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Comprehensive Mutation Scanning of NF1 in Apparently Sporadic Cases of Pheochromocytoma

Departments of Nephrology (B.B., H.P.H.N.) and Laboratory Medicine (M.M.H.), Albert-Ludwigs-University, D 79106 Freiburg, Germany; Departments of Endocrinology (A.-C.K., M.F., B.A.) and Dermatology (J.S.), Julius-Maximilians-University, D 97070 Würzburg, Germany; Genomic Medicine Institute (C.E.), Cleveland Clinic Foundation, Cleveland, Ohio 44195; and Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

Address all correspondence and requests for reprints to: Hartmut P. H. Neumann, M.D., Medizinische Universitätsklinik, Hugstetter Straße 55, D 79106 Freiburg, Germany. E-mail: neumann{at}med1.ukl.uni-freiburg.de.

Background: Pheochromocytoma is a rare manifestation in patients with neurofibromatosis type 1 (NF 1). The 57-exon susceptibility gene NF1 has so far not been systematically scanned for unexpected germline mutations in individuals with sporadic pheochromocytoma.

Methods: Twenty-seven patients with bilateral adrenal and/or extraadrenal abdominal pheochromocytoma not carrying germline mutations of the genes VHL, RET, SDHB, and SDHD were selected from the European-American pheochromocytoma registry. All 57 exons and flanking intronic regions of the NF1 gene were PCR amplified using newly designed primer pairs to exclude the amplification of pseudogenes. Intragenic mutation scanning was performed using denaturing HPLC and bidirectional direct sequencing.

Results: Of the 27 apparently sporadic cases, one (4%) was found to have a pathogenic germline NF1 mutation, Leu303Arg. Clinical reevaluation of this individual, who had bilateral pheochromocytoma, revealed classic, but very mild, features of NF 1, one cutaneous neurofibroma, axillary freckling, and Lisch nodules of the iris as well as a few café-au-lait spots.

Conclusions: In the absence of germline mutations in VHL, RET, SDHD, and SDHB, patients with pheochromocytoma, especially with bilateral disease, should be checked thoroughly for clinical lesions suggestive of underlying syndromes such as the cutaneous and ophthalmological features characteristic of NF 1.

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