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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. 甲状腺髄様癌：臨床症状、診断、および病期分類 medullary thyroid cancer clinical manifestations diagnosis and staging
5. 小児における甲状腺結節および癌 thyroid nodules and cancer in children

English Journal

RET receptor in the gut of developing cat.

Lucini C, D'angelo L, de Girolamo P, Castaldo L.SourceDepartment of Biological Structures, Functions and Technology, University of Naples Federico II, 80137 Napoli, Italy. Electronic address: lucini@unina.it.
Research in veterinary science.Res Vet Sci.2013 Feb;94(1):1-4. doi: 10.1016/j.rvsc.2012.07.026. Epub 2012 Aug 13.
RET receptor is a transmembrane protein which, together with the glial-cell-line derived neurotrophic factor family receptors alpha, forms a receptor complex upon activation by the glial-cell-line-derived neurotrophic ligands (GFLs). RET signaling is crucial for: (a) development of the enteric nervo
PMID 22895155

Ultrasonography Should Not Guide the Timing of Thyroidectomy in Pediatric Patients Diagnosed with Multiple Endocrine Neoplasia Syndrome 2A through Genetic Screening.

Morris LF, Waguespack SG, Edeiken-Monroe BS, Lee JE, Rich TA, Ying AK, Warneke CL, Evans DB, Perrier ND, Grubbs EG.SourceSection of Surgical Endocrinology, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Annals of surgical oncology.Ann Surg Oncol.2013 Jan;20(1):53-9. doi: 10.1245/s10434-012-2589-7. Epub 2012 Aug 14.
BACKGROUND: American Thyroid Association (ATA) guidelines suggest that thyroidectomy can be delayed in some children with multiple endocrine neoplasia syndrome 2A (MEN2A) if serum calcitonin (Ct) and neck ultrasonography (US) are normal. We hypothesized that normal US would not exclude a final patho
PMID 22890595

Systematic use of recurrent laryngeal nerve neuromonitoring changes the operative strategy in planned bilateral thyroidectomy

Sadowski SM, Soardo P, Leuchter I, Robert JH, Triponez F.SourceUniversity Hospitals of Geneva, Endocrine and Thoracic Surgery, Rue Gabrielle-Perret-Gentil 4, Geneva, Switzerland, 1211, +41 22 372 7862; samirasadowski@hotmail.com.
Thyroid : official journal of the American Thyroid Association.Thyroid.2012 Dec 18. [Epub ahead of print]
Background: The most dreadful complication in thyroid surgery is bilateral recurrent laryngeal nerve paralysis, which can lead to transient or definitive tracheotomy. Methods: We implemented a strict standard operative procedure beginning January 2010 and modified our operative procedure: in all pa
PMID 23249377

Japanese Journal

金地病院でのMEN1型およびMEN2A型2家系の診療の現況

神森眞,中山智祥,小野瀬裕之,石井新哉,岡本高宏,山田哲
内分泌外科 = Endocrine surgery 26(4), 201-207, 2009-12-30
NAID 10026329308

Parathyroid Gland Preservation in situ versus Total Parathyroidectomy with Autotransplantation in Patients at Risk of MEN2A

MACHENS ANDREAS,DRALLE HENNING
Endocrine journal 56(4), 633, 2009-07-20
NAID 10026914407

Related Pictures

★リンクテーブル★

国試過去問	「104A044」
リンク元	「多発性内分泌腫瘍症」「多発性内分泌腫瘍症2A型」「MEN 2」「MEN IIA」
関連記事	「MEN2」「MEN」

「104A044」

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

　　[★]

48歳の男性。動悸、頭痛および発汗を主訴に来院した。1年前の健康診断で高血圧を指摘されたが、放置していた。身長168cm、体重69kg。体温36.8℃。脈拍88/分、整。血圧168/104mmHg。血液生化学所見:Na 142mEq/l、K 4.5mEq/l、尿中アドレナリン 102μg/日(基準1-23)。腹部単純CTで副腎部に4×6cmの腫瘤を認める。

検査として有用なのはどれか。 2つ選べ。

[正答]

※国試ナビ4※　［104A043］←［国試_104］→［104A045］

「多発性内分泌腫瘍症」

　　[★]

英: multiple endocrine neoplasia, MEN
同: 多発性内分泌腫瘍、多発性内分泌腺腫; 多発性内分泌腫瘍症候群多発性内分泌腺腫症候群 multiple endocrine neoplasia syndrome
関: [[]]

[show details]

多発性内分泌腺腫症候群 : 13 件
多発性内分泌腫瘍症候群 : 約 11,000 件
多発性内分泌腫瘍症 : 約 84,800 件
多発性内分泌腺腫症 : 約 108,000 件

first aid step1 2006 p.253,254,255,257,294,427,428,,,,,,

遺伝形式はすべて常染色体優性遺伝

多発性内分泌腫瘍症1型：MEN1 　：腫瘍はPPP　：原因遺伝子はMEN1遺伝子。
多発性内分泌腫瘍症2A型：MEN2A 　：腫瘍はTPA：原因遺伝子はRET遺伝子。
多発性内分泌腫瘍症2B型：MEN2B 　：腫瘍はT　AN：原因遺伝子はRET遺伝子。

型	遺伝形式	疾患内分泌腺	腫瘍	発生頻度	関連疾患
MEN 1 (Wermer症候群)	常染色体優性遺伝	下垂体	下垂体腺腫	16-66%	腸管カルチノイド、脂肪腫(～10%)、平滑筋腫、副腎皮質腫瘍(～40%)、甲状腺腺腫(26%)
		副甲状腺	副甲状腺過形成副甲状腺腺腫	90-97%
		膵臓	膵島腫	30-80%
MEN 2A (Sipple症候群)		甲状腺	甲状腺髄様癌	60-95%	皮膚苔癬アミロイドーシス
		副甲状腺	副甲状腺過形成	10-25%
		副腎	褐色細胞腫	5-64%
MEN 2B		甲状腺	甲状腺髄様癌	100%	Marfan様体型およびそのほかの骨格異常(85-94%)、多発神経腫(粘膜神経腫あるいは節神経腫)(100%)
MEN 2B		副腎	褐色細胞腫	50%	Marfan様体型およびそのほかの骨格異常(85-94%)、多発神経腫(粘膜神経腫あるいは節神経腫)(100%)
FMTC		甲状腺	甲状腺髄様癌	100%

「多発性内分泌腫瘍症2A型」

　　[★]

英: multiple endocrine neoplasia type 2A, MEN-2A, MEN2A, MEN IIA
同: シップル症候群 Sipple症候群 Sipple syndrome Sipple's syndrome
関: 多発性内分泌腫瘍症、多発性内分泌腫瘍症2型、多発性内分泌腫瘍症2B型

腫瘍はTPA

病因

RET遺伝子の変異：gain-of function mutaion in the prooncogene RET on chromosome 10

遺伝

常染色体優性遺伝

症候

型	疾患内分泌腺	腫瘍	発生頻度	関連疾患
MEN 2A (Sipple症候群)	甲状腺	甲状腺髄様癌	60-95%	皮膚苔癬アミロイドーシス
	副甲状腺	副甲状腺過形成	10-25%
	副腎	褐色細胞腫	5-64%

甲状腺髄様癌 60-95%
副甲状腺過形成 10-25%：MEN 1よりは頻度が低く、高カルシウム血症の頻度が比較的低い(MEN 1の場合は副甲状腺過形成/腺腫がほぼ必発)。
褐色細胞腫 5-64%
皮膚苔癬アミロイドーシス

治療

褐色細胞腫の切除を先行させてから、甲状腺全摘を行いなさい！！　→　なんで？クリーゼが起こりやすいとかかいてあるけど。甲状腺ホルモンはコルチゾールの異化亢進させるから、甲状腺機能低下症と副腎機能不全が共存する場合、コルチゾールの補充を先行させなさいとあった。これは甲状腺ホルモンの投与によりコルチゾールが減少して副腎クリーゼを誘発しまうからだが。MEN2Aの場合はどうなの？