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The Journal of Investigative Dermatology Aug 2009Increased fibroblast growth factor receptor-2 (FGFR2) signaling has been proposed to be involved in acne pathogenesis and explains acne lesions in Apert syndrome and... (Review)
Review
Increased fibroblast growth factor receptor-2 (FGFR2) signaling has been proposed to be involved in acne pathogenesis and explains acne lesions in Apert syndrome and unilateral acneiform nevus associated with gain-of-function point mutations of FGFR2. If, indeed, increased FGFR2 signaling plays a major pathogenic role in follicular hyperkeratinization and sebaceous gland hypertrophy in acne, effective anti-acne drugs may attenuate increased FGFR2 signaling. The purpose of this article is to elucidate the hypothesis that known anti-acne agents may operate by downregulation of increased FGFR2 signaling. Anti-androgens suppress FGF-ligand expression, benzoyl peroxide induces FGFR2 downregulation by lysosomal receptor degradation, azelaic acid inhibits mitochondrial ATP formation required for receptor tyrosine kinase phosphorylation, tetracyclines inhibit the expression, and activity of FGFR2b downstream matrix metalloproteinases, and retinoids attenuate the FGFR2 pathway at several regulatory levels of the signal transduction cascade critical for cell cycle control, cell proliferation, differentiation, and lipogenesis. Erythromycin, a P-450 inhibitor, may interfere with FGFR2 signaling by its inhibitory effect on retinoid catabolism. The gain-of-function mutations of FGFR2 in Apert syndrome and unilateral acneiform nevus, and the proposed synergistic inhibitory interactions of anti-acne agents at various levels of the FGFR2-signaling cascade underline the role of FGFR2 signaling in the pathogenesis of acne.
Topics: Acne Vulgaris; Androgen Antagonists; Benzoyl Peroxide; Dicarboxylic Acids; Erythromycin; Humans; Interleukin-1alpha; Isotretinoin; Reactive Oxygen Species; Receptor, ErbB-2; Signal Transduction; Tetracyclines; Tretinoin; alpha-MSH
PubMed: 19225542
DOI: 10.1038/jid.2009.8 -
British Medical Journal (Clinical... Mar 1985
Topics: Acrocephalosyndactylia; Child, Preschool; Craniofacial Dysostosis; Craniosynostoses; Facial Neoplasms; Humans; Orbit; Surgery, Plastic; Wounds and Injuries
PubMed: 3918719
DOI: 10.1136/bmj.290.6469.693 -
Developmental Dynamics : An Official... Mar 2021Apert syndrome is an autosomal, dominant inherited disorder characterized by craniosynostosis and syndactyly caused by gain-of-function mutations in the fibroblast...
Aberrantly activated Wnt/β-catenin pathway co-receptors LRP5 and LRP6 regulate osteoblast differentiation in the developing coronal sutures of an Apert syndrome (Fgfr2 ) mouse model.
BACKGROUND
Apert syndrome is an autosomal, dominant inherited disorder characterized by craniosynostosis and syndactyly caused by gain-of-function mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. Wnt/β-catenin signaling plays critical roles in regulating the skeletal development. Here, we analyzed the role of this pathway in the developing coronal sutures (CS) of a murine Apert syndrome model (Fgfr2 ).
RESULTS
We observed aberrantly increased mRNA expression of Lrp5 and Lrp6 in CS of Fgfr2 mice, whereas both wild type (WT) and Fgfr2 mice showed similar expression of other Wnt/β-catenin-related genes, such as Wnt3, Wnt3a, Fzd4, Fzd6, Axin2, and Dkk1 as evidenced by in situ hybridization. Significantly increased Lrp5 and Lrp6 mRNA expression was observed by quantitative PCR analysis of cultured cells isolated from CS of Fgfr2 mice. Phospho-LRP5, phospho-LRP6, and non-phospho-β-catenin were upregulated in Fgfr2 CS compared with that in WT CS. Short-interfering RNA targeting Lrp5 and Lrp6 significantly reduced runt-related transcription factor 2, collagen type 1 alpha 1, and osteocalcin mRNA expression, and alkaline phosphatase activity in cultured cells.
CONCLUSIONS
The Wnt/β-catenin pathway was activated in the CS of Fgfr2 mice during craniofacial development, suggesting the involvement of the Wnt/β-catenin pathway in the pathogenesis of CS synostosis in Fgfr2 mice.
Topics: Acrocephalosyndactylia; Amino Acid Substitution; Animals; Cell Differentiation; Cranial Sutures; Disease Models, Animal; Low Density Lipoprotein Receptor-Related Protein-5; Low Density Lipoprotein Receptor-Related Protein-6; Mice; Mice, Transgenic; Mutation, Missense; Osteoblasts; Receptor, Fibroblast Growth Factor, Type 2; Wnt Signaling Pathway; beta Catenin
PubMed: 32822074
DOI: 10.1002/dvdy.239 -
Cureus Sep 2021Apert syndrome is a developmental malformation characterised by craniosynostosis (premature fusion of cranial sutures), midface hypoplasia, and syndactyly of hands and...
Apert syndrome is a developmental malformation characterised by craniosynostosis (premature fusion of cranial sutures), midface hypoplasia, and syndactyly of hands and feet. Early synostosis of the coronal suture, cranial base, as well as agenesis of the sagittal suture, result in characteristic appearance and dental features like maxillary transverse and sagittal hypoplasia with concomitant dental crowding, a pseudo-cleft palate, and skeletal and dental anterior open bite. In this report, we discuss a case of Apert syndrome, with special emphasis on craniofacial characteristics, a multidisciplinary approach to its treatment, and the dentist's role in management.
PubMed: 34659949
DOI: 10.7759/cureus.17735 -
Journal of Anatomy Nov 2005Normal and abnormal jaw growth and tooth eruption are topics of great importance for several dental and medical disciplines. Thus far, clinical studies on these topics... (Review)
Review
Normal and abnormal jaw growth and tooth eruption are topics of great importance for several dental and medical disciplines. Thus far, clinical studies on these topics have used two-dimensional (2D) radiographic techniques. The purpose of the present study was to analyse normal mandibular growth and tooth eruption in three dimensions based on computer tomography (CT) scans, extending the principles of mandibular growth analysis proposed by Björk in 1969 from two to three dimensions. As longitudinal CT data from normal children are not available (for ethical reasons), CT data from children with Apert syndrome were employed, because it has been shown that the mandible in Apert syndrome is unaffected by the malformation, and these children often have several craniofacial CT scans performed during childhood for planning of cranial and midface surgery and for follow-up after surgery. A total of 49 datasets from ten children with Apert syndrome were available for study. The number of datasets from each individual ranged from three to seven. The first CT scan in each of the ten series was carried out before 1 year of age, and the ages for the 49 scans ranged from 1 week to 14.5 years. The mandible and the teeth were segmented and iso-surfaces generated. Landmarks were placed on the surface of the mandible, along the mandibular canals, the inner contour of the cortical plate at the lower border of the symphysis menti, and on the teeth. Superimposition of the mandibles in the longitudinal series was performed using the symphysis menti and the mandibular canals as suggested by Björk. The study supported the findings of stability of the symphysis menti and the mandibular canals as seen in profile view previously reported by Björk & Skieller in 1983. However, the mandibular canals were, actually, relocated laterally during growth. Furthermore, the position of tooth buds remained relatively stable inside the jaw until root formation started. Eruption paths of canines and premolars were vertical, whereas molars erupted in a lingual direction. The 3D method would seem to offer new insight into jaw growth and tooth eruption, but further studies are needed.
Topics: Acrocephalosyndactylia; Adolescent; Bicuspid; Child; Child, Preschool; Cuspid; Female; Humans; Imaging, Three-Dimensional; Infant; Longitudinal Studies; Male; Mandible; Molar; Tomography, X-Ray Computed; Tooth Eruption
PubMed: 16313399
DOI: 10.1111/j.1469-7580.2005.00479.x -
Annual Review of Genomics and Human... Aug 2016Some de novo human mutations arise at frequencies far exceeding the genome average mutation rate. Examples include the common mutations at one or a few sites in the... (Review)
Review
Some de novo human mutations arise at frequencies far exceeding the genome average mutation rate. Examples include the common mutations at one or a few sites in the genes that cause achondroplasia, Apert syndrome, multiple endocrine neoplasia type 2B, and Noonan syndrome. These mutations are recurrent, provide a gain of function, are paternally derived, and are more likely to be transmitted as the father ages. Recent experiments have tested whether the high mutation frequencies are due to an elevated mutation rate per cell division, as expected, or to an advantage of the mutant spermatogonial stem cells over wild-type stem cells. The evidence, which includes the surprising discovery of testis mutation clusters, rules out the former model but not the latter. We propose how the mutations might alter spermatogonial stem cell function and discuss how germline selection contributes to the paternal age effect, the human mutational load, and adaptive evolution.
Topics: Adult Germline Stem Cells; Cell Division; Genetic Diseases, Inborn; Germ-Line Mutation; Humans; Male; Mutation; Selection, Genetic; Testis
PubMed: 27070266
DOI: 10.1146/annurev-genom-083115-022656 -
American Journal of Medical Genetics.... Dec 2016Craniosynostosis is a relatively common birth defect characterized by the premature fusion of one or more cranial sutures. Examples of craniosynostosis syndromes include...
Craniosynostosis is a relatively common birth defect characterized by the premature fusion of one or more cranial sutures. Examples of craniosynostosis syndromes include Crouzon (CS), Pfeiffer (PS), and Apert (AS) syndrome, with clinical characteristics such as midface hypoplasia, hypertelorism, and in some cases, limb defects. Mutations in Fibroblast Growth Factor Receptor-2 comprise the majority of known mutations in syndromic forms of craniosynostosis. A number of clinical reports of FGFR-associated craniosynostosis patients and mouse mutants have been linked to gastrointestinal tract (GIT) disorders, leading to the hypothesis of a direct link between FGFR-associated craniosynostosis syndromes and GIT malformations. We conducted an investigation to determine GIT symptoms in a sample of FGFR-associated craniosynostosis syndrome patients and a mouse model of CS containing a mutation (W290R) in Fgfr2. We found that, compared to the general population, the incidence of intestinal/bowel malrotation (IM) was present at a higher level in our sample population of patients with FGFR-associated craniosynostosis syndromes. We also showed that the mouse model of CS had an increased incidence of cecal displacement, suggestive of IM. These findings suggest a direct relationship between FGFR-related craniosynostosis syndromes and GIT malformations. Our study may shed further light on the potential widespread impact FGFR mutations on different developmental systems. Based on reports of GIT malformations in children with craniosynostosis syndromes and substantiation with our animal model, GIT malformations should be considered in any child with an FGFR2-associated craniosynostosis syndrome. © 2016 Wiley Periodicals, Inc.
Topics: Alleles; Amino Acid Substitution; Animals; Biopsy; Craniosynostoses; DNA Mutational Analysis; Female; Gastrointestinal Tract; Genetic Association Studies; Heterozygote; Humans; Male; Mice; Mice, Knockout; Mutation; Phenotype; Receptors, Fibroblast Growth Factor; Retrospective Studies; Syndrome
PubMed: 27481450
DOI: 10.1002/ajmg.a.37862 -
Archivos Argentinos de Pediatria Apr 2021The Saethre-Chotzen syndrome is a craniofacial malformation syndrome characterized by synostosis of coronal sutures and limb anomalies. The estimated prevalence of this...
The Saethre-Chotzen syndrome is a craniofacial malformation syndrome characterized by synostosis of coronal sutures and limb anomalies. The estimated prevalence of this syndrome is 1 in 25 000-50 000 live births. We present a case report of a neonate, without relevant family history, who presented craniofacial alterations at birth. Given the phenotypic features, a cranial computed tomography scan was performed, showing partial fusion of the coronal suture, evidencing the presence Síndrome de Saethre-Chotzen: a propósito de un caso Saethre-Chotzen syndrome: a case report of wormian bones in the metopic and right lambdoid location. With the clinical suspicion of craniofacial malformation syndrome, an analysis of the directed exome was requested confirming that the patient is a heterozygous carrier of the pathogenic variant c.415C>A, which induces a change of proline to threonine at position 139 of the TWIST1 gene, responsible for Saethre-Chotzen syndrome. The presence of wormian bones, a finding not described so far in the literature, extends the well-known phenotypic variability of this syndrome.
Topics: Acrocephalosyndactylia; Cranial Sutures; Heterozygote; Humans; Infant, Newborn; Nuclear Proteins; Twist-Related Protein 1
PubMed: 33749202
DOI: 10.5546/aap.2021.e129 -
Head & Face Medicine Feb 2007In the PubMed accessible literature, information on the characteristics of interdisciplinary orthodontic and surgical treatment of patients with Apert syndrome is rare....
In the PubMed accessible literature, information on the characteristics of interdisciplinary orthodontic and surgical treatment of patients with Apert syndrome is rare. The aim of the present article is threefold: (1) to show the spectrum of the phenotype, in order (2) to elucidate the scope of hindrances to orthodontic treatment, and (3) to demonstrate the problems of surgery and interdisciplinary approach.Children and adolescents who were born in 1985 or later, who were diagnosed with Apert syndrome, and who sought consultation or treatment at the Departments of Orthodontics or Craniomaxillofacial Surgery at the Dental School of the University Hospital of Münster (n = 22; 9 male, 13 female) were screened. Exemplarily, three of these patients (2 male, 1 female), seeking interdisciplinary (both orthodontic and surgical treatment) are presented. Orthodontic treatment before surgery was performed by one experienced orthodontist (AH), and orthognathic surgery was performed by one experienced surgeon (UJ), who diagnosed the syndrome according to the criteria listed in OMIM. In the sagittal plane, the patients suffered from a mild to a very severe Angle Class III malocclusion, which was sometimes compensated by the inclination of the lower incisors; in the vertical dimension from an open bite; and transversally from a single tooth in crossbite to a circular crossbite. All patients showed dentitio tarda, some impaction, partial eruption, idopathic root resorption, transposition or other aberrations in the position of the tooth germs, and severe crowding, with sometimes parallel molar tooth buds in each quarter of the upper jaw.Because of the severity of malocclusion, orthodontic treatment needed to be performed with fixed appliances, and mainly with superelastic wires. The therapy was hampered with respect to positioning of bands and brackets because of incomplete tooth eruption, dense gingiva, and mucopolysaccharide ridges. Some teeth did not move, or moved insufficiently (especially with respect to rotations and torque) irrespective of surgical procedures or orthodontic mechanics and materials applied, and without prognostic factors indicating these problems. Establishing occlusal contact of all teeth was difficult. Tooth movement was generally retarded, increasing the duration of orthodontic treatment. Planning of extractions was different from that of patients without this syndrome.In one patient, the sole surgical procedure after orthodontic treatment with fixed appliances in the maxilla and mandible was a genioplasty. Most patients needed two- jaw surgery (bilateral sagittal split osteotomy [BSSO] with mandibular setback and distraction in the maxilla). During the period of distraction, the orthodontist guided the maxilla into final position by means of bite planes and intermaxillary elastics.To our knowledge, this is the first article in the PubMed accessible literature describing the problems with respect to interdisciplinary orthodontic and surgical procedures. Although the treatment results are not perfect, patients undergoing these procedures benefit esthetically to a high degree.Patients need to be informed with respect to the different kinds of extractions that need to be performed, the increased treatment time, and the results, which may be reached using realistic expectations.
Topics: Acrocephalosyndactylia; Adolescent; Child; Female; Humans; Male; Oral Surgical Procedures; Orthodontics, Corrective; Phenotype; Young Adult
PubMed: 17286873
DOI: 10.1186/1746-160X-3-10 -
International Journal of Biological... 2017Apert syndrome (AS) is a common genetic syndrome in humans characterized with craniosynostosis. Apert patients and mouse models showed abnormalities in sutures, cranial...
Apert syndrome (AS) is a common genetic syndrome in humans characterized with craniosynostosis. Apert patients and mouse models showed abnormalities in sutures, cranial base and brain, that may all be involved in the pathogenesis of skull malformation of Apert syndrome. To distinguish the differential roles of these components of head in the pathogenesis of the abnormal skull morphology of AS, we generated mouse strains specifically expressing mutant FGFR2 in chondrocytes, osteoblasts, and progenitor cells of central nervous system (CNS) by crossing Fgfr2 mice with Col2a1-Cre, Osteocalcin-Cre (OC-Cre), and Nestin-Cre mice, respectively. We then quantitatively analyzed the skull and brain morphology of these mutant mice by micro-CT and micro-MRI using Euclidean distance matrix analysis (EDMA). Skulls of Col2a1-Fgfr2 mice showed Apert syndrome-like dysmorphology, such as shortened skull dimensions along the rostrocaudal axis, shortened nasal bone, and evidently advanced ossification of cranial base synchondroses. The OC-Fgfr2 mice showed malformation in face at 8-week stage. Nestin-Fgfr2 mice exhibited increased dorsoventral height and rostrocaudal length on the caudal skull and brain at 8 weeks. Our study indicates that the abnormal skull morphology of AS is caused by the combined effects of the maldevelopment in calvarias, cranial base, and brain tissue. These findings further deepen our knowledge about the pathogenesis of the abnormal skull morphology of AS, and provide new clues for the further analyses of skull phenotypes and clinical management of AS.
Topics: Acrocephalosyndactylia; Animals; Brain; Chondrocytes; Disease Models, Animal; Female; Magnetic Resonance Imaging; Male; Mice; Mice, Mutant Strains; Receptor, Fibroblast Growth Factor, Type 2; Skull; Skull Base; X-Ray Microtomography
PubMed: 28123344
DOI: 10.7150/ijbs.16287