SUN-283 - Concurrent Multiple Endocrine Neoplasia Type 4 and Birt-Hogg-Dubé Syndrome: A Case of Dual Germline Pathogenic Variants in CDKN1B and FLCN

Background: Multiple endocrine neoplasia type 4 (MEN4) is a rare autosomal dominant syndrome caused by germline CDKN1B mutations, characterized by primary hyperparathyroidism (PHPT), pituitary adenomas, and gastro-entero-pancreatic neuroendocrine tumors. Birt-Hogg-Dubé (BHD) syndrome, caused by FLCN mutations, presents with pulmonary cysts, renal cell carcinoma, and fibrofolliculomas. We report the first documented case of concurrent MEN4 and BHD syndromes.

Case: A 79-year-old male with renal cell carcinoma status post partial nephrectomy, pulmonary cysts, and fibrofolliculomas underwent genetic testing revealing heterozygous pathogenic variants in both FLCN (BHD) and CDKN1B (MEN4). He presented with hypercalcemia (11.7 mg/dL corrected), markedly elevated PTH (466.6 pg/mL), and nephrolithiasis. Imaging demonstrated an 11×14×21 mm right paratracheal parathyroid adenoma. Review of systems was negative for pituitary dysfunction or gastrinoma symptoms.
Management: Comprehensive MEN4 surveillance was initiated including biochemical screening for pituitary adenomas (IGF-1, prolactin, TSH, free T4, overnight dexamethasone suppression test), CT head, DEXA scan, and review of abdominal imaging for gastro-entero-pancreatic neuroendocrine tumors. The patient was referred for parathyroidectomy with calcium restriction and continued vitamin D supplementation.

Discussion: MEN4 prevalence is 0.07% among MEN1-suspected patients. MEN4 demonstrates a significantly more attenuated phenotype than MEN1, with lower penetrance, later onset (mean age 43.5 vs 31.8 years), and milder clinical course. Our patient's presentation at age 79 with isolated PHPT is consistent with the attenuated MEN4 phenotype. The concurrent BHD syndrome explained his renal cell carcinoma, pulmonary cysts, and fibrofolliculomas. Given the lack of standardized MEN4 surveillance guidelines, we adapted MEN1 screening protocols as recommended by NCCN and GeneReviews.

Conclusion: This case highlights the importance of comprehensive genetic testing in patients with multiple endocrine and non-endocrine neoplasms. The coexistence of MEN4 and BHD necessitates coordinated multidisciplinary surveillance. Understanding MEN4's distinct phenotype—particularly its more indolent course, later onset, and lower NET risk compared to MEN1—is essential for appropriate counseling and surveillance strategies.

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