THU613 Multiple Endocrine Neoplasia Type 5 Associated With Germline Max Mutations—New Insights Into This Proposed Entity

Disclosure: N. Charoenngam: None. P. Likasitwatanakul: None. C. Kansuttiviwat: None. B. Ponvilawan: None. A. Jaroenlapnopparat: None. M. Tanariyakul: None. M. Mannstadt: None. Heterozygous germline loss-of-function mutations in the MAX gene, encoding the tumor suppressor MYC-associated factor X, are associated with hereditary pheochromocytoma-paraganglioma (PCC/PGL) syndrome. Furthermore, there are reports of patients who developed additional endocrine and non-endocrine tumors. Thus, presence of multiple endocrine tumors associated with germline MAX mutations has been proposed to comprise “Multiple Endocrine Neoplasia type 5”. Despite multiple reports, a summary of phenotypic manifestations of germline MAX mutations is lacking. Therefore, using systematic review, we aimed to establish a summary of all reported patients with germline MAX mutations to comprehensively describe the phenotype of this syndrome. Potentially eligible articles were retrieved from MEDLINE and EMBASE databases from inception to February 2023 using search terms related to “MAX gene” and “Neoplasm”. Additionally, we identified supporting references of MAX variants reported in the ClinVar database. Eligible articles must report patient-level data on individuals with germline MAX mutations. We extracted data of all reported patients to generate a database. After systematic review, 113 patients with germline MAX variants were identified from 37 articles. Data were presented as median [IQR] or number of patients per available data point (%). Age onset of first tumor of the patients was 28.5 (22.0-38.3) years and 45/102 (44.1%) patients were female. The most common tumors/endocrinopathies were PCC (99/113, 87.6%; age onset 28.5 [23.0-37.8] years) and PGL (9/113, 8.0%; age onset 43.0 [32.0-46.0] years). Other tumors include pituitary adenoma (9/113, 8.0%; age onset 24.0 [29.5-34.3] years), ganglioneuroma (6/113, 5.3%; age onset: 5, 15, 20, 28, 61, N/A years), neuroblastoma (6/113, 5.3%; age onset: 8, 9, 11, 17 months, 27, N/A years), primary hyperparathyroidism (4/113, 3.5%; age onset 40, 49, 69, N/A years) and lung cancer (4/113, 3.5%; age onset 47, 64, N/A, N/A years). Among the 99 patients with PCC, 34/93 (36.6%) had unilateral PCC, 59/93 (63.4%) had bilateral PCC (14/31 synchronous, 17/31 asynchronous). There were 14/50 (28.0%) with metastatic PCC. Most of the PCCs were norepinephrine-producing (32/40, 80.0%), followed by norepinephrine+epinephrine-producing (4/40, 10.0%) and epinephrine-producing (2/40, 5.0%). In tumor tissue, loss of heterozygosity was observed in 27 patients with PCC/PGL, one with pancreatic neuroendocrine tumor, one with renal cell carcinoma and one with renal oncocytoma. In summary, pathogenic MAX mutations cause PCC/PGL with the age of onset in the 20s for PCC and 30s-40s for PGL. Other associated conditions include ganglioneuroma, neuroblastoma, primary hyperparathyroidism, lung cancer, pancreatic neuroendocrine tumor, renal cell carcinoma and renal oncocytoma. Future research will clarify which tumors are caused by the MAX mutations. Presentation: Thursday, June 15, 2023