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Multiple endocrine neoplasia, type 4(MEN4)

MedGen UID:
373469
Concept ID:
C1970712
Neoplastic Process
Synonyms: MEN4; MULTIPLE ENDOCRINE NEOPLASIA, TYPE IV
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
not inherited
MedGen UID:
832438
Concept ID:
CN227390
Intellectual Product
Source: Orphanet
Describes a disorder that is not inherited.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
not inherited (Orphanet)
 
Gene (location): CDKN1B (12p13.1)
OMIM®: 610755
Orphanet: ORPHA276152

Definition

Multiple endocrine neoplasia is a group of disorders that affect the body's network of hormone-producing glands called the endocrine system. Hormones are chemical messengers that travel through the bloodstream and regulate the function of cells and tissues throughout the body. Multiple endocrine neoplasia typically involves tumors (neoplasia) in at least two endocrine glands; tumors can also develop in other organs and tissues. These growths can be noncancerous (benign) or cancerous (malignant). If the tumors become cancerous, the condition can be life-threatening.The major forms of multiple endocrine neoplasia are called type 1, type 2, and type 4. These types are distinguished by the genes involved, the types of hormones made, and the characteristic signs and symptoms.Many different types of tumors are associated with multiple endocrine neoplasia. Type 1 frequently involves tumors of the parathyroid glands, the pituitary gland, and the pancreas. Tumors in these glands can lead to the overproduction of hormones. The most common sign of multiple endocrine neoplasia type 1 is overactivity of the parathyroid glands (hyperparathyroidism). Hyperparathyroidism disrupts the normal balance of calcium in the blood, which can lead to kidney stones, thinning of bones, nausea and vomiting, high blood pressure (hypertension), weakness, and fatigue.The most common sign of multiple endocrine neoplasia type 2 is a form of thyroid cancer called medullary thyroid carcinoma. Some people with this disorder also develop a pheochromocytoma, which is an adrenal gland tumor that can cause dangerously high blood pressure. Multiple endocrine neoplasia type 2 is divided into three subtypes: type 2A, type 2B (formerly called type 3), and familial medullary thyroid carcinoma (FMTC). These subtypes differ in their characteristic signs and symptoms and risk of specific tumors; for example, hyperparathyroidism occurs only in type 2A, and medullary thyroid carcinoma is the only feature of FMTC. The signs and symptoms of multiple endocrine neoplasia type 2 are relatively consistent within any one family.Multiple endocrine neoplasia type 4 appears to have signs and symptoms similar to those of type 1, although it is caused by mutations in a different gene. Hyperparathyroidism is the most common feature, followed by tumors of the pituitary gland, additional endocrine glands, and other organs.
[from GHR]

Clinical features

Carcinoid tumor
MedGen UID:
2838
Concept ID:
C0007095
Neoplastic Process
A slow growing neuroendocrine tumor, composed of uniform, round, or polygonal cells having monotonous, centrally located nuclei and small nucleoli, infrequent mitoses, and no necrosis. The tumor may show a variety of patterns, such as solid, trabecular, and acinar. Electron microscopy shows small secretory granules. Immunohistochemical studies reveal NSE, as well as chromogranin immunoreactivity. Malignant histology (cellular pleomorphism, hyperchromatic nuclei, prominent nucleoli, necrosis, and mitoses) can occasionally be seen. Such cases may have an aggressive clinical course. Gastrointestinal tract and lung are common sites of involvement.
Pituitary adenoma
MedGen UID:
45933
Concept ID:
C0032000
Neoplastic Process
A benign epithelial tumor derived from intrinsic cells of the adenohypophysis.
Renal angiomyolipoma
MedGen UID:
69146
Concept ID:
C0241961
Neoplastic Process
A benign renal neoplasm composed of fat, vascular, and smooth muscle elements.
Parathyroid adenoma
MedGen UID:
75502
Concept ID:
C0262587
Neoplastic Process
A benign tumor arising from the parenchymal cells of the parathyroid glands. In the vast majority of cases, the tumor involves a single parathyroid gland. It is associated with the symptoms of primary hyperparathyroidism, resulting from the excessive production of parathyroid hormone. It is usually surrounded by a well-defined capsule. Capsular invasion, vascular invasion, and perineural invasion are absent.
Growth hormone excess
MedGen UID:
1304
Concept ID:
C0001206
Disease or Syndrome
A condition caused by prolonged exposure to excessive HUMAN GROWTH HORMONE in adults. It is characterized by bony enlargement of the FACE; lower jaw (PROGNATHISM); hands; FEET; HEAD; and THORAX. The most common etiology is a GROWTH HORMONE-SECRETING PITUITARY ADENOMA. (From Joynt, Clinical Neurology, 1992, Ch36, pp79-80)
Carcinoid tumor
MedGen UID:
2838
Concept ID:
C0007095
Neoplastic Process
A slow growing neuroendocrine tumor, composed of uniform, round, or polygonal cells having monotonous, centrally located nuclei and small nucleoli, infrequent mitoses, and no necrosis. The tumor may show a variety of patterns, such as solid, trabecular, and acinar. Electron microscopy shows small secretory granules. Immunohistochemical studies reveal NSE, as well as chromogranin immunoreactivity. Malignant histology (cellular pleomorphism, hyperchromatic nuclei, prominent nucleoli, necrosis, and mitoses) can occasionally be seen. Such cases may have an aggressive clinical course. Gastrointestinal tract and lung are common sites of involvement.
Pituitary adenoma
MedGen UID:
45933
Concept ID:
C0032000
Neoplastic Process
A benign epithelial tumor derived from intrinsic cells of the adenohypophysis.
Renal angiomyolipoma
MedGen UID:
69146
Concept ID:
C0241961
Neoplastic Process
A benign renal neoplasm composed of fat, vascular, and smooth muscle elements.
Abnormality of the urinary system
MedGen UID:
867444
Concept ID:
C4021821
Disease or Syndrome
An abnormality of the urinary system.
Growth hormone excess
MedGen UID:
1304
Concept ID:
C0001206
Disease or Syndrome
A condition caused by prolonged exposure to excessive HUMAN GROWTH HORMONE in adults. It is characterized by bony enlargement of the FACE; lower jaw (PROGNATHISM); hands; FEET; HEAD; and THORAX. The most common etiology is a GROWTH HORMONE-SECRETING PITUITARY ADENOMA. (From Joynt, Clinical Neurology, 1992, Ch36, pp79-80)
Carcinoid tumor
MedGen UID:
2838
Concept ID:
C0007095
Neoplastic Process
A slow growing neuroendocrine tumor, composed of uniform, round, or polygonal cells having monotonous, centrally located nuclei and small nucleoli, infrequent mitoses, and no necrosis. The tumor may show a variety of patterns, such as solid, trabecular, and acinar. Electron microscopy shows small secretory granules. Immunohistochemical studies reveal NSE, as well as chromogranin immunoreactivity. Malignant histology (cellular pleomorphism, hyperchromatic nuclei, prominent nucleoli, necrosis, and mitoses) can occasionally be seen. Such cases may have an aggressive clinical course. Gastrointestinal tract and lung are common sites of involvement.
Pituitary adenoma
MedGen UID:
45933
Concept ID:
C0032000
Neoplastic Process
A benign epithelial tumor derived from intrinsic cells of the adenohypophysis.
Parathyroid adenoma
MedGen UID:
75502
Concept ID:
C0262587
Neoplastic Process
A benign tumor arising from the parenchymal cells of the parathyroid glands. In the vast majority of cases, the tumor involves a single parathyroid gland. It is associated with the symptoms of primary hyperparathyroidism, resulting from the excessive production of parathyroid hormone. It is usually surrounded by a well-defined capsule. Capsular invasion, vascular invasion, and perineural invasion are absent.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMultiple endocrine neoplasia, type 4
Follow this link to review classifications for Multiple endocrine neoplasia, type 4 in Orphanet.

Recent clinical studies

Etiology

Butz JJ, Yan Q, McKenzie TJ, Weingarten TN, Cavalcante AN, Bancos I, Young WF Jr, Schroeder DR, Martin DP, Sprung J
Surgery 2017 Dec;162(6):1259-1269. Epub 2017 Sep 14 doi: 10.1016/j.surg.2017.08.002. PMID: 28919049
Conemans EB, Brosens LAA, Raicu-Ionita GM, Pieterman CRC, de Herder WW, Dekkers OM, Hermus AR, van der Horst-Schrivers AN, Bisschop PH, Havekes B, Drent ML, Timmers HTM, Offerhaus GJ, Valk GD, Vriens MR
Pancreatology 2017 Sep - Oct;17(5):766-772. Epub 2017 Jul 31 doi: 10.1016/j.pan.2017.07.196. PMID: 28811081
Mucha L, Leidig-Bruckner G, Frank-Raue K, Bruckner T, Kroiss M, Raue F; German study group for rare thyroid cancer.
Clin Endocrinol (Oxf) 2017 Oct;87(4):320-326. Epub 2017 Jun 30 doi: 10.1111/cen.13386. PMID: 28605116
Tonelli F, Giudici F, Nesi G, Batignani G, Brandi ML
Surgery 2017 Mar;161(3):727-734. Epub 2016 Nov 15 doi: 10.1016/j.surg.2016.09.017. PMID: 27863775
Thakker RV
Mol Cell Endocrinol 2014 Apr 5;386(1-2):2-15. Epub 2013 Aug 8 doi: 10.1016/j.mce.2013.08.002. PMID: 23933118Free PMC Article

Diagnosis

Wang BP, Tian WJ, Zhang J, Jiang CX, Qu HQ, Zhu M
J Int Med Res 2018 Feb;46(2):908-915. Epub 2017 Sep 14 doi: 10.1177/0300060517728653. PMID: 29239255Free PMC Article
Mucha L, Leidig-Bruckner G, Frank-Raue K, Bruckner T, Kroiss M, Raue F; German study group for rare thyroid cancer.
Clin Endocrinol (Oxf) 2017 Oct;87(4):320-326. Epub 2017 Jun 30 doi: 10.1111/cen.13386. PMID: 28605116
Giusti F, Cianferotti L, Boaretto F, Cetani F, Cioppi F, Colao A, Davì MV, Faggiano A, Fanciulli G, Ferolla P, Ferone D, Fossi C, Giudici F, Gronchi G, Loli P, Mantero F, Marcocci C, Marini F, Masi L, Opocher G, Beck-Peccoz P, Persani L, Scillitani A, Sciortino G, Spada A, Tomassetti P, Tonelli F, Brandi ML
Endocrine 2017 Nov;58(2):349-359. Epub 2017 Jan 28 doi: 10.1007/s12020-017-1234-4. PMID: 28132167
Opsahl EM, Brauckhoff M, Schlichting E, Helset K, Svartberg J, Brauckhoff K, Mæhle L, Engebretsen LF, Sigstad E, Grøholt KK, Akslen LA, Jørgensen LH, Varhaug JE, Bjøro T
Thyroid 2016 Sep;26(9):1225-38. Epub 2016 Aug 11 doi: 10.1089/thy.2015.0673. PMID: 27400880
Thakker RV
Mol Cell Endocrinol 2014 Apr 5;386(1-2):2-15. Epub 2013 Aug 8 doi: 10.1016/j.mce.2013.08.002. PMID: 23933118Free PMC Article

Therapy

Wang BP, Tian WJ, Zhang J, Jiang CX, Qu HQ, Zhu M
J Int Med Res 2018 Feb;46(2):908-915. Epub 2017 Sep 14 doi: 10.1177/0300060517728653. PMID: 29239255Free PMC Article
Lairmore TC, Govednik CM, Quinn CE, Sigmond BR, Lee CY, Jupiter DC
Surgery 2014 Dec;156(6):1326-34; discussion 1334-5. Epub 2014 Sep 26 doi: 10.1016/j.surg.2014.08.006. PMID: 25262224
Fox E, Widemann BC, Chuk MK, Marcus L, Aikin A, Whitcomb PO, Merino MJ, Lodish M, Dombi E, Steinberg SM, Wells SA, Balis FM
Clin Cancer Res 2013 Aug 1;19(15):4239-48. Epub 2013 Jun 13 doi: 10.1158/1078-0432.CCR-13-0071. PMID: 23766359Free PMC Article
Machens A, Lorenz K, Dralle H
J Clin Endocrinol Metab 2013 Feb;98(2):E336-45. Epub 2013 Jan 2 doi: 10.1210/jc.2012-3192. PMID: 23284010
Barbe C, Murat A, Dupas B, Ruszniewski P, Tabarin A, Vullierme MP, Penfornis A, Rohmer V, Baudin E, Le Rhun M, Gaye D, Marcus C, Cadiot G; Groupe d’étude des Tumeurs Endocrines (GTE).
Dig Liver Dis 2012 Mar;44(3):228-34. Epub 2011 Nov 11 doi: 10.1016/j.dld.2011.09.014. PMID: 22078814

Prognosis

Raue F, Dralle H, Machens A, Bruckner T, Frank-Raue K
J Clin Endocrinol Metab 2018 Jan 1;103(1):235-243. doi: 10.1210/jc.2017-01884. PMID: 29077903
Butz JJ, Yan Q, McKenzie TJ, Weingarten TN, Cavalcante AN, Bancos I, Young WF Jr, Schroeder DR, Martin DP, Sprung J
Surgery 2017 Dec;162(6):1259-1269. Epub 2017 Sep 14 doi: 10.1016/j.surg.2017.08.002. PMID: 28919049
Conemans EB, Brosens LAA, Raicu-Ionita GM, Pieterman CRC, de Herder WW, Dekkers OM, Hermus AR, van der Horst-Schrivers AN, Bisschop PH, Havekes B, Drent ML, Timmers HTM, Offerhaus GJ, Valk GD, Vriens MR
Pancreatology 2017 Sep - Oct;17(5):766-772. Epub 2017 Jul 31 doi: 10.1016/j.pan.2017.07.196. PMID: 28811081
Giusti F, Cianferotti L, Boaretto F, Cetani F, Cioppi F, Colao A, Davì MV, Faggiano A, Fanciulli G, Ferolla P, Ferone D, Fossi C, Giudici F, Gronchi G, Loli P, Mantero F, Marcocci C, Marini F, Masi L, Opocher G, Beck-Peccoz P, Persani L, Scillitani A, Sciortino G, Spada A, Tomassetti P, Tonelli F, Brandi ML
Endocrine 2017 Nov;58(2):349-359. Epub 2017 Jan 28 doi: 10.1007/s12020-017-1234-4. PMID: 28132167
Opsahl EM, Brauckhoff M, Schlichting E, Helset K, Svartberg J, Brauckhoff K, Mæhle L, Engebretsen LF, Sigstad E, Grøholt KK, Akslen LA, Jørgensen LH, Varhaug JE, Bjøro T
Thyroid 2016 Sep;26(9):1225-38. Epub 2016 Aug 11 doi: 10.1089/thy.2015.0673. PMID: 27400880

Clinical prediction guides

Tonelli F, Giudici F, Nesi G, Batignani G, Brandi ML
Surgery 2017 Mar;161(3):727-734. Epub 2016 Nov 15 doi: 10.1016/j.surg.2016.09.017. PMID: 27863775
Donegan D, Singh Ospina N, Rodriguez-Gutierrez R, Al-Hilli Z, Thompson GB, Clarke BL, Young WF Jr
Clin Endocrinol (Oxf) 2017 Feb;86(2):199-206. Epub 2016 Nov 17 doi: 10.1111/cen.13264. PMID: 27770475
Kong J, Wang O, Nie M, Shi J, Hu Y, Jiang Y, Li M, Xia W, Meng X, Xing X
PLoS One 2016;11(11):e0166634. Epub 2016 Nov 15 doi: 10.1371/journal.pone.0166634. PMID: 27846313Free PMC Article
Opsahl EM, Brauckhoff M, Schlichting E, Helset K, Svartberg J, Brauckhoff K, Mæhle L, Engebretsen LF, Sigstad E, Grøholt KK, Akslen LA, Jørgensen LH, Varhaug JE, Bjøro T
Thyroid 2016 Sep;26(9):1225-38. Epub 2016 Aug 11 doi: 10.1089/thy.2015.0673. PMID: 27400880
Gonçalves TD, Toledo RA, Sekiya T, Matuguma SE, Maluf Filho F, Rocha MS, Siqueira SA, Glezer A, Bronstein MD, Pereira MA, Jureidini R, Bacchella T, Machado MC, Toledo SP, Lourenço DM Jr
J Clin Endocrinol Metab 2014 Jan;99(1):E89-96. Epub 2013 Dec 20 doi: 10.1210/jc.2013-1768. PMID: 24178797

Recent systematic reviews

Ye L, Wang W, Ospina NS, Jiang L, Christakis I, Lu J, Zhou Y, Zhu W, Cao Y, Wang S, Perrier ND, Young WF Jr, Ning G, Wang W
Clin Endocrinol (Oxf) 2017 Dec;87(6):706-716. Epub 2017 Oct 16 doi: 10.1111/cen.13480. PMID: 28940393
Coyle D, Friedmacher F, Puri P
Pediatr Surg Int 2014 Aug;30(8):751-6. Epub 2014 Jun 28 doi: 10.1007/s00383-014-3538-2. PMID: 24972642
Niederle B, Sebag F, Brauckhoff M
Langenbecks Arch Surg 2014 Feb;399(2):185-97. Epub 2013 Dec 3 doi: 10.1007/s00423-013-1139-5. PMID: 24297502
Lee M, Pellegata NS
Front Horm Res 2013;41:63-78. Epub 2013 Mar 19 doi: 10.1159/000345670. PMID: 23652671
Scholten A, Schreinemakers JM, Pieterman CR, Valk GD, Vriens MR, Borel Rinkes IH
Endocr Pract 2011 Jan-Feb;17(1):7-15. doi: 10.4158/EP10050.OR. PMID: 20570815

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