in RET exon 8 in familial medullary thyroid carcinoma.	Pigny P et al
10197589	1999	The phenotypes associated with ret mutations in the multiple endocrine neoplasia type 2 syndrome.	Ponder BA et al
7824936	1995	Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B.	Santoro M et al
6144286	1984	Genetic aspects of multiple endocrine neoplasia.	Schimke RN et al
8114940	1994	Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret.	Schuchardt A et al
7874109	1994	RET proto-oncogene mutations in French MEN 2A and FMTC families.	Schuffenecker I et al
2886918	1987	Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage.	Simpson NE et al
10220148	1999	Co-segregation of MEN2 and Hirschsprung's disease: the same mutation of RET with both gain and loss-of-function?	Takahashi M et al
7906865	1994	Genetics. One gene--four syndromes.	van Heyningen V et al