title: Germline NF1 mutational spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1.
abstract: BACKGROUND
  Neurofibromatosis type 1 (NF1) is a pheochromocytoma-associated syndrome. Because of the low prevalence of pheochromocytoma in NF1, we ascertained subjects by pheochromocytoma that also had NF1 in the hope of describing the germline NF1 mutational spectra of NF1-related pheochromocytoma.
  
  
  METHODS
  An international registry for NF1-pheochromocytomas was established. Mutation scanning was performed using denaturing HPLC for intragenic variation and quantitative PCR for large deletions. Loss-of-heterozygosity analysis using markers in and around NF1 was performed.
  
  
  RESULTS
  There were 37 eligible subjects (ages 14-70 yr). Of 21 patients with corresponding tumor available, 67% showed somatic loss of the nonmutated allele at the NF1 locus vs. 0 of 12 sporadic tumors (P = 0.0002). Overall, 86% of the 37 patients had exonic or splice site mutations, 14% large deletions or duplications; 79% of the mutations are novel. The cysteine-serine rich domain (CSR) was affected in 35% but the RAS GTPase activating protein domain (RGD) in only 13%. There did not appear to be an association between any clinical features, particularly pheochromocytoma presentation and severity, and NF1 mutation genotype.
  
  
  CONCLUSIONS
  The germline NF1 mutational spectra comprise intragenic mutations and deletions in individuals with pheochromocytoma and NF1. NF1 mutations tended to cluster in the CSR over the RAS-GAP domain, suggesting that CSR plays a more prominent role in individuals with NF1-pheochromocytoma than in NF1 individuals without this tumor. Loss-of-heterozygosity of NF1 markers in NF1-related pheochromocytoma was significantly more frequent than in sporadic pheochromocytoma, providing further molecular evidence that pheochromocytoma is a true component of NF1.
authors.affiliation: Department of Neurology, University Medical Center Freiburg, Germany.
authors.forename: Birke
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authors.lastname: Mannelli
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authors.lastname: Palazzo
authors.forename: Marta
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authors.lastname: Walz
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authors.forename: Ann-Cathrin
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authors.lastname: Koschker
authors.forename: Felix
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authors.lastname: Lohoefner
authors.forename: Markus
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authors.forename: Oliver
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authors.lastname: Gimm
authors.forename: Barbara
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authors.lastname: Jarzab
authors.forename: Sarah R
authors.initials: SR
authors.lastname: McWhinney
authors.forename: Giuseppe
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authors.lastname: Opocher
authors.forename: Andrzej
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authors.lastname: Januszewicz
authors.forename: Jürgen
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mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009456:Neurofibromatosis 1 / Q000453:epidemiology / Q000235:genetics*; D025542:Neurofibromin 1 / Q000235:genetics*; D010673:Pheochromocytoma / Q000453:epidemiology / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: D025542:Neurofibromin 1