title: Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention.
abstract: OBJECTIVE
  Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking.
  
  
  OBJECTIVE
  To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Department of Medicine II, Freiburg University Medical Center, Albert-Ludwigs University, Freiburg, Germany.
authors.forename: Birke
authors.initials: B
authors.lastname: Bausch
authors.affiliation: Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Padova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Schiavi
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ni
authors.affiliation: Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Welander
authors.affiliation: Second Department of Medicine, Semmelweis University, Budapest, Hungary.|Molecular Medicine Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Patocs
authors.affiliation: Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore and Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
authors.forename: Joanne
authors.initials: J
authors.lastname: Ngeow
authors.affiliation: Department of Surgery, University of Lübeck, Lübeck, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Wellner
authors.affiliation: Department of Nephrology and General Medicine, University Medical Center, Albert-Ludwigs University, Freiburg, Germany.
authors.forename: Angelica
authors.initials: A
authors.lastname: Malinoc
authors.affiliation: Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Padova, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Taschin
authors.affiliation: Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Padova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Barbon
authors.affiliation: Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Padova, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Lanza
authors.affiliation: Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Söderkvist
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Karolinska University Hospital Stockholm, Stockholm, Sweden.
authors.forename: Adam
authors.initials: A
authors.lastname: Stenman
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Karolinska University Hospital Stockholm, Stockholm, Sweden.
authors.forename: Catharina
authors.initials: C
authors.lastname: Larsson
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Karolinska University Hospital Stockholm, Stockholm, Sweden.
authors.forename: Fredrika
authors.initials: F
authors.lastname: Svahn
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Jin-Lian
authors.initials: JL
authors.lastname: Chen
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Jessica
authors.initials: J
authors.lastname: Marquard
authors.affiliation: Department of Medicine, Endocrinology, and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Merav
authors.initials: M
authors.lastname: Fraenkel
authors.affiliation: Institute of Nuclear Medicine, University Hospital, Bern, Switzerland.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Walter
authors.affiliation: Department of Hypertension, Institute of Cardiology, Warsaw, Poland.
authors.forename: Mariola
authors.initials: M
authors.lastname: Peczkowska
authors.affiliation: Department of Hypertension, Institute of Cardiology, Warsaw, Poland.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Prejbisz
authors.affiliation: Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Jarzab
authors.affiliation: Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Hasse-Lazar
authors.affiliation: Center for Endocrine Tumors, Hamburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Petersenn
authors.affiliation: Department of Endocrinology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Lars C
authors.initials: LC
authors.lastname: Moeller
authors.affiliation: Department of Endocrinology, Helios Klinikum, Erfurt, Germany.
authors.forename: Almuth
authors.initials: A
authors.lastname: Meyer
authors.affiliation: Department of Endocrinology, Ludwigs-Maximilians University of Munich, Munich, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Reisch
authors.affiliation: Department of Surgery, City Hospital, Starnberg, Germany.
authors.forename: Arnold
authors.initials: A
authors.lastname: Trupka
authors.affiliation: Department of Otorhinolaryngology, University of Erlangen, Erlangen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Brase
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Galiano
authors.affiliation: Department of Otolaryngology, University of Cologne, Cologne, Germany.
authors.forename: Simon F
authors.initials: SF
authors.lastname: Preuss
authors.affiliation: Department of Otorhinolaryngology, University of Regensburg, Regensburg, Germany.
authors.forename: Pingling
authors.initials: P
authors.lastname: Kwok
authors.affiliation: Molecular Medicine Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
authors.forename: Nikoletta
authors.initials: N
authors.lastname: Lendvai
authors.affiliation: Department of Nephrology and General Medicine, University Medical Center, Albert-Ludwigs University, Freiburg, Germany.
authors.forename: Gani
authors.initials: G
authors.lastname: Berisha
authors.affiliation: Division of Endocrine Surgery, Department of General Surgery, Ege University, Izmir, Turkey.
authors.forename: Özer
authors.initials: Ö
authors.lastname: Makay
authors.affiliation: Department of Otolaryngology, HELIOS Hanseklinikum Stralsund, Stralsund, Germany.
authors.forename: Carsten C
authors.initials: CC
authors.lastname: Boedeker
authors.affiliation: Department of Endocrinology, University of Nancy, Nancy, France.
authors.forename: Georges
authors.initials: G
authors.lastname: Weryha
authors.affiliation: Second Department of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Karoly
authors.initials: K
authors.lastname: Racz
authors.affiliation: Department of Hypertension, Institute of Cardiology, Warsaw, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Januszewicz
authors.affiliation: Department of Surgery and Center of Minimally Invasive Surgery, Kliniken Essen-Mitte, Essen, Germany.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Walz
authors.affiliation: Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.|Department of Surgery, Region Östergötland, Linköping, Sweden.
authors.forename: Oliver
authors.initials: O
authors.lastname: Gimm
authors.affiliation: Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Opocher
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
authors.affiliation: Section for Preventive Medicine, University Medical Center, Albert-Ludwigs University, Freiburg, Germany.
authors.forename: Hartmut P H
authors.initials: HPH
authors.lastname: Neumann
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics*; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D002648:Child; D004252:DNA Mutational Analysis; D055088:Early Detection of Cancer / Q000379:methods; D042963:Electron Transport Complex II / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D018095:Germ-Line Mutation; D006258:Head and Neck Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics*; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics; D016609:Neoplasms, Second Primary / Q000235:genetics*; D010236:Paraganglioma, Extra-Adrenal / Q000000981:diagnostic imaging / Q000235:genetics*; D019683:Penetrance; D010673:Pheochromocytoma / Q000000981:diagnostic imaging / Q000235:genetics*; D011446:Prospective Studies; D012042:Registries; D055815:Young Adult
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C499330:MAX protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C543341:SDHAF2 protein, human; C548370:TMEM127 protein, human; D042963:Electron Transport Complex II; C511268:SDHA protein, human