Fibroblast growth factor receptor mutational screening in newborns affected by metopic synostosis

Abstract

A number of craniosynostotic disorders have recently been ascribed to mutations in genes coding for the fibroblast growth factor receptors(FGFRs). The common feature of these FGFR-associated conditions is the unilateral or bilateral premature ossification of the coronal suture. One distinct craniosynostotic condition is trigonocephaly, which results from the premature fusion of the metopic suture. Trigonocephaly mostly occurs as isolated cranial defect; however, the premature closure of the metopic suture may represent a feature of more complex craniosynostotic conditions in which a progressive involvement of other cranial sutures with age is observed. The possible involvement of mutated FGFRs in trigonocephaly was investigated in nine newborns affected by isolated premature synostosis of the metopic suture. All except one of these cases carried no mutations in the FGFR1-3 domains indicated as hot spots for craniosynostosis-associated mutations. A T(978)C transition in the FGFR2 exon IIIa was found in a patient who had a phenotype that apparently fitted the trigonocephalic condition at birth, but showed additional facial anomalies, which worsened progressively with age towards a Crouzon-like profile. The present finding points out the importance, from both diagnostic and prognostic points of view, of early FGFR mutational screening in craniosynostotic conditions, even in forms that apparently do not involve closure of the coronal suture at birth.

An unusual FGFR1 mutation (fibroblast growth factor receptor 1 mutation) in a girl with non-syndromic trigonocephaly

“…Trigonocephaly at birth was described in at least one patient with an FGFR2 mutation (Tartaglia et al, 1999); but with progressing age it changed towards a Crouzon-like phenotype. This did not occur in our patient.…”

Metopic craniosynostosis due to mutations inGLI3: A novel association

“…Examples of syndromic metopic craniosynostosis include: valproic acid embryopathy [Lajeunie et al, 2001]; chromosomal aneuploidy such as deletions of 9p and 11q [Azimi et al, 2003; Johnston et al, 2005]; and several previously described malformation syndromes whose molecular basis has yet to be defined including Frydman syndrome [Frydman et al, 1984], Opitz C trigonocephaly syndrome [Opitz, 1969; Azimi et al, 2003], Say Meyer trigonocephaly syndrome [Say and Meyer, 1981; Azimi et al, 2003], and autosomal dominant trigonocephaly [Hennekam and Van Den Boogaard, 1990]. In addition, trigonocephaly has occasionally been observed in association with well described craniosynostosis conditions such as Crouzon syndrome due to a Ser267Pro mutation in FGFR2 [Tartaglia et al, 1999]; Muenke syndrome due to the Pro250Arg mutation in FGFR3 [van der Meulen et al, 2006]; and Saethre–Chotzen syndrome, prior to the availability of mutational analysis/microdeletion testing [Cristofori and Filippi, 1992; and Hunter et al, 1976 as suggested by Cohen and MacLean, 2000]. Moreover, a child with nonsyndromic trigonocephaly was recently reported with an unusual mutation in the IgIII loop domain of FGFR1 (Ile300Trp) [Kress et al, 2000].…”

Mutational Screening of FGFR1, CER1, and CDON in a Large Cohort of Trigonocephalic Patients

“…Although most mutations in the known craniosynostosis-related genes (FGFR1-3 and TWIST1) result in syndromic coronal synostosis, several investigators have looked at the involvement of these genes in patients with metopic synostosis (Tartaglia et al, 1999;Kress et al, 2000;Kan et al, 2004). Kress et al (2000) found an unusual mutation in the IgIII loop domain of FGFR1 (Ile300Trp) in 1 of 10 patients with trigonocephaly.…”