Penetrance and Clinical Features of Pheochromocytoma in a Six-Generation Family Carrying a Germline TMEM127 Mutation

• Published in: The journal of clinical endocrinology and metabolism Vol. 100; no. 2; pp. E308 - E318
• Main Authors: Toledo, Sergio P. A, Lourenço, Delmar M, Sekiya, Tomoko, Lucon, Antonio M, Baena, Marcos E. S, Castro, Claudio C, Bortolotto, Luiz A, Zerbini, Maria C. N, Siqueira, Sheila A. C, Toledo, Rodrigo A, Dahia, Patricia L. M
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.02.2015; Copyright by The Endocrine Society
• Subjects: Adrenal Gland Neoplasms - genetics; Adrenal Gland Neoplasms - pathology; Adult; Age of Onset; Family; Female; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Male; Membrane Proteins - genetics; Middle Aged; Pedigree; Penetrance; Phenotype; Pheochromocytoma - genetics; Pheochromocytoma - pathology; Young Adult
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2014-2473

Context: The phenotype of familial pheochromocytoma (PHEO) associated with germline TMEM127 mutations (TMEM127-related PHEO) has not been clearly defined. Objective: This study aimed to investigate the penetrance, full phenotypic spectrum and effectiveness of clinical/genetic screening in TMEM127-related PHEO. Design, Setting, and Participants: Clinical and genetic screening, and genetic counseling were offered to 151 individuals from a six-generation family carrying a TMEM127 germline mutation in a referral center. Intervention and Main Outcome Measures: TMEM127 genetic testing was offered to at-risk relatives and clinical surveillance for pheochromocytoma was performed in mutation-positive carriers. Results: Forty seven individuals carried the c.410-2A>C TMEM127 mutation. Clinical data were obtained from 34 TMEM127-mutation carriers followed up for 8.7 ± 8.1 years (range, 1–20 y). Pheochromocytoma was diagnosed in 11 carriers (32%) at a median age of 43 years. In nine patients, symptoms started at 29 years (range, 10–55 y) and two cases were asymptomatic. Tumors were multicentric in five (45%) and bilateral in five (45%) patients. Six patients (54%) had at least one adrenomedullary nodule less than 10 mm. No paragangliomas, distant metastases, or other manifestations were detected. Cumulative penetrance of pheochromocytoma was 0% at 0–20 years, 3% at 21–30 years, 15% at 31–40 years, 24% at 41–50 years, and 32% at 51–65 years. The youngest case was diagnosed at 22 years and the earliest symptoms were reported at age 10. Conclusions: Tumor multicentricity, nodular adrenomedullary hyperplasia, and the occurrence of symptoms more than a decade earlier than the age at diagnosis are novel findings in TMEM127-related PHEO. The high penetrance of pheochromocytoma in this condition validates the benefits of genetic testing of at-risk relatives. We thus recommend that TMEM127 genetic testing should be offered to at-risk individuals at age 22 years and mutation carriers should undergo clinical surveillance annually.