Cancer prone diseases
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Multiple endocrine neoplasia type 2 (MEN2)
Laboratoire de Génétique, Hôpital E. Herriot, 69437 Lyon cedex 03, France
Multiple endocrine neoplasia type 2 (MEN2)
Sipple syndrome , Gorlin syndrome (not to be confused with the Gorlin-Goltz\/naevoid basal cell carcinoma syndrome)
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
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
653 Multiple endocrine neoplasia type 2
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.
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
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.
Pheochromocytoma could be letal by hypertension episodes but prognosis is essentially dependant from MTC.
Genes involved and Proteins
21 exons; genomic sequence of 55kb
RET is expressed predominantly in the developing central and peripheral nervous system, the excretory system and the migratory neural-crest cells during embryogenesis.
Receptor tyrosine kinase
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
http:\/\/sf-endocrino.net\/pathologies\/cancer\/articles\/contedevolx1.html NEM2 - SFE
Clinical characteristics distinguishing hereditary from sporadic medullary thyroid carcinoma. Treatment implications.
Block MA et al
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
Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours, and hirschsprung disease.
Eng C et al
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
A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma.
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Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype.
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A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations.
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Prophylactic thyroidectomy for medullary thyroid carcinoma in gene carriers of MEN2 syndrome.
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Development of medullary thyroid carcinoma in transgenic mice expressing the RET protooncogene altered by a multiple endocrine neoplasia type 2A mutation.
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Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.
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Early treatment of hereditary medullary thyroid carcinoma after attribution of multiple endocrine neoplasia type 2 gene carrier status by screening for ret gene mutations.
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Co-segregation of MEN2 and Hirschsprung's disease: the same mutation of RET with both gain and loss-of-function?
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Genetics. One gene--four syndromes.
van Heyningen V et al
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