SAT-492 Bilateral Pheochromocytomas from TMEM127 Mutations: A Case Series on the Relevance of Genetic Testing

Abstract Disclosure: M.D. Lundholm: None. P.P. Rao: None. Introduction: There is a paucity of information on rare TMEM127 mutation-associated pheochromocytoma (PCC) or paraganglioma (PGL). Case Presentations: A 48-year-old otherwise healthy Caucasian woman presented with headaches and flank pain, and was found to have incidental bilateral adrenal masses on abdominal US. She had no family history of PCC/PGL but was found to have significantly elevated plasma metanephrines at 1390 pg/mL (12-67), plasma normetanephrines (NM) at 601 pg/mL (18-101), urinary metanephrines at 6037 ug/24hr (52-341), and urinary NM at 1494 ug/24hr (88-444). On adrenal CT, she had a right 3.4 cm mass with unattenuated Hounsfield units (HU) of 39. On the left, she had a 3.2 cm mass with HU of 32. She had laparoscopic bilateral adrenalectomy with pathology confirmation of bilateral PCC (PASS 2 on left and 6 on right). Genetic testing showed a TMEM127 mutation with c.3G>A transposition in a start codon. In the 6 years following her surgery there has been no evidence of metastatic disease. A 30-year-old Caucasian woman presented with palpitations, anxiety, pallor, tremor, and vomiting. She had no family history of PCC/PGL, but ten years prior at age 20 she was diagnosed with 9 cm left-sided PCC based on a similar presentation with elevated metanephrine and NM, for which she had a left adrenalectomy back then. Now she had recurrence of symptoms with plasma metanephrine 269 pg/mL, plasma NM 120 pg/mL, urinary metanephrine 914 ug/24hr, and urinary NM 324 ug/24hr. On adrenal CT, she had new 2.4 cm right adrenal mass with unattenuated HU of 35. She had laparoscopic right adrenalectomy with pathology confirmation of right PCC (PASS 5). Genetic testing revealed a TMEM127 mutation with c.157T>G (p.Trp53Gly), which has not been previously reported. In the 12 years since her original PCC diagnosis there has been no evidence of metastatic disease. Discussion: The TMEM127 gene encodes a transmembrane protein and mutations are associated with PCC/PGL that exhibit increased kinase signaling (Cluster 2). Compared to other hereditary PCC/PGL conditions such as Von Hippel-Lindau syndrome, succinate dehydrogenase mutations (SDHx), or RET mutations, TMEM127 mutations are more rare and little is known about their clinical significance. We describe 2 cases of PCC associated with TMEM127 mutations, both with metanephrine and NM secretion and sporadic, bilateral, non-metastatic disease. Other cases in the literature similarly suggest TMEM127 mutations confer a higher risk of bilateral disease and are associated with a low risk of metastasis. Therefore, genetic identification of TMEM127 mutations can help guide surveillance for patients and families. For example, earlier diagnosis of hereditary PCC may have led to more prompt recognition of recurrent disease in our second case. Multi-institutional or registry studies are needed to better understand the features associated with these rare mutations. Presentation: Saturday, July 12, 2025