関: MEN 2、multiple endocrine neoplasia type 2、multiple endocrine neoplasia type II

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/09/12 00:34:01」(JST)

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Multiple endocrine neoplasia type 2 (MEN2) (also known as "Pheochromocytoma and amyloid producing medullary thyroid carcinoma",^[1] "PTC syndrome,"^[1] and "Sipple syndrome"^[1]) is a group of medical disorders associated with tumors of the endocrine system. The tumors may be benign or malignant (cancer). They generally occur in endocrine organs (e.g. thyroid, parathyroid, and adrenals), but may also occur in endocrine tissues of organs not classically thought of as endocrine.^[2]

MEN2 is a sub-type of MEN (multiple endocrine neoplasia) and itself has sub-types, as discussed below.

Classification

Before gene testing was available, the type and location of tumors determined which type of MEN2 a person had. Gene testing now allows a diagnosis before tumors or symptoms develop.

A table in the multiple endocrine neoplasia article compares the various MEN syndromes. MEN2 and MEN1 are distinct conditions, despite their similar names. MEN2 includes MEN2A, MEN2B and familial medullary thyroid cancer (FMTC).

The common feature among the three sub-types of MEN2 is a high propensity to develop medullary thyroid carcinoma.

Signs and symptoms

MEN2 can present with a sign or symptom related to a tumor or, in the case of multiple endocrine neoplasia type 2b, with characteristic musculoskeletal and/or lip and/or gastrointestinal findings.

Medullary thyroid carcinoma (MTC) represent the most frequent initial diagnosis. Occasionally pheochromocytoma and primary hyperparathyroidism may be the initial diagnosis.

Pheochromocytoma occurs in 50% of cases.^[3]

In MEN2A primary hyperparathyroidism occurs in only 10–30% and is usually diagnosed after the third decade of life. It can occur in children but this is rare. It may be the sole clinical manifestation of this syndrome but this is unusual.

MEN2A associates medullary thyroid carcinoma with pheochromocytoma in about 20–50% of cases and with primary hyperparathyroidism in 5–20% of cases.

MEN2B associates medullary thyroid carcinoma with pheochromocytoma in 50% of cases, with marfanoid habitus and with mucosal and digestive neurofibromatosis.

In familial isolated medullary thyroid carcinoma the other components of the disease are absent.

In a review of 85 patients 70 had Men2A and 15 had Men2B.^[4] The initial manifestation of MEN2 was medullary thyroid carcinoma in 60% of patients, medullary thyroid carcinoma synchronous with pheochromocytoma in 34% and pheochromocytoma alone in 6%. 72% had bilateral pheochromocytomas.

Management

Management of MEN2 patients includes thyroidectomy including cervical central and bilateral lymph nodes dissection for MTC, unilateral adrenalectomy for unilateral pheochromocytoma or bilateral adrenalectomy when both glands are involved and selective resection of pathologic parathyroid glands for primary hyperparathyroidism.

Familial genetic screening is recommended to identify at risk subjects who will develop the disease, permitting early management by performing prophylactic thyroidectomy, giving them the best chance of cure.

Prognosis of MEN2 is mainly related to the stage-dependant prognosis of MTC indicating the necessity of a complete thyroid surgery for index cases with MTC and the early thyroidectomy for screened at risk subjects.

Causes

The table in the multiple endocrine neoplasia article lists the genes involved in the various MEN syndromes. Most cases of MEN2 derive from a variation in the RET proto-oncogene, and are specific for cells of neural crest origin. A database of MEN" implicated RET mutations is maintained by the University of Utah Department of Physiology.^[5]

The protein produced by the RET gene plays an important role in the TGF-beta (transforming growth factor beta) signaling system. Because the TGF-beta system operates in nervous tissues throughout the body, variations in the RET gene can have effects in nervous tissues throughout the body.

MEN2 generally results from a gain-of-function variant of a RET gene. Other diseases, such as Hirschsprung disease, result from loss-of-function variants. OMIM #164761 lists the syndromes associated with the RET gene.

Genetics

Most cases of multiple endocrine neoplasia type 2 are inherited in an autosomal dominant pattern.

When inherited, multiple endocrine neoplasia type 2 is transmitted in an autosomal dominant pattern, which means affected people have one affected parent, and possibly-affected siblings and children. Some cases, however, result from spontaneous new mutations in the RET gene. These cases occur in people with no family history of the disorder. In MEN2B, for example, about half of all cases arise as spontaneous new mutations.

Differences in presentation

As noted, all types of MEN2 include pheochromocytoma and medullary thyroid carcinoma.

MEN2A is additionally characterized by the presence of parathyroid hyperplasia.

MEN2B is additionally characterized by the presence of mucocutaneous neuroma, gastrointestinal symptoms (e.g. constipation and flatulence), and muscular hypotonia.

MEN2B can present with a Marfanoid habitus.^[6]

References

^ ^a ^b ^c Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0.
^ Moline J, Eng C. (2011). "Multiple endocrine neoplasia type 2: an overview.". Genet Med. 9 (13): 755–64. doi:10.1097/GIM.0b013e318216cc6d. PMID 21552134.
^ Thosani S, Ayala-Ramirez M, Palmer L, Hu MI, Rich T, Gagel RF, Cote G, Waguespack SG, Habra MA, Jimenez C (2013) The characterization of pheochromocytoma and its impact on overall survival in Multiple Endocrine Neoplasia type 2. J Clin Endocrinol Metab
^ Thosani S, Ayala-Ramirez M, Palmer L, Hu MI, Rich T, Gagel RF, Cote G, Waguespack SG, Habra MA, Jimenez C (2013) The characterization of pheochromocytoma and its impact on overall survival in Multiple Endocrine Neoplasia type 2. J Clin Endocrinol Metab
^ "MEN2 Database". University of Utah.
^ Wray CJ, Rich TA, Waguespack SG, Lee JE, Perrier ND, Evans DB (January 2008). "Failure to recognize multiple endocrine neoplasia 2B: more common than we think?". Ann. Surg. Oncol. 15 (1): 293–301. doi:10.1245/s10434-007-9665-4. PMID 17963006.

External links

MEN2 (RET) gene variant database
GeneReview/NIH/UW entry on Multiple Endocrine Neoplasia Type 2
The Association for Multiple Endocrine Neoplasia Disorders (AMEND)

UpToDate Contents

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1. 多発性内分泌腫瘍2型の臨床症状および診断 clinical manifestations and diagnosis of multiple endocrine neoplasia type 2
2. 多発性内分泌腫瘍2型の治療のアプローチ approach to therapy in multiple endocrine neoplasia type 2
3. 多発性内分泌腫瘍2型の分類および遺伝学 classification and genetics of multiple endocrine neoplasia type 2
4. 遺伝的疾患における褐色細胞腫 pheochromocytoma in genetic disorders
5. 褐色細胞腫の臨床症状および診断 clinical presentation and diagnosis of pheochromocytoma

English Journal

Assessing the effect of RET Transmembrane Domain Mutations in receptor self-association capability using the in vivo TOXCAT System.

Benej M, Fekecsova S, Poturnajova M.AbstractMutations of c-RET proto-oncogene with a unique localization within the human transmembrane receptor represent a challenge for contemporary molecular oncology techniques. RET transmembrane domain (TMD)-driven dimerization of the receptor leads to its permanent activation that eventually results in the development of medullary thyroid neoplasia. In this study, we describe the employment of the TOXCAT system which enables to investigate mutation-induced alterations in the strength of RET TMD dimerization in vivo. We suggest an improvement of the method by adding reporter gene quantification at the mRNA levels as a support to the commonly used reporter protein level. We have investigated possible changes in RET TMD dimerization in case of two germline RET TMD mutations found in in several individual cases and MEN2 families worldwide, p.Ala641Ser and p.Ser649Leu. According to our results, substitution of Ser-649 residue by leucine, found as a result of germline mutation, caused a significant decrease of RET TMD self-association in comparison to RET wild-type transmembrane domain. The impaired ability of self-association suggests a novel, yet unknown mechanism of tyrosine kinase domain activation, possibly independent of RET homodimerization. Keywords: RET mutation, transmembrane domain, molecular oncology, TOXCAT system, oncoprotein dimerization.
Neoplasma.Neoplasma.2013;60(1):111-20. doi: 10.4149/neo_2013_015.
Mutations of c-RET proto-oncogene with a unique localization within the human transmembrane receptor represent a challenge for contemporary molecular oncology techniques. RET transmembrane domain (TMD)-driven dimerization of the receptor leads to its permanent activation that eventually results
PMID 23067224

Acquired hypermethylation of the P16INK4A promoter in abdominal paraganglioma: relation to adverse tumor phenotype and predisposing mutation.

Kiss NB, Muth A, Andreasson A, Juhlin CC, Geli J, Bäckdahl M, Höög A, Wängberg B, Nilsson O, Ahlman H, Larsson C.SourceN Kiss, Cancer Centre Karolinska, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
Endocrine-related cancer.Endocr Relat Cancer.2012 Nov 15. [Epub ahead of print]
Recurrent alterations in promoter methylation of tumor suppressor genes (TSG) and LINE-1 repeat elements were previously reported in pheochromocytoma and abdominal paraganglioma. The present study was undertaken to explore CpG methylation abnormalities in an extended tumor panel, and assess possible
PMID 23154831

Japanese Journal

4. 多発性内分泌腫瘍症2型集計結果(<特集>内分泌外科稀少疾患の日本の現状把握と診療指針の作成)

内野眞也
日本外科学会雑誌 113(4), 362-367, 2012-07-01
NAID 110009479953

2. 多発性内分泌腫瘍症研究コンソーシアム(<特集>内分泌外科稀少疾患の日本の現状把握と診療指針の作成)

櫻井晃洋
日本外科学会雑誌 113(4), 351-355, 2012-07-01
NAID 110009479951

Related Pictures

★リンクテーブル★

リンク元	「褐色細胞腫」「多発性内分泌腫瘍症2型」「MEN 2」
拡張検索	「MEN2B」「MEN2A」
関連記事	「ME」「MEN」

「褐色細胞腫」

MEN type 2A (Sipple syndrome)
	Bilateral pheochromocytomas associated with Multiple endocrine neoplasia type 2
Classification and external resources
Specialty	oncology
ICD-10	D44.8
ICD-9-CM	258.02
OMIM	171400
DiseasesDB	7984
MedlinePlus	000399
eMedicine	med/1520
MeSH	D018813
GeneReviews	Multiple Endocrine Neoplasia Type 2;

　　[★]

英: pheochromocytoma PC, phaeochromocytoma
同: クロム親和細胞腫 chromaffin cell tumor chromaffinoma
関: 副腎外褐色細胞腫、傍神経節腫 paraganglioma。アドレナリン受容体

概念

副腎髄質や傍神経節などのクロム親和性細胞から発生する腫瘍。
カテコールアミン分泌する

病型

臨床像：発作型・持続型
腫瘍発生様式：散発性、家族性(10%)　：　:*家族性発生のものはMEN2の可能性あり。
発生部位：副腎原発(90%)(片側性、両側性(10%))、副腎外発生(10%)
腫瘍の数：単発性、多発性(10%)
腫瘍の正常：良性、悪性(10%)

病因

10% disease

embfc　←　なんか適当な語呂にして

extraadrenal：副腎外10%
malignancy：悪性10%
bilateral：両側10%
familial：家族性10%
child：小児10%

疫学

20-40歳

遺伝形式

常染色体優性遺伝

原因となる遺伝子

Location	Phenotype	Phenotype	Gene/Locus	Gene/Locus
Location	Phenotype	MIM number	Gene/Locus	MIM number
1p36.22	Pheochromocytoma	171300	KIF1B	605995
1p36.13	Pheochromocytoma	171300	SDHB	185470
2q11.2	{Pheochromocytoma, susceptibility to}	171300	TMEM127	613403
3p25.3	Pheochromocytoma	171300	VHL	608537
5p13.2	{Pheochromocytoma, modifier of}	171300	GDNF	600837
10q11.21	Pheochromocytoma	171300	RET	164761
11q23.1	Pheochromocytoma	171300	SDHD	602690
14q23.3	{Pheochromocytoma, susceptibility to}	171300	MAX	154950