Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention.
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Bausch Birke, Schiavi Francesca, Ni Ying, Welander Jenny, Patocs Attila, Ngeow Joanne, Wellner Ulrich, Malinoc Angelica, Taschin Elisa, Barbon Giovanni, Lanza Virginia, Söderkvist Peter, Stenman Adam, Larsson Catharina, Svahn Fredrika, Chen Jin-Lian, Marquard Jessica, Fraenkel Merav, Walter Martin A, Peczkowska Mariola, Prejbisz Aleksander, Jarzab Barbara, Hasse-Lazar Kornelia, Petersenn Stephan, Moeller Lars C, Meyer Almuth, Reisch Nicole, Trupka Arnold, Brase Christoph, Galiano Matthias, Preuss Simon F, Kwok Pingling, Lendvai Nikoletta, Berisha Gani, Makay Özer, Boedeker Carsten C, Weryha Georges, Racz Karoly, Januszewicz Andrzej, Walz Martin K, Gimm Oliver, Opocher Giuseppe, Eng Charis, Neumann Hartmut P H, European-American-Asian Pheochromocytoma-Paraganglioma Registry Study Group
Аннотация
OBJECTIVE: To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes.
DESIGN, SETTING, AND PATIENTS: This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes.
MAIN OUTCOMES AND MEASURES: Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized.
RESULTS: Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P < .001).
CONCLUSIONS AND RELEVANCE: The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.