title: Phenotypic diversity in patients with craniosynostoses unrelated to Apert syndrome: the role of fibroblast growth factor receptor gene mutations.
abstract: OBJECTIVE
  The goal of this study was to elucidate the genotype-phenotype relationship in syndromic craniosynostoses by analyzing the mutations of the fibroblast growth factor receptor (FGFR) gene and its clinical manifestations in patients, particularly those in atypical cases.
  
  
  METHODS
  Twenty patients with craniosynostoses unrelated to Apert syndrome were enrolled in this study. The phenotypes indicated the following syndromes: 12 patients with unrelated Crouzon syndrome, including nine sporadic and three familial cases; two with sporadic Pfeiffer syndrome; and one with Antley-Bixler syndrome. The Crouzon phenotype was subdivided into three clinical forms: regular, top, and bottom ones. Two patients who demonstrated craniofacial anomalies and bilateral elbow joint contractures were categorized as having an unspecified craniosynostosis. Three cases of unclassifiable cloverleaf skull malformation were also analyzed. Fourteen mutations of the FGFR2 gene were identified in these patients; seven of the 10 cysteine-related mutations were substitutions of codon 342 in the third immunoglobulin-like domain of this gene. The phenotypes of these seven cases were three of regular Crouzon, two of unspecified craniosynostosis, and one each of top Crouzon and unclassifiable cloverleaf skull malformation. In addition, four of the seven patients were found to have the same genotype (Cys342Arg). The phenotypes of these patients, however, were quite variable, ranging from regular Crouzon to unclassifiable cloverleaf skull malformation.
  
  
  CONCLUSIONS
  The phenotypes of patients with craniosynostoses unrelated to Apert syndrome proved quite variable, even in cases in which patients demonstrated the same genotype. In view of the phenotypic diversity evident in cases in which the same mutation in the FGFR2 gene is present, it is possible that other disease-modifying genetic factors exist to control the abnormal gain-of-function that accompanies FGFR signaling.
authors.affiliation: Department of Neurosurgery, Yokohama City University Medical Center and Yokohama City University School of Medicine, Japan. sinito@mars.dti.ne.jp
authors.forename: Susumu
authors.initials: S
authors.lastname: Ito
authors.forename: Ken'ichi
authors.initials: K
authors.lastname: Sekido
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kanno
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sato
authors.forename: Masaaki
authors.initials: M
authors.lastname: Tanaka
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Isao
authors.initials: I
authors.lastname: Yamamoto
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003398:Craniosynostoses / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D010641:Phenotype; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D012720:Severity of Illness Index; D015398:Signal Transduction; D012886:Skull / Q000002:abnormalities
chemical_list: D017468:Receptors, Fibroblast Growth Factor