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Review
. 2019 Sep 1;104(9):3637-3646.
doi: 10.1210/jc.2019-00082.

Clinical Features of Multiple Endocrine Neoplasia Type 4: Novel Pathogenic Variant and Review of Published Cases

Anja Frederiksen  1   2 , Maria Rossing  3 , Pernille Hermann  4 , Charlotte Ejersted  4 , Rajesh V Thakker  5 , Morten Frost  2   4
Affiliations
Review

Clinical Features of Multiple Endocrine Neoplasia Type 4: Novel Pathogenic Variant and Review of Published Cases

Anja Frederiksen et al. J Clin Endocrinol Metab. .

Abstract

Context: The clinical phenotype of multiple endocrine neoplasia type 4 (MEN4) is undefined due to a limited number of published cases. Knowledge on disease manifestation in MEN4 is essential for developing prevention programs and treatment.

Objective: To expand current knowledge of the MEN4 phenotype including assessment of penetrance.

Design: This is a case report and a brief review of previously published MEN4 cases.

Patients: We report a large Danish family with multiple cases of endocrine tumors that segregated with a pathogenic variant in the CDKN1B gene.

Main outcome/result: The medical history of the proband included primary hyperparathyroidism and Cushing disease. Genetic analysis identified a pathogenic variant in CDKN1B (c.121_122delTT, p.Leu41Asnfs*83). Among the family members, another 12 individuals were identified as carriers of the same variant, which segregated with development of endocrine tumors. Hypercalcemia due to primary hyperparathyroidism occurred in all 13 of the available carriers of the genetic variant, and 4 patients also had functioning or nonfunctioning pituitary adenomas, whereas 1 patient had a metastatic neuroendocrine tumor (carcinoid). Loss-of-heterozygosity was detected in two of five parathyroid adenomas, supporting that CDKN1B acts as a tumor suppressor gene. Thirty cases representing 16 different CDKN1B variants have previously been reported, and these cases presented primarily with primary hyperparathyroidism and functioning and nonfunctioning pituitary tumors.

Conclusion: Hypercalcemia due to primary hyperparathyroidism and pituitary tumors are common in MEN4. Gastrointestinal neuroendocrine tumors appear to be less prevalent in MEN4 than in MEN1.

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Figures

Figure 1.
Figure 1.
Pedigree showing a family with 13 CDKN1B mutation carriers. Pituitary adenoma is indicated by a circle with the top left fourth shaded; hyperparathyroidism by a circle with the top right fourth shaded; tumor unspecified by a circle with the bottom left fourth shaded; neuroendocrine tumor by a circle with the bottom right fourth shaded; male is indicated by an open square; female is indicated by an open circle; and deceased is indicated by a line through the symbol. +, mutation positive; −, mutation negative.
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References

    1. Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F, Brandi ML; Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012;97(9):2990–3011. - PubMed
    1. Thakker RV. Multiple endocrine neoplasia--syndromes of the twentieth century. J Clin Endocrinol Metab. 1998;83(8):2617–2620. - PubMed
    1. Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol. 2014;386(1-2):2–15. - PMC - PubMed
    1. Wells SA Jr, Pacini F, Robinson BG, Santoro M. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab. 2013;98(8):3149–3164. - PMC - PubMed
    1. Lemos MC, Thakker RV. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat. 2008;29(1):22–32. - PubMed

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