title: Legius syndrome in fourteen families.
abstract: Legius syndrome presents as an autosomal dominant condition characterized by café-au-lait macules with or without freckling and sometimes a Noonan-like appearance and/or learning difficulties. It is caused by germline loss-of-function SPRED1 mutations and is a member of the RAS-MAPK pathway syndromes. Most mutations result in a truncated protein and only a few inactivating missense mutations have been reported. Since only a limited number of patients has been reported up until now, the full clinical and mutational spectrum is still unknown. We report mutation data and clinical details in fourteen new families with Legius syndrome. Six novel germline mutations are described. The Trp31Cys mutation is a new pathogenic SPRED1 missense mutation. Clinical details in the 14 families confirmed the absence of neurofibromas, and Lisch nodules, and the absence of a high prevalence of central nervous system tumors. We report white matter T2 hyperintensities on brain MRI scans in 2 patients and a potential association between postaxial polydactyly and Legius syndrome.
authors.affiliation: Department of Human Genetics, Catholic University of Leuven, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: Denayer
authors.forename: Magdalena
authors.initials: M
authors.lastname: Chmara
authors.forename: Hilde
authors.initials: H
authors.lastname: Brems
authors.forename: Anneke Maat
authors.initials: AM
authors.lastname: Kievit
authors.forename: Yolande
authors.initials: Y
authors.lastname: van Bever
authors.forename: Ans M W
authors.initials: AM
authors.lastname: Van den Ouweland
authors.forename: Rick
authors.initials: R
authors.lastname: Van Minkelen
authors.forename: Arja
authors.initials: A
authors.lastname: de Goede-Bolder
authors.forename: Rianne
authors.initials: R
authors.lastname: Oostenbrink
authors.forename: Phillis
authors.initials: P
authors.lastname: Lakeman
authors.forename: Eline
authors.initials: E
authors.lastname: Beert
authors.forename: Takuma
authors.initials: T
authors.lastname: Ishizaki
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Mori
authors.forename: Kathelijn
authors.initials: K
authors.lastname: Keymolen
authors.forename: Jenneke
authors.initials: J
authors.lastname: Van den Ende
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
authors.forename: Sirkku
authors.initials: S
authors.lastname: Peltonen
authors.forename: Glen
authors.initials: G
authors.lastname: Brice
authors.forename: Julia
authors.initials: J
authors.lastname: Rankin
authors.forename: Karin Y
authors.initials: KY
authors.lastname: Van Spaendonck-Zwarts
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Eric
authors.initials: E
authors.lastname: Legius
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D001921:Brain / Q000473:pathology; D019080:Cafe-au-Lait Spots / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D009634:Noonan Syndrome / Q000175:diagnosis / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C504812:SPRED1 protein, human