Germline NF1 mutational spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1

Birke Bausch, Wiktor Borozdin, Victor F. Mautner, Michael M. Hoffmann, Detlef Boehm, Mercedes Robledo, Alberto Cascon, Tomas Harenberg, Francesca Schiavi, Christian Pawlu, Mariola Peczkowska, Claudio Letizia, Stefano Calvieri, Giorgio Arnaldi, Rolf D. Klingenberg-Noftz, Nicole Reisch, Ambrogio Fassina, Laurent Brunaud, Martin A. Walter, Massimo MannelliGraham MacGregor, F. Fausto Palazzo, Marta Barontini, Martin K. Walz, Bernhard Kremens, Georg Brabant, Roland Pfäffle, Ann Cathrin Koschker, Felix Lohoefner, Markus Mohaupt, Oliver Gimm, Barbara Jarzab, Sarah R. McWhinney, Giuseppe Opocher, Andrzej Januszewicz, Jürgen Kohlhase, Charis Eng, Hartmut P H Neumann

Research output: Contribution to journalArticlepeer-review


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. Materials and 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 RASGAP 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.

Original languageEnglish
Pages (from-to)2784-2792
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Issue number7
Publication statusPublished - Jul 2007

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism


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