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Developmental Biology Oct 2022Heterozygous loss of function mutations in TWIST1 cause Saethre-Chotzen syndrome, which is characterized by craniosynostosis, facial asymmetry, ptosis, strabismus, and...
Heterozygous loss of function mutations in TWIST1 cause Saethre-Chotzen syndrome, which is characterized by craniosynostosis, facial asymmetry, ptosis, strabismus, and distinctive ear appearance. Individuals with syndromic craniosynostosis have high rates of strabismus and ptosis, but the underlying pathology is unknown. Some individuals with syndromic craniosynostosis have been noted to have absence of individual extraocular muscles or abnormal insertions of the extraocular muscles on the globe. Using conditional knock-out alleles for Twist1 in cranial mesenchyme, we test the hypothesis that Twist1 is required for extraocular muscle organization and position, attachment to the globe, and/or innervation by the cranial nerves. We examined the extraocular muscles in conditional Twist1 knock-out animals using Twist2-cre and Pdgfrb-cre drivers. Both are expressed in cranial mesoderm and neural crest. Conditional inactivation of Twist1 using these drivers leads to disorganized extraocular muscles that cannot be reliably identified as specific muscles. Tendons do not form normally at the insertion and origin of these dysplastic muscles. Knock-out of Twist1 expression in tendon precursors, using scleraxis-cre, however, does not alter EOM organization. Furthermore, developing motor neurons, which do not express Twist1, display abnormal axonal trajectories in the orbit in the presence of dysplastic extraocular muscles. Strabismus in individuals with TWIST1 mutations may therefore be caused by abnormalities in extraocular muscle development and secondary abnormalities in innervation and tendon formation.
Topics: Acrocephalosyndactylia; Animals; Craniosynostoses; Mice; Neural Crest; Oculomotor Muscles; Strabismus; Twist-Related Protein 1
PubMed: 35944701
DOI: 10.1016/j.ydbio.2022.07.010 -
Genes Jun 2022Craniosynostosis are a heterogeneous group of genetic conditions characterized by the premature fusion of the skull bones. The most common forms of craniosynostosis are...
Craniosynostosis are a heterogeneous group of genetic conditions characterized by the premature fusion of the skull bones. The most common forms of craniosynostosis are Crouzon, Apert and Pfeiffer syndromes. They differ from each other in various additional clinical manifestations, e.g., syndactyly is typical of Apert and rare in Pfeiffer syndrome. Their inheritance is autosomal dominant with incomplete penetrance and one of the main genes responsible for these syndromes is FGFR2, mapped on chromosome 10, encoding fibroblast growth factor receptor 2. We report an FGFR2 gene variant in a mother and daughter who present with different clinical features of Crouzon syndrome. The daughter is more severely affected than her mother, as also verified by a careful study of the face and oral cavity. The c.1032G>A transition in exon 8, already reported as a synonymous p.Ala344 = variant in Crouzon patients, also activates a new donor splice site leading to the loss of 51 nucleotides and the in-frame removal of 17 amino acids. We observed lower FGFR2 transcriptional and translational levels in the daughter compared to the mother and healthy controls. A preliminary functional assay and a molecular modeling added further details to explain the discordant phenotype of the two patients.
Topics: Acrocephalosyndactylia; Craniosynostoses; Female; Humans; Mothers; Phenotype; Receptor, Fibroblast Growth Factor, Type 2
PubMed: 35885943
DOI: 10.3390/genes13071161 -
Developmental Dynamics : An Official... Oct 2022Major cell-to-cell signaling pathways, such as the fibroblast growth factors and their four receptors (FGF/FGFR), are conserved across a variety of animal forms....
BACKGROUND
Major cell-to-cell signaling pathways, such as the fibroblast growth factors and their four receptors (FGF/FGFR), are conserved across a variety of animal forms. FGF/FGFRs are necessary to produce several "vertebrate-specific" structures, including the vertebrate head. Here, we examine the effects of the FGFR2 S252W mutation associated with Apert syndrome on patterns of cranial integration. Our data comprise micro-computed tomography images of newborn mouse skulls, bred to express the Fgfr2 S252W mutation exclusively in either neural crest or mesoderm-derived tissues, and mice that express the Fgfr2 S252W mutation ubiquitously.
RESULTS
Procrustes-based methods and partial least squares analysis were used to analyze craniofacial integration patterns. We found that deviations in the direction and degree of integrated shape change across the mouse models used in our study were potentially driven by the modular variation generated by differing expression of the Fgfr2 mutation in cranial tissues.
CONCLUSIONS
Our overall results demonstrate that covariation patterns can be biased by the spatial distribution and magnitude of variation produced by underlying developmental-genetic mechanisms that often impact the phenotype in disproportionate ways.
Topics: Acrocephalosyndactylia; Animals; Disease Models, Animal; Fibroblast Growth Factors; Mice; Mutation; Receptor, Fibroblast Growth Factor, Type 2; Skull; X-Ray Microtomography
PubMed: 35582939
DOI: 10.1002/dvdy.498 -
Scientific Reports Apr 2022This meta-analysis aims to compare Apert syndrome (AS) patients with non-AS populations (not clinically or genetically diagnosed) on craniofacial cephalometric... (Meta-Analysis)
Meta-Analysis
This meta-analysis aims to compare Apert syndrome (AS) patients with non-AS populations (not clinically or genetically diagnosed) on craniofacial cephalometric characteristics (CCC) to combine publicly available scientific information while also improving the validity of primary study findings. A comprehensive search was performed in the following databases: PubMed, Google Scholar, Scopus, Medline, and Web of Science, an article published between 1st January 2000 to October 17th, 2021. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed to carry out this systematic review. We used the PECO system to classify people with AS based on whether or not they had distinctive CCC compared to the non-AS population. Following are some examples of how PECO has been used: People with AS are labeled P; clinical or genetic diagnosis of AS is labeled E; individuals without AS are labeled C; CCC of AS are labeled O. Using the Newcastle-Ottawa Quality-Assessment-Scale, independent reviewers assessed the articles' methodological quality and extracted data. 13 studies were included in the systematic review. 8 out of 13 studies were score 7-8 in NOS scale, which indicated that most of the studies were medium to high qualities. Six case-control studies were analyzed for meta-analysis. Due to the wide range of variability in CCC, we were only able to include data from at least three previous studies. There was a statistically significant difference in N-S-PP (I: 76.56%; P = 0.014; CI 1.27 to - 0.28) and Greater wing angle (I: 79.07%; P = 0.008; CI 3.07-1.17) between AS and control subjects. Cleft palate, anterior open bite, crowding in the upper jaw, and hypodontia occurred more frequently among AS patients. Significant shortening of the mandibular width, height and length is the most reported feature in AS patients. CT scans can help patients with AS decide whether to pursue orthodontic treatment alone or to have their mouth surgically expanded. The role of well-informed orthodontic and maxillofacial practitioners is critical in preventing and rehabilitating oral health issues.
Topics: Acrocephalosyndactylia; Cephalometry; Cleft Palate; Humans; Research Report
PubMed: 35383244
DOI: 10.1038/s41598-022-09764-y -
BMJ Case Reports Mar 2022The management of patients with Apert syndrome (AS) is complex and reflects the multisystem disease as a result of premature fusion of cranial vault, cranial base and...
The management of patients with Apert syndrome (AS) is complex and reflects the multisystem disease as a result of premature fusion of cranial vault, cranial base and midface sutures as well as extremity anomalies characterised by syndactyly. Early cranial sutural fusion results in craniocerebral disproportion which can lead to crisis surgical intervention due to raised intracranial pressure, ophthalmic and compromised airway concerns. Childhood inventions are often determined by psychosocial concerns and adult surgical interventions are often determined by cosmetic concerns. Treatments are provided by many different specialists within multidisciplinary teams (MDT). The treatment pathway extends from birth well into adulthood and is often associated with a heavy burden of care. Due to the extensive nature of the interaction with these patients MDT members have opportunities to provide enhanced patient-centred care and support.This case report provides an overview of the current knowledge of the aetiology of AS, illustrates the pathway of surgical and non-surgical management of AS and provides a long-term review of the dentofacial treatment outcomes.By having a better understanding of the impact of AS and treatment provided, MDT members can not only provide improved clinical treatment but also offer improved patient experiences for those with craniofacial anomalies, in particular, an increased awareness of the psychosocial challenges they endure.
Topics: Acrocephalosyndactylia; Adult; Child; Cranial Sutures; Craniofacial Abnormalities; Face; Humans; Skull Base
PubMed: 35236672
DOI: 10.1136/bcr-2021-245224 -
Molecular Genetics & Genomic Medicine Apr 2022Craniosynostosis is the result of the early fusion of cranial sutures. Syndromic craniosynostosis includes but not limited by Crouzon syndrome and Pfeiffer syndrome....
OBJECTIVE
Craniosynostosis is the result of the early fusion of cranial sutures. Syndromic craniosynostosis includes but not limited by Crouzon syndrome and Pfeiffer syndrome. Considerable phenotypic overlap exists among these syndromes and mutations in FGFR2 may cause different syndromes. This study aims to investigate the explanation of the phenotypic variability via clinical and genetic evaluation for eight patients in a large pedigree.
METHODS
For each patient, comprehensive physical examination, cranial plain CT scan with three-dimensional CT reconstruction (3D-CT), and eye examinations were conducted. Whole exome sequencing was applied for genetic diagnosis of the proband. Variants were analyzed and interpreted following the ACMG/AMP guidelines. Sanger sequencing was performed to reveal genotypes of all the family members.
RESULTS
A pathogenic variant in the FGFR2 gene, c.833G > T (p.C278F), was identified and proved to be co-segregate with the disease. Some symptoms of head, hearing, vision, mouth, teeth expressed differently by affected individuals. Nonetheless, all the eight patients manifested core symptoms of Crouzon syndrome without abnormality in the limbs, which could exclude diagnosis of Pfeiffer syndrome.
CONCLUSION
We have established clinical and genetic diagnosis of Crouzon syndrome for eight patients in a five-generation Chinese family. Variability of clinical features among these familial patients was slighter than that in previously reported sporadic cases.
Topics: Acrocephalosyndactylia; Biological Variation, Population; Craniofacial Dysostosis; Craniosynostoses; Humans; Receptor, Fibroblast Growth Factor, Type 2; Syndrome
PubMed: 35235708
DOI: 10.1002/mgg3.1901 -
Journal of Cellular Physiology Apr 2022The fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling pathway plays important roles in the development and growth of the skeleton. Apert syndrome caused by...
The fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling pathway plays important roles in the development and growth of the skeleton. Apert syndrome caused by gain-of-function mutations of FGFR2 results in aberrant phenotypes of the skull, midface, and limbs. Although short limbs are representative features in patients with Apert syndrome, the causative mechanism for this limb defect has not been elucidated. Here we quantitatively confirmed decreases in the bone length, bone mineral density, and bone thickness in the Apert syndrome model of gene knock-in Fgfr2 (EIIA-Fgfr2 ) mice. Interestingly, despite these bone defects, histological analysis showed that the endochondral ossification process in the mutant mice was similar to that in wild-type mice. Tartrate-resistant acid phosphatase staining revealed that trabecular bone loss in mutant mice was associated with excessive osteoclast activity despite accelerated osteogenic differentiation. We investigated the osteoblast-osteoclast interaction and found that the increase in osteoclast activity was due to an increase in the Rankl level of osteoblasts in mutant mice and not enhanced osteoclastogenesis driven by the activation of FGFR2 signaling in bone marrow-derived macrophages. Consistently, Col1a1-Fgfr2 mice, which had osteoblast-specific expression of Fgfr2 S252W, showed significant bone loss with a reduction of the bone length and excessive activity of osteoclasts was observed in the mutant mice. Taken together, the present study demonstrates that the imbalance in osteoblast and osteoclast coupling by abnormally increased Rankl expression in Fgfr2 mutant osteoblasts is a major causative mechanism for bone loss and short long bones in Fgfr2 mice.
Topics: Acrocephalosyndactylia; Animals; Cell Differentiation; Gene Knock-In Techniques; Humans; Mice; Osteoblasts; Osteoclasts; Osteogenesis; RANK Ligand; Receptor, Fibroblast Growth Factor, Type 2; Skull
PubMed: 35048384
DOI: 10.1002/jcp.30682 -
The Pan African Medical Journal 2021Pfeiffer syndrome is a rare genetic condition that includes anomalies of the head, hands, and feet. It was originally described by Rudolf Pfeiffer in 1964. As a result...
Pfeiffer syndrome is a rare genetic condition that includes anomalies of the head, hands, and feet. It was originally described by Rudolf Pfeiffer in 1964. As a result of varied clinical presentations, there is a low threshold for missing the diagnosis. Three (3) cases were found by the authors in the medical literature from the African continent, all of which lacked molecular studies. The main dysmorphic features we observed in our patient were; macrocephaly with widely gaped sagittal sutures, proptosis with ocular hypertelorism, ankylosed elbows, wide sandal gap and medially deviated broad great toes. In this case, sequence analysis using Illumina technology and deletion/duplication testing of 65 genes for variants associated with craniosynostosis syndromes was performed at Invitae Medical Genetic laboratory. A diagnosis of Pfeiffer syndrome type 3 with FGFR2 c.1052C>G (p.Ser351Cys) variant was made. In conclusion, this case will aid health care providers especially in areas of low accessibility to molecular studies to promptly identify, appropriately manage the condition as well as counselling the parents to offset the risk of abandonment of neonates with dysmorphic features.
Topics: Acrocephalosyndactylia; Africa, Western; Craniosynostoses; Humans; Infant, Newborn
PubMed: 34909104
DOI: 10.11604/pamj.2021.40.136.31395 -
Clinical Oral Investigations Mar 2022To determine whether the midface of patients with Muenke syndrome, Saethre-Chotzen syndrome, or TCF12-related craniosynostosis is hypoplastic compared to skeletal facial...
OBJECTIVES
To determine whether the midface of patients with Muenke syndrome, Saethre-Chotzen syndrome, or TCF12-related craniosynostosis is hypoplastic compared to skeletal facial proportions of a Dutch control group.
MATERIAL AND METHODS
We included seventy-four patients (43 patients with Muenke syndrome, 22 patients with Saethre-Chotzen syndrome, and 9 patients with TCF12-related craniosynostosis) who were referred between 1990 and 2020 (age range 4.84 to 16.83 years) and were treated at the Department of Oral Maxillofacial Surgery, Special Dental Care and Orthodontics, Children's Hospital Erasmus University Medical Center, Sophia, Rotterdam, the Netherlands. The control group consisted of 208 healthy children.
RESULTS
Cephalometric values comprising the midface were decreased in Muenke syndrome (ANB: β = -1.87, p = 0.001; and PC1: p < 0,001), Saethre-Chotzen syndrome (ANB: β = -1.76, p = 0.001; and PC1: p < 0.001), and TCF12-related craniosynostosis (ANB: β = -1.70, p = 0.015; and PC1: p < 0.033).
CONCLUSIONS
In this study, we showed that the midface is hypoplastic in Muenke syndrome, Saethre-Chotzen syndrome, and TCF12-related craniosynostosis compared to the Dutch control group. Furthermore, the rotation of the maxilla and the typical craniofacial buildup is significantly different in these three craniosynostosis syndromes compared to the controls.
CLINICAL RELEVANCE
The maxillary growth in patients with Muenke syndrome, Saethre-Chotzen syndrome, or TCF12-related craniosynostosis is impaired, leading to a deviant dental development. Therefore, timely orthodontic follow-up is recommended. In order to increase expertise and support treatment planning by medical and dental specialists for these patients, and also because of the specific differences between the syndromes, we recommend the management of patients with Muenke syndrome, Saethre-Chotzen syndrome, or TCF12-related craniosynostosis in specialized multidisciplinary teams.
Topics: Acrocephalosyndactylia; Adolescent; Basic Helix-Loop-Helix Transcription Factors; Cephalometry; Child; Child, Preschool; Craniosynostoses; Humans; Syndrome
PubMed: 34904178
DOI: 10.1007/s00784-021-04275-y -
Genes Oct 2021Greig cephalopolysyndactyly syndrome (GCPS) is a rare genetic disorder (about 200 cases reported), characterized by macrocephaly, hypertelorism, and polysyndactyly. Most... (Review)
Review
Greig cephalopolysyndactyly syndrome (GCPS) is a rare genetic disorder (about 200 cases reported), characterized by macrocephaly, hypertelorism, and polysyndactyly. Most of the reported GCPS cases are the results of heterozygous loss of function mutations affecting the gene (OMIM# 175700), while a small proportion of cases arise from large deletions on chromosome 7p14 encompassing the gene. To our knowledge, only 6 patients have been reported to have a deletion with an exact size (given by genomic coordinates) and a gene content larger than 1 Mb involving the gene. This report presents a patient with Greig cephalopolysyndactyly contiguous gene syndrome (GCP-CGS) diagnosed with a large, 18 Mb deletion on chromosome 7p14.2-p11.2. Similar cases are reviewed in the literature for a more accurate comparison between genotype and phenotype.
Topics: Acrocephalosyndactylia; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 7; Comparative Genomic Hybridization; Humans; Karyotype; Male; Nerve Tissue Proteins; Zinc Finger Protein Gli3
PubMed: 34828280
DOI: 10.3390/genes12111674