FaCD Online Syndrome Fact Sheet

Last updated: 01 Nov 2010

Name: Multiple Endocrine Neoplasia type 4

Synonym: MEN4

Mode of Inheritance: AD

Genes

CDKN1B/p27, mapped to 12p13

Tumor features

carcinoid, general
cervix, carcinoid of the
pituitary adenoma

Tumor features (possible)

pheochromocytoma
renal angiomyolipomas
testicular malignancy

Non-tumor features

acromegaly
hyperparathyroidism

Comment

A germline CDKN1B (p27) was detected in a 48-year-old Caucasian female who had developed acromegaly and was diagnosed with a pituitary growth hormone producing tumor at age 30. She also developed primary hyperparathyroidism(not operated, no histology). Her sister had a renal angiomyolipoma (diagnosed at age 55). The proband's father had acromegaly, her brother died at age 39 from hypertension (pheochromocytoma?). The son of a mutation carrying sister developed testicular cancer at age 28. A few relatives were shown to carry the mutation and were symptom free, but could not be tested for the presence of tumors.[1].
In general, germline CDKN1B muations appear to be rare in familial and sporadic pituitary adenoma and/or MEN1 suspected cases[2-4]. A mutation was detected in a Dutch patient with a pituitary gland tumor (causing Cushing's deisease), carcinoid of the cervix and hyperparathyroidism[2]. A mutation was also identified in an 79-year-old Caucasian female with bilateral multiple lung metastases of bronchial carcinoid, type 2 diabetes mellitus and a non-functioning pituitary microadenoma[6]. At age 67 she had been diagnosed with multiple typical bronchial carcinoids and a subcutaneous epigastric lipoma, and a parathyroid adenoma causing HPT, and at age 64 with papillary thyroid carcinoma. Family history was negative.
In a series of MEN1 and MEN1-like families, rare germline mutations in Cyclin-Dependent Kinase Inhibitor genes p15, p18, p21 and p27 have been detected[5]. Marinoni and Pellegata recently reviewed all patients with germline CDKN1B mutations[7]. Whether MEN4 should be regarded as a truly distinct MEN disorder remains to be seen.

References

[1] Pellegata NS, Quintanilla-Martinez L, Siggelkow H, Samson E, Bink K, Höfler H, Fend F, Graw J, Atkinson MJ. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proceedings of the National Academy of Sciences of the United States of America 2006; 103(42):15558-63.
[2] Georgitsi M, Raitila A, Karhu A, van der Luijt RB, Aalfs CM, Sane T, Vierimaa O, Mäkinen MJ, Tuppurainen K, Paschke R, Gimm O, Koch CA, Gündogdu S, Lucassen A, Tischkowitz M, Izatt L, Aylwin S, Bano G, Hodgson S, De Menis E, Launonen V, Vahteristo P, Aaltonen LA. Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia. The Journal of clinical endocrinology and metabolism 2007; 92(8):3321-5.
[3] Ozawa A, Agarwal SK, Mateo CM, Burns AL, Rice TS, Kennedy PA, Quigley CM, Simonds WF, Weinstein LS, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ. The parathyroid/pituitary variant of multiple endocrine neoplasia type 1 usually has causes other than p27Kip1 mutations. The Journal of clinical endocrinology and metabolism 2007; 92(5):1948-51.
[4] Owens M, Stals K, Ellard S, Vaidya B. Germline mutations in the CDKN1B gene encoding p27(Kip1) are a rare cause of Multiple Endocrine Neoplasia type 1. Clinical endocrinology 2008; epub ahead of print .
[5] Agarwal SK, Mateo CM, Marx SJ. Rare Germline Mutations in Cyclin-Dependent Kinase Inhibitor Genes in MEN1 and Related States. J Clin Endocrinol Metab. 2009 Jan 13. [Epub ahead of print]
[6] Molatore S, Marinoni I, Lee M, Pulz E, Ambrosio MR, Uberti EC, Zatelli MC, Pellegata NS. A novel germline CDKN1B mutation causing multiple endocrine tumors: clinical, genetic and functional characterization. Hum Mutat. 2010 Sep 7. [Epub ahead of print]
[7] Marinoni I, Pellegata NS. p27kip1: A New Multiple Endocrine Neoplasia Gene?Neuroendocrinology. 2010 Oct 27. [Epub ahead of print]