Multiple endocrine neoplasia

Template:Short description Template:MOS Template:Infobox medical condition (new) Multiple endocrine neoplasia (abbreviated MEN) is a condition which encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign. Benign or malignant tumors of nonendocrine tissues occur as components of some of these tumor syndromes.

MEN syndromes are inherited as autosomal dominant disorders.<ref>Template:DorlandsDict</ref>

Presentation

Related conditions

Although not officially categorized as multiple endocrine neoplasia syndromes, Von Hippel–Lindau disease<ref name="pmid9681839">Template:Cite journal</ref> and Carney complex<ref name="pmid18672144">Template:Cite journal</ref> are two other autosomal dominant endocrine tumor syndromes with features that overlap the clinical features of the MEN syndromes. Although not transmitted in the germline, McCune–Albright syndrome is a genetic disorder characterized by endocrine neoplastic features involving endocrine glands that overlap with those involved in MEN1 or MEN2.<ref>Template:Cite book</ref>

Comparison

Percentages in the table below refer to the percentage of people with the MEN type who develop the neoplasia type.

Feature	MEN 1	MEN 2
		MEN 2A	MEN 2B	FMTC
Eponym	Wermer syndrome	Sipple syndrome	Wagenmann–Froboese syndrome	(none)
OMIM	none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 131100	none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 171400	none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 162300	none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 155240
Pancreatic tumors	gastrinoma (50%<ref name=agabegi2nd4-7/>), insulinoma (20%<ref name=agabegi2nd4-7/>), VIPoma, glucagonoma, PPoma	-	-	-
Pituitary adenoma	66%<ref name=agabegi2nd4-7>Table 4-7 in:Template:Cite book</ref>	-	-	-
Angiofibroma	64%*<ref name=Asgharian>Template:Cite journal</ref>	-	-	-
Lipoma	17%*<ref name=Asgharian />	-	-	-
Parathyroid hyperplasia	90%<ref name=agabegi2nd4-7/>	50%<ref name=agabegi2nd4-7/>	-	-
Medullary thyroid carcinoma	-	100%<ref name=agabegi2nd4-7/>	85%<ref name=agabegi2nd4-7/>	100%
Pheochromocytoma	-	>33%<ref name=agabegi2nd4-7/>	50%	-
Marfanoid body habitus	-	-	80%	-
Mucosal neuroma	-	-	100%<ref name=agabegi2nd4-7/>	-
Gene(s)	MEN1 ({{#ifeq:none|none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 613733)	RET ({{#ifeq:none|none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 164761)	RET ({{#ifeq:none|none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 164761)	RET ({{#ifeq:none|none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 164761), NTRK1 ({{#ifeq:none|none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 191315)
Approx. prevalence	1 in 35,000 (1 in 20,000 to 1 in 40,000)<ref>[1] Template:Webarchive 123I labeled metaiodobenzylguanidine for diagnosis of neuroendocrine tumors. Jiang L, Schipper ML, Li P, Cheng Z, Reports in Medical Imaging. 2009: 2 79-89</ref>	1 in 40,000<ref>Template:Cite journal</ref>	1 in 1,000,000 (1 in 600,000<ref>Template:Cite book</ref> to 1 in 4,000,000<ref>Template:Cite journal</ref>)<ref>Template:Cite book - Chapter: Multiple Endocrine Neoplasia Type 2B by Electron Kebebew, Jessica E. Gosnell and Emily Reiff. Pages 695-701. [2] This reference quotes a prevalence of 1 in 40,000, but this figure is inconsistent with the same reference's calculated incidence of 4 per 100 million per year for MEN2B.</ref>
Initial description (year)	1954<ref>Template:Cite journal</ref>	1961<ref>Template:Cite journal</ref>	1965

*- of patients with MEN1 and gastrinoma

FMTC = familial medullary thyroid cancer

File:Medullary thyroid carcinoma - 2 - high mag.jpg

Micrograph of a medullary thyroid carcinoma, as may be seen in MEN 2A and MEN 2B. H&E stain

MEN 2B is sometimes known as MEN 3 and the designation varies by institution (cf. www.ClinicalReview.com). Although a variety of additional eponyms have been proposed for MEN2B (e.g. Williams-Pollock syndrome, Gorlin-Vickers syndrome, and Wagenmann–Froboese syndrome), none ever gained sufficient traction to merit continued use and, indeed, are all but abandoned in the medical literature. Another early report was Schimke et al. in 1968.<ref>Template:Cite journal</ref>

OMIM also includes a fourth form of multiple endocrine neoplasia ("MEN4"), associated with CDKN1B.<ref>{{#ifeq:|none||{{#switch: | short = OMIM: | shortlink = OMIM: | plain = Online Mendelian Inheritance in Man: | full | #default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if:MULTIPLE ENDOCRINE NEOPLASIA, TYPE IV; MEN4 |MULTIPLE ENDOCRINE NEOPLASIA, TYPE IV; MEN4 - }} 610755</ref> The presentation is believed to overlap that of MEN1 and MEN2.<ref name="pmid17030811">Template:Cite journal</ref>

Multiple Endocrine Neoplasia Type 1 (MEN1)

The MEN1 gene

The MEN1 gene consists of ten exons, spanning about 10 kb, and encodes a 610 amino acid protein named menin. The first exon and the last part of exon 10 are not translated. The main transcript of 2.8 kb has been described in a large variety of human tissues (pancreas, thymus, adrenal glands, thyroid, testis, leukocytes, heart, brain, lung, muscle, small intestine, liver, and kidney); an additional transcript of approximately 4 kb has been detected in pancreas and thymus, suggesting tissue-specific alternative splicing.<ref name="auto">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

The Menin Protein

Menin is a 610 amino acid (67Kda) nuclear protein, highly conserved from mouse (98%), rat (97%) and, more distantly, zebrafish (75%) and Drosophila (47%) (47-51). Human and mouse MEN1 amino acid sequences share 95.8% identity and 98.4% similarity. Analysis of menin amino acid sequence did not reveal homologies to any other known human or mammalian protein, sequence motif, or signal peptide. The absence of significant homology to any other protein complicates efforts to elucidate the functions of menin.Template:Citation needed

Pathophysiology

MEN1 follows Knudson's “two-hit” model for tumor suppressor gene carcinogenesis (30). The first hit is a heterozygous MEN1 germline mutation, inherited from one parent (familial cases) or developed in an early embryonic stage (sporadic cases) and present in all cells at birth. The second hit is a MEN1 somatic mutation, usually a large deletion, that occurs in the predisposed endocrine cell as loss of the remaining wild-type allele and gives cells the survival advantage needed for tumor development.<ref name="auto"/>

Mnemonic

A useful mnemonic to remember the associated neoplasias is below:

MEN I (3 Ps) - Pituitary, Parathyroid, Pancreatic
MEN IIa (2Ps, 1M) - Pheochromocytoma, Parathyroid, Medullary Thyroid Ca
MEN IIb (1P, 2Ms) - Pheochromocytoma, Medullary Thyroid Ca, Marfanoid habitus/mucosal neuroma

MEN1 mutations in multiple endocrine neoplasia patients and clinical genetics

MEN1 gene mutations can be identified in 70–95% of MEN1 patients and in about 20% of familial isolated hyperparathyroidism cases. Almost all patients are heterozygous for mutations. One affected family has been identified with individuals both homozygous and heterozygous for MEN1 mutations. In this family, there was no difference in disease history between the homozygous and heterozygous mutation carriers.<ref name="auto"/>

50% of patients develop signs and symptoms by 20 years of age and more than 95% have symptoms by 40 years of age. There is significant intra- and inter-familial variability in the age of onset, the severity of disease, and tumor types. Despite numerous studies, no genotype-phenotype correlations have been established, suggesting that unknown genetic and environmental modifiers are involved in the expression of the MEN1 phenotype.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Manifestations

Multiple Endocrine Neoplasia type 1 (MEN1) is a rare hereditary endocrine cancer syndrome characterized primarily by tumors of the parathyroid glands (95% of cases), endocrine gastroenteropancreatic (GEP) tract (30–80% of cases), and anterior pituitary (15–90% of cases).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Other endocrine and non-endocrine neoplasms including adrenocortical and thyroid tumors, visceral and cutaneous lipomas, meningiomas, facial angiofibromas and collagenomas, and thymic, gastric, and bronchial carcinoids also occur. The phenotype of MEN1 is broad, and over 20 different combinations of endocrine and non-endocrine manifestations have been described. MEN1 should be suspected in patients with an endocrinopathy of two of the three characteristic affected organs, or with an endocrinopathy of one of these organs plus a first-degree relative affected by MEN1 syndrome.Template:Citation needed

MEN1 patients usually have a family history of MEN1. Inheritance is autosomal dominant; any affected parent has a 50% chance to transmit the disease to his or her progeny. MEN1 gene mutations can be identified in 70–95% of MEN1 patients.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Many endocrine tumors in MEN1 are benign and cause symptoms by overproduction of hormones or local mass effects, while other MEN1 tumors are associated with an elevated risk for malignancy. About one-third of patients affected with MEN1 will die early from MEN1-related cancer or associated malignancy. Entero-pancreatic gastrinomas and thymic and bronchial carcinoids are the leading cause of morbidity and mortality. Consequently, the average age of death in untreated individuals with MEN1 is significantly lower (55.4 years for men and 46.8 years for women) than that of the general population.Template:Citation needed

Recommended cancer surveillance

A recommend surveillance program for Multiple Endocrine Neoplasia Type 1 has been suggested by the International Guidelines for Diagnosis and Therapy of MEN syndromes group.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

History

In 1903 Erdheim described the case of an acromegalic patient with a pituitary adenoma and three enlarged parathyroid glands.<ref>Brandi ML, Gagel RF, Angeli A, et al. Multiple Endocrine Neoplasia Type 1: Clinical and Genetic Features of the Disease. *Endocrine Reviews*. 2001;22(6):667-707. doi:10.1210/edrv.22.6.0447</ref>

In 1953 Underdahl et al. reported a case series of 8 patients with a syndrome of pituitary, parathyroid, and pancreatic islet adenomas.<ref>Marx SJ. Multiple Endocrine Neoplasia Type 1. *The New England Journal of Medicine*. 2000;342(19):1619-1627. doi:10.1056/NEJM200005113421907</ref>

In 1954 Wermer noted that this syndrome was transmitted as a dominant trait.<ref>Brandi ML, Gagel RF, Angeli A, et al. Multiple Endocrine Neoplasia Type 1: Clinical and Genetic Features of the Disease. *Endocrine Reviews*. 2001;22(6):667-707. doi:10.1210/edrv.22.6.0447</ref>

In 1959 Hazard et al. described medullary (solid) thyroid carcinoma.<ref>Marx SJ. Multiple Endocrine Neoplasia Type 1. *The New England Journal of Medicine*. 2000;342(19):1619-1627. doi:10.1056/NEJM200005113421907</ref>

In 1961 Sipple described a combination of a pheochromocytoma, medullary thyroid carcinoma and parathyroid adenoma.<ref>Brandi ML, Gagel RF, Angeli A, et al. Multiple Endocrine Neoplasia Type 1: Clinical and Genetic Features of the Disease. *Endocrine Reviews*. 2001;22(6):667-707. doi:10.1210/edrv.22.6.0447</ref>

In 1966 Williams et al. described the combination of mucosal neuromas, pheochromocytoma and medullary thyroid carcinoma.<ref>Marx SJ. Multiple Endocrine Neoplasia Type 1. *The New England Journal of Medicine*. 2000;342(19):1619-1627. doi:10.1056/NEJM200005113421907</ref>

In 1968 Steiner et al. introduced the term "multiple endocrine neoplasias" (MEN) to describe disorders featuring combinations of endocrine tumors and proposed the terms 'Wermer syndrome' for MEN 1 and 'Sipple syndrome' for MEN 2.<ref>Brandi ML, Gagel RF, Angeli A, et al. Multiple Endocrine Neoplasia Type 1: Clinical and Genetic Features of the Disease. *Endocrine Reviews*. 2001;22(6):667-707. doi:10.1210/edrv.22.6.0447</ref>

In 1974 Sizemore et al. showed that the MEN 2 category included two groups of patients with MTC and pheochromocytoma: one with parathyroid disease and a normal appearance (MEN 2A) and the other without parathyroid disease but with mucosal neuromas and mesodermal abnormalities (MEN 2B).<ref>Marx SJ. Multiple Endocrine Neoplasia Type 1. *The New England Journal of Medicine*. 2000;342(19):1619-1627. doi:10.1056/NEJM200005113421907</ref>

In 1988 the MEN1 locus was assigned to Chromosome 11 (11q13).<ref>Guru SC, Manickam P, Crabtree JS, Olufemi SE, Agarwal SK, Debelenko LV. Identification and characterization of the multiple endocrine neoplasia type 1 (MEN1) gene. *J Intern Med*. 1998 Jun;243(6):433-9. doi:10.1046/j.1365-2796.1998.00346.x</ref>

In 1993 mutations in the RET oncogene were shown to be the cause of MEN 2A by Lois Mulligan, working in the laboratory of Bruce Ponder in Cambridge.<ref>Template:Cite journal</ref>

In 1998 the MEN1 gene was cloned.<ref name="Guru1998">Template:Cite journal</ref>

Terminology

The older names, "multiple endocrine adenomas" and "multiple endocrine adenomatosis" (MEA), have been replaced by the current terminology.<ref>Thakker RV. Multiple Endocrine Neoplasia Syndromes. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2014. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279084/</ref><ref>Brandi ML, Gagel RF, Angeli A, et al. Multiple Endocrine Neoplasia Type 1: Clinical and Genetic Features of the Disease. *Endocrine Reviews*. 2001;22(6):667-707. doi:10.1210/edrv.22.6.0447</ref><ref>Marx SJ. Multiple Endocrine Neoplasia Type 1. *The New England Journal of Medicine*. 2000;342(19):1619-1627. doi:10.1056/NEJM200005113421907</ref>

The term multiple endocrine neoplasias are used when two or more endocrine tumor types, known to occur as a part of one of the defined MEN syndromes, occurs in a single patient and there is evidence for either a causative mutation or hereditary transmission. The presence of two or more tumor types in a single patient does not automatically designate that individual as having MEN because there is a small statistical chance that the development of two "sporadic" tumors that occur in one of the MEN syndromes could occur by chance.<ref>Chandrasekharappa SC, et al. Multiple Endocrine Neoplasia Type 1. GeneReviews. 1999 Jul 21 [updated 2023 Mar 9]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1538/</ref><ref>Thakker RV, et al. Clinical Practice Guidelines for Multiple Endocrine Neoplasia Type 1. J Clin Endocrinol Metab. 2012 Sep;97(9):2990-3011. doi:10.1210/jc.2012-1232.</ref><ref>Multiple endocrine neoplasia syndromes. BMJ Best Practice. 2024 Aug 23. Available from: https://bestpractice.bmj.com/topics/en-gb/866</ref>

The term "multiple endocrine neoplasia" was introduced in 1968, but descriptions of the condition date back to 1903.<ref name="pmid15644784">Template:Cite journal</ref>

See also

• Multiple endocrine neoplasia type 1
• Multiple endocrine neoplasia type 2a
• Multiple endocrine neoplasia type 2b