Penetrance and clinical features of pheochromocytoma in a six-generation family carrying a germline TMEM127 mutation.
BACKGROUND
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.


METHODS
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.


METHODS
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.
Divisions of Endocrinology (S.P.A.T., D.M.L.J., T.S.), Urology (A.M.L.), Hypertension and Radiology (M.E.S.B., C.C.C., L.A.B.), and Pathology (M.C.N.Z., S.A.C.S.), University of São Paulo School of Medicine, Hospital das Clínicas and Heart Institute (INCOR), São Paulo 01246-903, Brazil; and Division of Hematology and Oncology, Department of Medicine, Cancer Therapy and Research Center (R.A.T., P.L.M.D.), Greehey Childhood Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
Sergio P A
SP
Toledo
Delmar M
DM
Lourenço
Tomoko
T
Sekiya
Antonio M
AM
Lucon
Marcos E S
ME
Baena
Claudio C
CC
Castro
Luiz A
LA
Bortolotto
Maria C N
MC
Zerbini
Sheila A C
SA
Siqueira
Rodrigo A
RA
Toledo
Patricia L M
PL
Dahia
D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000473:pathology; D000328:Adult; D017668:Age of Onset; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D010673:Pheochromocytoma / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
D008565:Membrane Proteins; C548370:TMEM127 protein, human