title: Clinical predictors and algorithm for the genetic diagnosis of pheochromocytoma patients.
abstract: OBJECTIVE
  Six pheochromocytoma susceptibility genes causing distinct syndromes have been identified; approximately one of three of all pheochromocytoma patients carry a predisposing germline mutation. When four major genes (VHL, RET, SDHB, SDHD) are analyzed in a clinical laboratory, costs are approximately $3,400 per patient. The aim of the study is to systematically obtain a robust algorithm to identify who should be genetically tested, and to determine the order in which genes should be tested.
  
  
  METHODS
  DNA from 989 apparently nonsyndromic patients were scanned for germline mutations in the genes VHL, RET, SDHB, SDHC, and SDHD. Clinical parameters were analyzed as potential predictors for finding mutations by multiple logistic regression, validated by bootstrapping. Cost reduction was calculated between prioritized gene testing compared with that for all genes.
  
  
  RESULTS
  Of 989 apparently nonsyndromic pheochromocytoma cases, 187 (19%) harbored germline mutations. Predictors for presence of mutation are age <45 years, multiple pheochromocytoma, extra-adrenal location, and previous head and neck paraganglioma. If we used the presence of any one predictor as indicative of proceeding with gene testing, then 342 (34.6%) patients would be excluded, and only 8 carriers (4.3%) would be missed. We were also able to statistically model the priority of genes to be tested given certain clinical features. E.g., for patients with prior head and neck paraganglioma, the priority would be SDHD>SDHB>RET>VHL. Using the clinical predictor algorithm to prioritize gene testing and order, a 44.7% cost reduction in diagnostic process can be achieved.
  
  
  CONCLUSIONS
  Clinical parameters can predict for mutation carriers and help prioritize gene testing to reduce costs in nonsyndromic pheochromocytoma presentations.
authors.affiliation: Department of Nephrology, Section of Preventive Medicine, Albert-Ludwigs-University, Hugstetter Strasse 55, Freiburg, Germany.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Erlic
authors.forename: Lisa
authors.initials: L
authors.lastname: Rybicki
authors.forename: Mariola
authors.initials: M
authors.lastname: Peczkowska
authors.forename: Henriette
authors.initials: H
authors.lastname: Golcher
authors.forename: Peter H
authors.initials: PH
authors.lastname: Kann
authors.forename: Michael
authors.initials: M
authors.lastname: Brauckhoff
authors.forename: Karsten
authors.initials: K
authors.lastname: Müssig
authors.forename: Michaela
authors.initials: M
authors.lastname: Muresan
authors.forename: Andreas
authors.initials: A
authors.lastname: Schäffler
authors.forename: Nicole
authors.initials: N
authors.lastname: Reisch
authors.forename: Matthias
authors.initials: M
authors.lastname: Schott
authors.forename: Martin
authors.initials: M
authors.lastname: Fassnacht
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Opocher
authors.forename: Silke
authors.initials: S
authors.lastname: Klose
authors.forename: Christian
authors.initials: C
authors.lastname: Fottner
authors.forename: Flavio
authors.initials: F
authors.lastname: Forrer
authors.forename: Ursula
authors.initials: U
authors.lastname: Plöckinger
authors.forename: Stephan
authors.initials: S
authors.lastname: Petersenn
authors.forename: Dimitry
authors.initials: D
authors.lastname: Zabolotny
authors.forename: Oleg
authors.initials: O
authors.lastname: Kollukch
authors.forename: Svetlana
authors.initials: S
authors.lastname: Yaremchuk
authors.forename: Andrzej
authors.initials: A
authors.lastname: Januszewicz
authors.forename: Martin K
authors.initials: MK
authors.lastname: Walz
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
authors.forename: Hartmut P H
authors.initials: HP
authors.lastname: Neumann
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D000465:Algorithms; D005192:Family Health; D005260:Female; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000191:economics; D006258:Head and Neck Neoplasms / Q000150:complications; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010235:Paraganglioma / Q000150:complications; D010673:Pheochromocytoma / Q000175:diagnosis* / Q000191:economics / Q000235:genetics*