Disease relevance of Craniosynostoses

• Pfeiffer syndrome (PS; McKusick MIM 101,600) is an autosomal dominant craniosynostosis syndrome with characteristic craniofacial anomalies and broad thumbs and big toes [1].
• Since the Gly380Arg achondroplasia mutation was recognized, similar observations regarding the conserved nature of FGFR mutations and resulting phenotype have been made regarding other skeletal phenotypes, including hypochondroplasia, thanatophoric dysplasia, and Muenke coronal craniosynostosis [2].
• Gain-of-function mutations of FGF receptors (FGFR) cause craniosynostosis, premature fusion of the skull, and dwarfism syndromes [3].
• Females have frontonasal dysplasia and coronal craniosynostosis (fusion of the coronal sutures); in males, hypertelorism is the only typical manifestation [4].
• Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are responsible for several autosomal dominant craniosynostosis syndromes and chondrodysplasias i.e. hypochondroplasia, achondroplasia, SADDAN and thanatophoric dysplasia--a neonatal lethal dwarfism syndrome [5].

Psychiatry related information on Craniosynostoses

• Apert syndrome is characterized by coronal craniosynostosis, midfacial hypoplasia, symmetrical syndactyly of the hands and feet described as 'mitten-like' with varying degrees of mental retardation [6].

High impact information on Craniosynostoses

• Gain of function mutations in fibroblast growth factor (FGF) receptors cause chondrodysplasia and craniosynostosis syndromes [7].
• INTERPRETATION: The C749G mutation in FGFR3 is a frequent cause of apparently non-syndromic coronal craniosynostosis [8].
• We aimed to find out the proportion of cases of apparently non-syndromic coronal craniosynostosis attributable to this mutation [8].
• Dominantly acting mutations of the fibroblast growth factor (FGF) receptor 2 (FGFR2) gene have been implicated in various craniosynostosis syndromes [9].
• Human craniosynostosis syndromes, resulting from activating or neomorphic mutations in fibroblast growth factor receptor 2 (FGFR2), underscore an essential role for FGFR2 signaling in skeletal development [10].

Chemical compound and disease context of Craniosynostoses

• We have studied the biological effects of the most commonly mutated cysteine residue in FGFR-2 which is detected in individuals with Crouzon syndrome, an autosomally dominant trait which causes premature fusion of the skull bones (craniosynostosis) [11].
• A morphometric, neuroanatomical, and behavioral study on the effects of geometric constraint on the growing brain: the methyl 2-cyanoacrylate craniosynostosis model [12].
• OBJECT: A recurrent point mutation in the fibroblast growth factor receptor 3 gene that converts proline 250 into arginine has been reported recently in cases of apparently nonsyndromic coronal craniosynostosis [13].
• Polyglycolic acid membrane interpositioning for the prevention of skull deformity following experimental craniosynostosis [14].

Biological context of Craniosynostoses

• Apert, Crouzon, Jackson-Weiss, and Pfeiffer syndromes are craniosynostoses genetically linked in part to 10q25-q26 and are associated with point mutations in the extracellular domain of FGFR2 [15].
• Mutation of the FGFR genes has been recognized recently in human craniosynostoses where a single base pair mutation in the FGFR gene results in skeletal malformations specific to each syndrome [16].
• We performed the first in utero correction of a unilateral right coronal craniosynostosis using 70-day gestation fetal lambs [17].
• These experimental data on bone growth factors support the recent human genetics data linking growth factor/fibroblast growth factor receptor deletions to syndromal craniosynostoses [18].
• Because of the incomplete penetrance of this anomaly, the suspicion of Muenke syndrome must be raised in any child with uni- or bilateral coronal craniosynostosis, and the genetic analysis propounded even in the absence of extracranial features [19].

Anatomical context of Craniosynostoses

• Prevalence of Pro250Arg mutation of fibroblast growth factor receptor 3 in coronal craniosynostosis [8].
• Saethre-Chotzen syndrome (ACS III) is an autosomal dominant craniosynostosis syndrome recently ascribed to mutations in the TWIST gene, a basic helix-loop-helix (b-HLH) transcription factor regulating head mesenchyme cell development during cranial neural tube formation in mouse [20].
• Raman imaging demonstrates FGF2-induced craniosynostosis in mouse calvaria [21].
• The craniosynostosis was created in eight fetuses by excising their right coronal sutures, and then placing demineralized bone powder, transforming growth factor-beta, and bone morphogenetic protein-2 into the defect [17].
• This study was designed to test this hypothesis by surgically manipulating the coronal suture and dura mater in rabbits with familial craniosynostosis to prevent postsurgical resynostosis [22].

Gene context of Craniosynostoses

• Here we report two identical mutations in FGFR2 that cause craniosynostosis syndromes, Crouzon, Apert, and Pfeiffer in gastric carcinoma [23].
• OBJECT: Heterogeneous mutations in the fibroblast growth factor receptor 2 gene (FGFR2) cause a range of craniosynostosis syndromes [24].
• Description of a new mutation and characterization of FGFR1, FGFR2, and FGFR3 mutations among Brazilian patients with syndromic craniosynostoses [25].
• Mutations in FGFR1, -2, and -3 are linked to five human craniosynostosis syndromes [26].
• The p148h mutation in Msx2 augments the Miz1 effect on Msx2 DNA binding, suggesting a reason why this mutation behaves in vivo as a dominant positive, and providing a potential explanation of the craniosynostosis phenotype [27].
• These results illustrate a pathogenic role for ERK activation in craniosynostosis resulting from FGFR2 with the S252W substitution and introduce a new concept of small-molecule inhibitor-mediated prevention and therapy for diseases caused by gain-of-function mutations in the human genome [28].

Analytical, diagnostic and therapeutic context of Craniosynostoses

• OBJECTIVE: The role of the human fibroblast growth factor receptor (FGFR) gene family in current prenatal diagnosis and management of craniosynostosis syndromes and skeletal dysplasias is discussed [29].
• Coronal suture response to distraction osteogenesis in rabbits with delayed-onset craniosynostosis [30].
• FGFR3 P250R mutation increases the risk of reoperation in apparent 'nonsyndromic' coronal craniosynostosis [31].

References