SUN-287 Unmasking Multiple Endocrine Neoplasia Type 4: A CDKN1B Mutation Discovered During Bilateral Breast Cancer Workup

Abstract Disclosure: N.R. Brott: None. A. Cornea: None. A. Jawahar: None. Background: Multiple Endocrine Neoplasia type 4 (MEN4) is the most recently recognized subtype of MEN syndromes—a group of autosomal dominant disorders characterized by the development of endocrine and neuroendocrine tumors. Clinically, MEN4 closely resembles MEN1, with the most common manifestations being hyperparathyroidism due to parathyroid adenomas, pituitary adenomas, and enteropancreatic neuroendocrine tumors (NETs). One key distinction lies in its genetic basis: MEN4 results from germline mutations in the CDKN1B gene, which codes for the cell-cycle regulator p27Kip1. Unlike MEN1, MEN4 exhibits variable penetrance, later age of onset, and a less clearly defined tumor spectrum, making clinical recognition and surveillance more challenging. Clinical Case: A 42-year-old female with a history of obesity presented with a palpable left breast mass. Diagnostic mammography and ultrasound-guided biopsy revealed invasive lobular carcinoma (ILC) of the left breast (ER+/PR+, HER2-equivocal, grade 2) and invasive ductal carcinoma (IDC) of the right breast (ER+/PR+, HER2-equivocal, grade 1). MRI showed a 5 cm area of enhancement in the left breast and a 1.5 cm lesion in the right. She underwent a bilateral mastectomy. Final pathology confirmed multifocal ILC (52 mm, pT3N1a) and IDC (11 mm, pT1cN0), with a single positive sentinel node on the left and negative margins bilaterally. She completed adjuvant radiation therapy to the left chest wall and remains disease-free. Given her early-onset, bilateral breast cancers, germline genetic testing was performed, revealing a CDKN1B mutation consistent with MEN4. She had no history of hypercalcemia, nephrolithiasis, pituitary symptoms, or pancreatic tumors. Family history was negative for endocrine neoplasms. Laboratory evaluation was normal, including PTH, prolactin, IGF-1, 8 AM cortisol, TSH, and free T4. Conclusion: MEN4 is a recently defined syndrome with overlapping but distinct features from MEN1. While breast cancer is not classically associated with MEN4, reports of non-endocrine malignancies in CDKN1B mutation carriers raise the question of broader phenotypic expression. Surveillance in MEN4 is typically modeled after MEN1 protocols, though optimal guidelines are lacking. This case underscores the importance of considering germline testing in patients with early-onset malignancies with multiple primary sources and highlights the evolving understanding of CDKN1B-associated syndromes. Presentation: Sunday, July 13, 2025