title: Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations.
abstract: Thirty-two unrelated patients with features of Saethre-Chotzen syndrome, a common autosomal dominant condition of craniosynostosis and limb anomalies, were screened for mutations in TWIST, FGFR2, and FGFR3. Nine novel and three recurrent TWIST mutations were found in 12 families. Seven families were found to have the FGFR3 P250R mutation, and one individual was found to have an FGFR2 VV269-270 deletion. To date, our detection rate for TWIST or FGFR mutations is 68% in our Saethre-Chotzen syndrome patients, including our five patients elsewhere reported with TWIST mutations. More than 35 different TWIST mutations are now known in the literature. The most common phenotypic features, present in more than a third of our patients with TWIST mutations, are coronal synostosis, brachycephaly, low frontal hairline, facial asymmetry, ptosis, hypertelorism, broad great toes, and clinodactyly. Significant intra- and interfamilial phenotypic variability is present for either TWIST mutations or FGFR mutations. The overlap in clinical features and the presence, in the same genes, of mutations for more than one craniosynostotic condition-such as Saethre-Chotzen, Crouzon, and Pfeiffer syndromes-support the hypothesis that TWIST and FGFRs are components of the same molecular pathway involved in the modulation of craniofacial and limb development in humans.
authors.affiliation: Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21287-3914, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Paznekas
authors.forename: M L
authors.initials: ML
authors.lastname: Cunningham
authors.forename: T D
authors.initials: TD
authors.lastname: Howard
authors.forename: B R
authors.initials: BR
authors.lastname: Korf
authors.forename: M H
authors.initials: MH
authors.lastname: Lipson
authors.forename: A W
authors.initials: AW
authors.lastname: Grix
authors.forename: M
authors.initials: M
authors.lastname: Feingold
authors.forename: R
authors.initials: R
authors.lastname: Goldberg
authors.forename: Z
authors.initials: Z
authors.lastname: Borochowitz
authors.forename: K
authors.initials: K
authors.lastname: Aleck
authors.forename: J
authors.initials: J
authors.lastname: Mulliken
authors.forename: M
authors.initials: M
authors.lastname: Yin
authors.forename: E W
authors.initials: EW
authors.lastname: Jabs
mesh_terms: D000168:Acrocephalosyndactylia / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D002675:Child, Preschool; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins; D010641:Phenotype; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics*; D051879:Twist-Related Protein 1
chemical_list: D009687:Nuclear Proteins; D017468:Receptors, Fibroblast Growth Factor; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1