Jaffe-Campanacci syndrome, revisited: detailed clinical and molecular analyses determine whether patients have neurofibromatosis type 1, coincidental manifestations, or a distinct disorder

Purpose: "Jaffe-Campanacci syndrome" describes the complex of multiple nonossifying fibromas of the long bones, mandibular giant cell lesions, and cafe-au-lait macules in individuals without neurofibromas. We sought to determine whether Jaffe-Campanacci syndrome is a distinct genetic entity or a variant of neurofibromatosis type 1. Methods: We performed germline NF1, SPRED1, and GNAS1 (exon 8) mutation testing on patients with Jaffe-Cainpanacci syndrome of Jaffe-Campanacci syndrome-related features, We also performed somatic NF1 mutation testing on nonossifying fibromas and giant, cell lesions. Results: Pathogenic germline NF1 mutations Were identified 13 of 14 patients with multiple cafe-au-lait macules and niultiple non-ossifying fibromas or giant cell lesions ("classicar Jaffe-Campanacci syndrome); all 13 also fulfilled the National Institues of Health diagnostic criteria for neurofibromatosis type 1. Somatic NFI mutations were detected in two giant cell lesions but not in two nonossifying fibromas. No SPRED1 or GNAS1 (exon 8) mutations were detected in the seven NF1-negative patients with Jaffe-Campanacci syndrome, nonossifying fibromas, or giant cell lesions. Conclusion: In this study, the majority of patients with cafe-au-lait macules and nonossifying fibromas Or giant cell lesions harbored a pathogenic gerinline NF1 mutation,suggesting that many Jaffe-Campanacci syndrome cases may-actually have neurofibromatosis type 1. We provide the first proof of specific somatic second-hit mutations affecting NFI in two giant cell lesions from two unrelated patients, establishing these as neurofibromatosis type 1-associated tumors.