Genotype-Phenotype Features of Germline Variants of the TMEM127 Pheochromocytoma Susceptibility Gene: A 10-Year Update

Abstract

Purpose To evaluate genotype-phenotype associations in individuals carrying germline variants of TMEM127, a poorly known gene that confers susceptibility to pheochromocytoma (PHEO) and paraganglioma (PGL) Design Data collected from a registry of probands with TMEM127 variants, published reports and public databases Main outcome analysis clinical, genetic and functional associations Results The cohort comprised 110 index patients (111 variants) with a mean age of 45 (range, 21-84 years). Females were predominant (76 vs. 34, P<0.001). Most patients had PHEO (n=94; 85.5%), although PGL (n=10; 9%) and renal cell carcinoma (RCC, n=6; 5.4%) were also detected, either alone or in combination with PHEO. One-third of the cases had multiple tumors and known family history was reported in 15.4%. Metastatic PHEO/PGL was rare (2.8%). Epinephrine alone, or combined with norepinephrine, accounted for 82% of the catecholamine profiles of PHEO/PGLs. Most variants (n=63) occurred only once and 13 were recurrent (2-12 times). Although non-truncating variants were less frequent than truncating changes overall, they were predominant in non-PHEO clinical presentations (36% PHEOs vs. 69% other, P<0.0001) and clustered disproportionately within transmembrane regions (P<0.01), underscoring the relevance of these domains for TMEM127 function. Integration of clinical and previous experimental data supported classification of variants into four groups based on mutation type, localization and predicted disruption. Conclusions Patients with TMEM127 variants often resemble sporadic nonmetastatic PHEOs. PGL and RCC may also co-occur, although their causal link requires further evaluation. We propose a new classification to predict variant pathogenicity and assist with carrier surveillance.

Is the Adrenal Incidentaloma Functionally Active? An Approach-To-The-Patient-Based Review

“…Before adrenalectomy, preoperative exams should screen also for the presence of genetic disease, and/or metastatic or multifocal disease. Genetic disease seems to account for up to 40% of the cases [ 36 , 37 , 38 ] and it can predispose to bilateral pheocromocytoma. Genetic disease includes MEN2A, MEN2B, von-Hippel Lindau (VHL), neurofibromatosis type 1 (NF1), as well as mutations in the genes of myc-associated factor-X ( MAX ), transmembrane protein 127 ( TMEM127 ) [ 38 ], and the succinate dehydrogenase complex ( SDHx ).…”

“…Genetic disease seems to account for up to 40% of the cases [ 36 , 37 , 38 ] and it can predispose to bilateral pheocromocytoma. Genetic disease includes MEN2A, MEN2B, von-Hippel Lindau (VHL), neurofibromatosis type 1 (NF1), as well as mutations in the genes of myc-associated factor-X ( MAX ), transmembrane protein 127 ( TMEM127 ) [ 38 ], and the succinate dehydrogenase complex ( SDHx ). Dopaminergic, noradrenergic, and adrenergic phenotypes should be used to establish the priorities for specific testing [ 33 ].…”

“…In particular, patients with pheochromocytomas related to some of the above-mentioned genetic syndromes should be offered a cortical-sparing (partial) adrenalectomy to maximize adrenal function [ 39 , 40 ]. These include patients with a TMEM127 mutation or VHL disease that infrequently progress to metastases [ 38 ]. By contrast, an open approach (and consideration for lymphadenectomy) may be preferred in patients with SDHB mutations, who have a higher rate of metastatic or multisite disease [ 39 ].…”

Metastatic pheochromocytomas and paragangliomas: where are we?

“…75 In a cohort of 110 subjects with germline variants of TMEM127, pheochromocytoma was frequent (85.5%), but metastatic PPGL was rare (2.8%). 76 The MAX gene encodes MYC-associated protein X (MAX), which plays a role in downregulation of oncogenic MYC signaling. 77…”

Pheochromocytoma and paraganglioma: germline genetics and hereditary syndromes

“…Renal cell carcinoma was found in 5.4% of the cohort (6 of 110). Average age of presentation was 45 years old (Armaiz-Pena et al, 2021). Guidelines suggest similar screening to those with SDHx PVs with annual biochemical testing and MRI from the skull base to pelvis every 2 years (Rednam et al, 2017).…”