Genetic basis of potential therapeutic strategies for craniosynostosis

  title={Genetic basis of potential therapeutic strategies for craniosynostosis},
  author={Heather Melville and Yingli Wang and Peter J. Taub and Ethylin Wang Jabs},
  journal={American Journal of Medical Genetics Part A},
Craniosynostosis, the premature fusion of one or more cranial sutures, is a common malformation of the skull that can result in facial deformity and increased intracranial pressure. Syndromic craniosynostosis is present in ∼15% of craniosynostosis patients and often is clinically diagnosed by neurocranial phenotype as well as various other skeletal abnormalities. The most common genetic mutations identified in syndromic craniosynostosis involve the fibroblast growth factor receptor (FGFR… 
Current Approaches in the Development of Molecular and Pharmacological Therapies in Craniosynostosis Utilizing Animal Models
Various molecular and pharmacological approaches for the treatment of craniosynostosis that have been tested using in vitro and in vivo assays are presented and their potential application in humans is discussed focusing on the case of tyrosine kinase inhibitors.
A Genetic-Pathophysiological Framework for Craniosynostosis.
Clinical applications of molecular basis for Craniosynostosis. A narrative review.
Future preventive therapeutic strategies may include the use of specific drugs that can regulate the expression and activation of FGF signaling pathways, TGF-β or BMPs, to prevent or avoid craniosynostosis or re-synostosis after a surgery.
Syndromic Craniosynostosis Can Define New Candidate Genes for Suture Development or Result from the Non-specifc Effects of Pleiotropic Genes: Rasopathies and Chromatinopathies as Examples
It is found that craniosynostosis is a relatively common component manifestation of cardio-facio-cutaneous (CFC) syndrome and is randomly associated with Kabuki, Koolen-de Vries/KANSL1 haploinsufficiency and Mowat–Wilson syndromes and in KAT6B-related disorders.
Evidence-Based Medicine: Nonsyndromic Craniosynostosis
Nonsyndromic craniosynostosis is a pathologic condition associated with the premature fusion of one or more cranial sutures that leads to a compensatory expansion into regions of the skull that are not affected.
Mutation Screening of Candidate Genes in Patients with Nonsyndromic Sagittal Craniosynostosis
The low mutation detection rate indicates that these genes account for only a small proportion of sagittal nonsyndromic craniosynostosis patients, and adds to the perception that sagittal nondouble-craniosynostosis is a complex developmental defect with considerable genetic heterogeneity.
Recent advances in neurosurgery, neuromonitoring and neurointensive care (NIC) have dramatically improved the outcome in patients affected by surgical lesions of central nervous system (CNS), most of these techniques were applied in the adult population; paediatric patients present a set of inherent challenges.
Reliable manifestations of increased intracranial pressure in patients with syndromic craniosynostosis.
  • S. Y. Kim, J. Choi, H. Shin, S. Lim
  • Medicine
    Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery
  • 2019
Endoscopic craniosynostosis repair.
Clinical experience and a large number of publications have substantiated the benefits of minimally invasive endoscopic techniques for the treatment of craniosynostosis, and these techniques should be part of the standard of care for this condition at craniofacial centers.
Craniosynostosis with Ectopia Lentis and a Homozygous 20-base Deletion in ADAMTSL4
A homozygous deletion in exon 6 of ADAMTSL4 (c.767_786del 20) that has been shown to cause isolated ectopia lentis was found and may represent an overlapping syndrome with a causative mutation in ADAMtsL4.


Craniosynostosis syndromes: from genes to premature fusion of skull bones.
The observation of mutations in different genes in atients and families with syndromal craniosynososis confirmed the proposed genetic heterogeneity and supported the idea of addiional genetic and environmental factors modifyng the initial mutation effect and/or contributing to he pathogenesis in isolated cases of unknown etiolgy.
Skeletal analysis of the Fgfr3P244R mouse, a genetic model for the Muenke craniosynostosis syndrome
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    Developmental dynamics : an official publication of the American Association of Anatomists
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It is concluded that although both cranial and long bone development is variably affected by the murine Fgfr3P244R mutation, coronal craniosynostosis is not reliably reproduced.
A model for the pharmacological treatment of crouzon syndrome.
The successful use of PD173074 is reported to prevent in vitro suture fusion in a model for Crouzon syndrome to develop a pharmacological strategy using tyrosine kinase inhibition as a novel treatment for craniosynostotic syndromes caused by constitutive FGFR activation.
Medical treatment of craniosynostosis: recombinant Noggin inhibits coronal suture closure in the rat craniosynostosis model.
The chimeric nude rate model is a viable model of craniosynostosis and the addition of rhNoggin to prematurely fusing sutures should prevent synostosis, demonstrating one of the mechanisms for premature suture fusion.
Clinical dividends from the molecular genetic diagnosis of craniosynostosis
It is shown how mutations in the FGFR2, FGFR3, TWIST1, and EFNB1 genes have been shown to account for ∼25% of craniosynostosis, whilst several additional genes make minor contributions.
Attenuation of signaling pathways stimulated by pathologically activated FGF-receptor 2 mutants prevents craniosynostosis
Experiments show that attenuation of FGFR signaling by pharmacological intervention could be applied for the treatment of craniosynostosis or other severe bone disorders caused by mutations in FGFRs that currently have no treatment.
FGFR3 P250R Mutation Increases the Risk of Reoperation in Apparent ‘Nonsyndromic’ Coronal Craniosynostosis
The authors present a retrospective study of 76 patients with isolated coronal synostosis who were operated on in a single dedicated craniofacial unit over 25 years to investigate whether any single factor, including the presence of a FGFR3 Pro250Arg mutation, predisposed to an increased transcranial reoperation rate.
Timing of treatment for craniosynostosis and facio-craniosynostosis: a 20-year experience.
The timing of surgery for craniosynostosis is still controversial, but the same basic techniques since 1973 are used, with some modifications, such as a tongue in groove advancement for brachycephalies, and a complete closure of the bony defects after 2 years of age.