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Review
. 2024 Jun 17;109(7):e1482-e1493.
doi: 10.1210/clinem/dgae055.

Beyond MEN1, When to Think About MEN4? Retrospective Study on 5600 Patients in the French Population and Literature Review

Benjamin Chevalier  1   2   3 , Lucie Coppin  4   5 , Pauline Romanet  6 , Thomas Cuny  7 , Jean-Christophe Maïza  8 , Juliette Abeillon  9 , Julien Forestier  10 , Thomas Walter  10   11 , Olivier Gilly  12 , Maëlle Le Bras  13 , Sarra Smati  13 , Marie Laure Nunes  14 , Aurore Geslot  15 , Solange Grunenwald  15 , Céline Mouly  15 , Gwenaelle Arnault  16 , Kathy Wagner  17 , Eugénie Koumakis  18 , Christine Cortet-Rudelli  1 , Émilie Merlen  1 , Arnaud Jannin  1   2   4 , Stéphanie Espiard  1   2 , Isabelle Morange  7 , Éric Baudin  19 , Mathias Cavaille  20   21 , Igor Tauveron  22   23 , Marie-Pierre Teissier  24   25 , Françoise Borson-Chazot  9 , Delphine Mirebeau-Prunier  26 , Frédérique Savagner  27 , Éric Pasmant  28   29 , Sophie Giraud  30 , Marie-Christine Vantyghem  1   2   31 , Pierre Goudet  32 , Anne Barlier  6 , Catherine Cardot-Bauters  1 , Marie Françoise Odou  5   33
Affiliations
Review

Beyond MEN1, When to Think About MEN4? Retrospective Study on 5600 Patients in the French Population and Literature Review

Benjamin Chevalier et al. J Clin Endocrinol Metab. .

Erratum in

Abstract

Context: Germline CDKN1B variants predispose patients to multiple endocrine neoplasia type 4 (MEN4), a rare MEN1-like syndrome, with <100 reported cases since its discovery in 2006. Although CDKN1B mutations are frequently suggested to explain cases of genetically negative MEN1, the prevalence and phenotype of MEN4 patients is poorly known, and genetic counseling is unclear.

Objective: To evaluate the prevalence of MEN4 in MEN1-suspected patients and characterize the phenotype of MEN4 patients.

Design: Retrospective observational nationwide study. Narrative review of literature and variant class reassessment.

Patients: We included all adult patients with class 3/4/5 CDKN1B variants identified by the laboratories from the French Oncogenetic Network on Neuroendocrine Tumors network between 2015 and 2022 through germline genetic testing for MEN1 suspicion. After class reassessment, we compared the phenotype of symptomatic patients with class 4/5 CDKN1B variants (ie, with genetically confirmed MEN4 diagnosis) in our series and in literature with 66 matched MEN1 patients from the UMD-MEN1 database.

Results: From 5600 MEN1-suspected patients analyzed, 4 with class 4/5 CDKN1B variant were found (0.07%). They presented with multiple duodenal NET, primary hyperparathyroidism (PHPT) and adrenal nodule, isolated PHPT, PHPT, and pancreatic neuroendocrine tumor. We listed 29 patients with CDKN1B class 4/5 variants from the literature. Compared with matched MEN1 patients, MEN4 patients presented lower NET incidence and older age at PHPT diagnosis.

Conclusion: The prevalence of MEN4 is low. PHPT and pituitary adenoma 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.

Keywords: CDKN1B; MEN1; MEN4; multiple endocrine neoplasia; neuroendocrine tumor; parathyroid; pituitary.

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