Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations.
Noonan syndrome (NS) is an autosomal dominant disorder caused by mutations in PTPN11, KRAS, SOS1, and RAF1. We performed SOS1, RAF1, BRAF, MEK1, and MEK2 mutation analysis in a cohort of 102 PTPN11- and KRAS-negative NS patients and found pathogenic SOS1 mutations in 10, RAF1 mutations in 4, and BRAF mutations in 2 patients. Three novel SOS1 mutations were found. One was classified as a rare benign variant and the other remains unclassified. We confirm a high prevalence of pulmonic stenosis and ectodermal abnormalities in SOS1-positive patients. Three patients with SOS1 mutations presented with tumors (embryonal rhabdomyosarcoma, Sertoli cell testis tumor, and granular cell tumors of the skin). One patient with a RAF1 mutation had a lesion suggestive for a giant cell tumor. This is the first report describing different tumor types in NS patients with germ line SOS1 mutations.
Denayer
Ellen
E
Department of Human Genetics, University of Leuven, Leuven, Belgium.
Devriendt
Koen
K
de Ravel
Thomy
T
Van Buggenhout
Griet
G
Smeets
Eric
E
Francois
Inge
I
Sznajer
Yves
Y
Craen
Margarita
M
Leventopoulos
George
G
Mutesa
Léon
L
Vandecasseye
Willy
W
Massa
Guy
G
Kayserili
Hulya
H
Sciot
Raf
R
Fryns
Jean-Pierre
JP
Legius
Eric
E
D000293:Adolescent; D019943:Amino Acid Substitution; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods; D005091:Exons; D020440:Gene Duplication; D006801:Humans; D007962:Leukocytes / Q000502:physiology; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D048370:MAP Kinase Kinase 2 / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics*; D009634:Noonan Syndrome / Q000150:complications / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D020837:SOS1 Protein / Q000235:genetics*; D055815:Young Adult
D020837:SOS1 Protein; C482128:MAP2K2 protein, human; D019908:Proto-Oncogene Proteins c-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human