The Natural History of Patients Treated for FGFR3-Associated (Muenke-Type) Craniosynostosis

ArticleinPlastic and Reconstructive Surgery 121(3):919-31 · April 2008with9 Reads
DOI: 10.1097/01.prs.0000299936.95276.24 · Source: PubMed
Muenke-type craniosynostosis is defined as fibroblast growth factor receptor 3 (FGFR3)-associated coronal craniosynostosis with or without mental retardation. With complementary genetic information, more precise diagnosis and long-term functional outcome of cranial vault remodeling in affected patients can be studied, and additional distinct features of Muenke syndrome can now be investigated. This study was undertaken to assess craniofacial growth and long-term functional outcome in patients with Muenke-type craniosynostosis. A chart review of all FGFR3 patients at The Children's Hospital of Philadelphia who had undergone cranial vault remodeling for unicoronal or bicoronal synostosis (n = 16) was performed. Need for reoperation, midface surgery, and functional corrections were assessed. Audiology and orthodontic records were reviewed. All patients underwent cranial remodeling during infancy. Repeated intracranial surgery was performed or is currently scheduled for aesthetic reasons only (n = 7). Sexual dimorphism with male preponderance in FGFR3 unicoronal synostosis was detected. Despite dental crowding amenable to palatal expansion in patients with bicoronal synostosis, significant midface hypoplasia was not observed. Sensorineural hearing loss with a distinctive pattern was present in all patients who had undergone audiology testing. Patients with FGFR3-associated craniosynostosis demonstrate a sexual dimorphism, with a male preponderance for unicoronal synostosis. A secondary major intracranial procedure is required for recurrent supraorbital retrusion in at least 43 percent of patients. A secondary or tertiary extracranial forehead contouring procedure should be anticipated in nearly all patients. No patient required any midface correctional procedure. These patients demonstrate characteristic bilateral, symmetric, low- to mid-frequency sensorineural hearing loss.
    • "Once activated, this dimer permits autophosphorylation of the FGF receptor, which recruits intracellular signaling molecules such as phospholipase C and the mitogen-activated protein kinase cascade (Green et al., 1996 ). This has been shown to trigger a variety of subsequent paracrine responses, including chemotaxis, angiogenesis , apoptosis, and differentiation of mesenchymal and neuroectodermal cells (Green et al., 1996; Anderson et al., 1998; Ibrahimi et al., 2005; Coussens et al., 2007; Honnebier et al., 2008). Numerous growth factors also influence FGF receptor dimerization and the associated receptor expression in different tissues, allowing a diversity of response, development, and differ- entiation. "
    [Show abstract] [Hide abstract] ABSTRACT: Pediatric craniofacial surgery is a specialty that grew dramatically in the 20th century and continues to evolve today. Out of the efforts to correct facial deformities encountered during World War II, the techniques of modern craniofacial surgery developed. An analysis of the relevant literature allowed the authors to explore this historical progression. Current advances in technology, tissue engineering, and molecular biology have further refined pediatric craniofacial surgery. The development of distraction osteogenesis and the progressive study of craniosynostosis provide remarkable examples of this momentum. The growing study of genetics, biotechnology, the influence of growth factors, and stem cell research provide additional avenues of innovation for the future. The following article is intended to reveal a greater understanding of pediatric craniofacial surgery by examining the past, present, and possible future direction. It is intended both for the surgeon, as well as for the nonsurgical individual specialists vital to the multidisciplinary craniofacial team.
    Article · Jul 2011
    • "Muenke syndrome: The affected patients have macrocephaly, brachycephaly, plagiocephaly, with midfacial hypoplasia, coronal craniosynostosis, developmental delay, and sensorineural hearing loss.[1213] The acral anomalies include brachydactyly, clinodactyly, broad thimble like middle phalanges, broad toes, capitate-hamate fusions, and calcaneocuboidal fusions. "
    [Show abstract] [Hide abstract] ABSTRACT: Craniosynsostosis syndromes exhibit considerable phenotypic and genetic heterogeneity. Sagittal synostosis is common form of isolated craniosynostosis. The sutures involved, the shape of the skull and associated malformations give a clue to the specific diagnosis. Crouzon syndrome is one of the most common of the craniosynostosis syndromes. Apert syndrome accounts for 4.5% of all craniosynostoses and is one of the most serious of these syndromes. Most syndromic craniosynostosis require multidisciplinary management. The following review provides a brief appraisal of the various genes involved in craniosynostosis syndromes, and an approach to diagnosis and genetic counseling.
    Article · Mar 2011
    • "There is a higher likelihood of re-operation after remodelling of the skull in Muenke syndrome, compared to non-syndromic coronal synostosis (Thomas et al., 2005) and the cosmetic outcome may be less satisfactory (Arnaud et al., 2002; Honnebier et al., 2008). Further complications include developmental delay and a characteristic pattern of mild to moderate hearing loss, mostly sensorineural, with sparing at higher frequencies (Hollway et al., 1998; Doherty et al., 2007; Honnebier et al., 2008). The homozygous phenotype of the FGFR3 Pro250Arg mutation has not yet been recorded. "
    [Show abstract] [Hide abstract] ABSTRACT: Muenke syndrome, defined by heterozygosity for a Pro250Arg substitution in fibroblast growth factor receptor 3 (FGFR3), is the most common genetic cause of craniosynostosis in humans. We have used gene targeting to introduce the Muenke syndrome mutation (equivalent to P244R) into the murine Fgfr3 gene. A rounded skull and shortened snout (often skewed) with dental malocclusion was observed in a minority of heterozygotes and many homozygotes. Development of this incompletely penetrant skull phenotype was dependent on genetic background and sex, with males more often affected. However, these cranial abnormalities were rarely attributable to craniosynostosis, which was only present in 2/364 mutants; more commonly, we found fusion of the premaxillary and/or zygomatic sutures. We also found decreased cortical thickness and bone mineral densities in long bones. We conclude that although both cranial and long bone development is variably affected by the murine Fgfr3(P244R) mutation, coronal craniosynostosis is not reliably reproduced.
    Full-text · Article · Feb 2009
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