Jaffe-Campanacci syndrome, revisited: detailed clinical and molecular analyses determine whether patients have neurofibromatosis type 1, coincidental manifestations, or a distinct disorder.
OBJECTIVE
"Jaffe-Campanacci syndrome" describes the complex of multiple nonossifying fibromas of the long bones, mandibular giant cell lesions, and café-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-Campanacci syndrome or 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 in 13 of 14 patients with multiple café-au-lait macules and multiple nonossifying fibromas or giant cell lesions ("classical" Jaffe-Campanacci syndrome); all 13 also fulfilled the National Institutes of Health diagnostic criteria for neurofibromatosis type 1. Somatic NF1 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.


CONCLUSIONS
In this study, the majority of patients with café-au-lait macules and nonossifying fibromas or giant cell lesions harbored a pathogenic germline 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 NF1 in two giant cell lesions from two unrelated patients, establishing these as neurofibromatosis type 1-associated tumors.
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA.
Douglas R
DR
Stewart
1] Department of Human Genetics, University of Leuven, Leuven, Belgium [2] Center for Human Genetics, Leuven University Hospitals, Leuven, Belgium.
Hilde
H
Brems
Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Alabama, USA.
Alicia G
AG
Gomes
Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Sarah L
SL
Ruppert
Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Alabama, USA.
Tom
T
Callens
Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Alabama, USA.
Jennifer
J
Williams
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Kathleen
K
Claes
Division of Medical Genetics, Department of Pediatrics A.I. duPont Hospital for Children, Wilmington, Delaware, USA.
Michael B
MB
Bober
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Rachel
R
Hachen
Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
Leonard B
LB
Kaban
Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida, USA.
Hua
H
Li
Genetics Unit, MassGeneral Hospital for Children, Boston, Massachusetts, USA.
Angela
A
Lin
1] Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA [2] Department of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA.
Marie
M
McDonald
1] Department of Medical Genetics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada [2] Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
Serge
S
Melancon
1] Department of Medical Genetics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada [2] Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
June
J
Ortenberg
Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.
Heather B
HB
Radtke
Department of Orthopedic Surgery, University Hospitals Leuven, Leuven, Belgium.
Ignace
I
Samson
Greenwood Genetic Center, Greenwood, South Carolina, USA.
Robert A
RA
Saul
Medical Genetics/Metabolism, Children's Hospital Central California, Madera, California, USA.
Joseph
J
Shen
Children's Hospitals and Clinics of Minnesota, Department of Genetics, Minneapolis, Minnesota, USA.
Elizabeth
E
Siqveland
Division of Medical Genetics, Massachusetts General Hospital, Boston, Massachusetts, USA.
Tomi L
TL
Toler
Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands.
Merel
M
van Maarle
Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida, USA.
Margaret
M
Wallace
LewisGale Regional Health System, Department of Clinical Genetics, Salem, Virginia, USA.
Misti
M
Williams
1] Department of Human Genetics, University of Leuven, Leuven, Belgium [2] Center for Human Genetics, Leuven University Hospitals, Leuven, Belgium.
Eric
E
Legius
Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Alabama, USA.
Ludwine
L
Messiaen
D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D001859:Bone Neoplasms / Q000235:genetics; D019080:Cafe-au-Lait Spots / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002864:Chromogranins; D005260:Female; D005350:Fibroma / Q000235:genetics; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009456:Neurofibromatosis 1 / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D025542:Neurofibromin 1 / Q000235:genetics*; D012744:Sex Ratio; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; D002864:Chromogranins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D025542:Neurofibromin 1; C504812:SPRED1 protein, human; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs