CDKN1B mutation

The prevalence of MEN4 is low. PHPT and PA represent the main associated lesions, NETs are rare. Our results suggest a milder and later phenotype than in MEN1. Our observations will help to improve genetic counseling and management of MEN4 families.

Germline mutations in CDKIs should be included in gene panels for genetic testing of primary hyperparathyroidism. New germline variants here described can be added to the current knowledge.

However, MEN4 appears to be a variant of MEN with milder clinical features and later onset. Therefore, these patients might need a different and personalized approach in clinical management and a peculiar screening and follow-up strategy.

Germline CDKN1B pathogenic variants cause the syndrome Multiple Endocrine Neoplasia type 4. The phenotype resulting from the three pathogenic variants described in this series highlights the heterogenous nature of this syndrome, ranging from isolated primary hyperparathyroidism to the full spectrum of endocrine manifestations. We report the first described cases of a prolactinoma and an atypical thymic carcinoid tumor in MEN4.

Notably, many of the identified somatic mutations resulted in p27 protein truncation leading to loss of most of the protein or of its C-terminal domain. Using a gene editing approach in a luminal BC cell line, MCF-7, we observed that the expression of p27 truncating mutants that lose the C-terminal domains failed to rescue most of the phenotypes induced by CDKN1B gene knock-out, indicating that the functions retained by the C-terminal portion are critical for its role as oncosuppressor, at least in luminal BC.

Driver mutations occur in 50% of metastasized SI-NETs and their presence is associated with high Ki67 proliferation index. The identification of targetable mutations render these patients potentially eligible for targeted therapy.

The biochemical phenotype of pheochromocytoma (elevated metanephrines) is consistent with cluster 2 tumors of kinase signaling pathway as seen in tumors of MEN syndrome and neurofibromatosis. We hope to gain more insight via whole exome sequencing to evaluate for potential novel gene mutation(s).