CDKN1B – Multiple Endocrine Neoplasia Type 4

Multiple endocrine neoplasia type 4 (MEN4) is an autosomal dominant syndrome caused by germline inactivating variants in CDKN1B, encoding the cyclin-dependent kinase inhibitor p27^Kip1^, and clinically overlaps MEN1 with a predilection for primary hyperparathyroidism, pituitary adenomas, and neuroendocrine tumors ([PMID:24819502]).

Genetic evidence supporting a strong gene–disease association includes >28 distinct CDKN1B variants reported in ≥48 unrelated probands with MEN4 (frameshift, nonsense, missense, and 5ʹ-UTR indels) and segregation of c.121_122del (p.Leu41AsnfsTer83) with endocrine tumors in a large Danish kindred (13 carriers with hypercalcemia) ([PMID:30990521]). A recurrent germline frameshift c.371delCT (p.Asn124_Ser125insTer) was found in a proband and her affected son with recurrent primary hyperparathyroidism (PHPT) and gastroenteropancreatic tumors ([PMID:24819502]).

Inheritance is autosomal dominant with incomplete penetrance. Segregation analysis demonstrated 12 additional affected relatives carrying pathogenic CDKN1B alleles. Case series total >48 symptomatic individuals presented predominantly with primary hyperparathyroidism (75%), pituitary adenomas (44%), and gastroenteropancreatic neuroendocrine tumors (15%) ([PMID:30990521]).

Variant spectrum encompasses truncating alleles (frameshift, nonsense) across exons 1–2 and upstream regulatory deletions, as well as rare missense substitutions in the kinase-binding domain (e.g., c.397C>A (p.Pro133Thr)). We highlight c.374_375del (p.Asn124_Ser125insTer) as a pathogenic frameshift example disrupting the C-terminal nuclear localization signal critical for tumor suppressive function.

Functional studies in patient-derived cells and HeLa/GH3 models show that truncating p27_S125X (c.374_375del) yields cytoplasmic mislocalization, loss of nuclear p27 staining, and failure to suppress CDK2 activity ([PMID:25416039]). Concordant animal model data from the rat MENX syndrome, caused by Cdkn1b germline mutation, reproduce multiglandular endocrine tumorigenesis, confirming haploinsufficiency as the mechanism ([PMID:20541671]).

Conflicting evidence includes rare heterozygous missense variants (c.397C>A (p.Pro133Thr)) found in single case reports without clear segregation or functional impact, leaving their pathogenic role uncertain ([PMID:26762354]).

In summary, CDKN1B germline loss-of-function variants cause MEN4 via haploinsufficiency, leading to PHPT and pituitary adenomas with variable penetrance. These data support clinical genetic testing of CDKN1B in MEN1-like presentations negative for MEN1 mutations. Key take-home: CDKN1B pathogenic variants define MEN4, guiding diagnosis, family screening, and personalized management.

References

• European journal of endocrinology • 2014 • A heterozygous frameshift mutation in exon 1 of CDKN1B gene in a patient affected by MEN4 syndrome PMID:24819502
• Endocrine connections • 2015 • Functional characterization of a CDKN1B mutation in a Sardinian kindred with multiple endocrine neoplasia type 4 (MEN4). PMID:25416039
• The Journal of clinical endocrinology and metabolism • 2019 • Clinical Features of Multiple Endocrine Neoplasia Type 4: Novel Pathogenic Variant and Review of Published Cases. PMID:30990521
• Frontiers of hormone research • 2013 • Multiple endocrine neoplasia type 4. PMID:23652671
• Progress in brain research • 2010 • The MENX syndrome and p27: relationships with multiple endocrine neoplasia. PMID:20541671
• BMJ case reports • 2016 • Uncommon association of cerebral meningioma, parathyroid adenoma and papillary thyroid carcinoma in a patient harbouring a rare germline variant in the CDKN1B gene. PMID:26762354

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