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

Autor(es):Mostrar menos -

Toledo, Sergio P. A. ^[1] ; Lourenco, Jr., Delmar M. ^[1] ; Sekiya, Tomoko ^[1] ; Lucon, Antonio M. ^[2] ; Baena, Marcos E. S. ^[3] ; Castro, Claudio C. ^[3] ; Bortolotto, Luiz A. ^[3] ; Zerbini, Maria C. N. ^[4] ; Siqueira, Sheila A. C. ^[4] ; Toledo, Rodrigo A. ^[5] ; Dahia, Patricia L. M. ^[5]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sch Med, Hosp Clin, Div Endocrinol, BR-01246903 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Sch Med, Hosp Clin, Div Urol, BR-01246903 Sao Paulo - Brazil

^[3] Univ Sao Paulo, Sch Med, Hosp Clin, Div Hypertens & Radiol, BR-01246903 Sao Paulo - Brazil

^[4] Univ Sao Paulo, Sch Med, Hosp Clin, Div Pathol, BR-01246903 Sao Paulo - Brazil

^[5] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, Dept Med, Div Hematol & Oncol, San Antonio, TX 78229 - USA

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 100, n. 2, p. E308-E318, FEB 2015.
• Citações Web of Science: 22

Resumo

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. (AU)

• Processo FAPESP: 13/19810-2 - Avaliação da eficácia do método de sequenciamento de nova geração na análise dos genes MEN1, CDKN2B/p15, CDKN2C/p18 CDKN1A/p21, CDKN1B/p27Kip1 e AIP em pacientes com neoplasia endócrina múltipla tipo 1 (MEN1)
• Beneficiário: Delmar Muniz Lourenço Jr
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/01476-9 - Rastreamento de variantes de significado desconhecido (VUS) no proto-oncogene RET em pacientes com neoplasia endócrina múltipla tipo 2 e indivíduos saudáveis da população brasileira
• Beneficiário: Sergio Pereira de Almeida Toledo
• Modalidade de apoio: Auxílio à Pesquisa - Regular