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

Division of Plastic Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pa. 19104, USA.
Plastic and Reconstructive Surgery (Impact Factor: 2.99). 04/2008; 121(3):919-31. 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.

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    • "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. "
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    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.
    No preview · Article · Mar 2011 · Indian Journal of Human Genetics
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    • "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. "
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    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 · Developmental Dynamics
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    • "Our data indicate that Fgfr3P244R/+ mice, a model of Muenke syndrome, have dominant, fully penetrant hearing loss that is more severe at low than at high frequencies. This is qualitatively similar, but more severe, than the hearing loss that we have documented in the largest audiological study of subjects with the Muenke syndrome mutation reported to date and is consistent with other recent work (20,22). These findings emphasize the need to ensure that all individuals heterozygous for the P250R mutation in FGFR3 are offered audiological testing and appropriate management for hearing loss. "
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    ABSTRACT: The heterozygous Pro250Arg substitution mutation in fibroblast growth factor receptor 3 (FGFR3), which increases ligand-dependent signalling, is the most common genetic cause of craniosynostosis in humans and defines Muenke syndrome. Since FGF signalling plays dosage-sensitive roles in the differentiation of the auditory sensory epithelium, we evaluated hearing in a large group of Muenke syndrome subjects, as well as in the corresponding mouse model (Fgfr3(P244R)). The Muenke syndrome cohort showed significant, but incompletely penetrant, predominantly low-frequency sensorineural hearing loss, and the Fgfr3(P244R) mice showed dominant, fully penetrant hearing loss that was more severe than that in Muenke syndrome individuals, but had the same pattern of relative high-frequency sparing. The mouse hearing loss correlated with an alteration in the fate of supporting cells (Deiters'-to-pillar cells) along the entire length of the cochlear duct, with the most extreme abnormalities found at the apical or low-frequency end. In addition, there was excess outer hair cell development in the apical region. We conclude that low-frequency sensorineural hearing loss is a characteristic feature of Muenke syndrome and that the genetically equivalent mouse provides an excellent model that could be useful in testing hearing loss therapies aimed at manipulating the levels of FGF signalling in the inner ear.
    Full-text · Article · Oct 2008 · Human Molecular Genetics
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