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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 -
The Laryngoscope Apr 2021To characterize tracheal cartilage morphology in mouse models of fibroblast growth factor receptor (Fgfr2)-related craniosynostosis syndromes. To establish relationships...
OBJECTIVES
To characterize tracheal cartilage morphology in mouse models of fibroblast growth factor receptor (Fgfr2)-related craniosynostosis syndromes. To establish relationships between specific Fgfr2 mutations and tracheal cartilaginous sleeve (TCS) phenotypes in these mouse models.
METHODS
Postnatal day 0 knock-in mouse lines with disease-specific genetic variations in the Fgfr2 gene (Fgfr2 , Fgfr2 , Fgfr2 , Fgfr2 , and Fgfr2 ) as well as line-specific controls were utilized. Tracheal cartilage morphology as measured by gross analyses, microcomputed tomography (μCT), and histopathology were compared using Chi-squared and single-factor analysis of variance statistical tests.
RESULTS
A greater proportion of rings per trachea were abnormal in Fgfr2 tracheas (63%) than Fgfr2 (17%), Fgfr2 (17%), Fgfr2 (12%), and controls (10%) (P < .001 for each vs. Fgfr2 ). TCS segments were found only in Fgfr2 (100%) and Fgfr2 (72%) tracheas. Cricoid and first-tracheal ring fusion was noted in all Fgfr2 and 94% of Fgfr2 samples. The Fgfr2 and Fgfr2 groups were found to have greater areas and volumes of cartilage than other lines on gross analysis and μCT. Histologic analyses confirmed TCS among the Fgfr2 and Fgfr2 groups, without appreciable differences in cartilage morphology, cell size, or density; no histologic differences were observed among other Fgfr2 lines compared to controls.
CONCLUSION
This study found TCS phenotypes only in the Fgfr2 mouse lines. These lines also had increased tracheal cartilage compared to other mutant lines and controls. These data support further study of the Fgfr2 mouse lines and the investigation of other Fgfr2 variants to better understand their role in tracheal development and TCS formation.
LEVEL OF EVIDENCE
NA Laryngoscope, 131:E1349-E1356, 2021.
Topics: Acanthosis Nigricans; Acrocephalosyndactylia; Animals; Cartilage; Craniofacial Dysostosis; Craniosynostoses; Disease Models, Animal; Ear; Genetic Association Studies; Humans; Mice; Mutation; Phenotype; Receptor, Fibroblast Growth Factor, Type 2; Scalp Dermatoses; Skin Abnormalities; Trachea; Tracheal Diseases; X-Ray Microtomography
PubMed: 32886384
DOI: 10.1002/lary.29060 -
The Journal of Neuroscience : the... Sep 2022multiple epidermal growth factor-like domains 8 (dMegf8) is a homolog of human encodes a multidomain transmembrane protein which is highly conserved across species....
multiple epidermal growth factor-like domains 8 (dMegf8) is a homolog of human encodes a multidomain transmembrane protein which is highly conserved across species. In humans, mutations cause a rare genetic disorder called Carpenter syndrome, which is frequently associated with abnormal left-right patterning, cardiac defects, and learning disabilities. is also associated with psychiatric disorders. Despite its clinical relevance, remains poorly characterized; and although it is highly conserved, studies on animal models of Megf8 are also very limited. The presence of intellectual disabilities in Carpenter syndrome patients and association of with psychiatric disorders indicate that mutations in cause underlying defects in synaptic structure and functions. In this study, we investigated the role of dMegf8 in glutamatergic synapses of the larval neuromuscular junctions (NMJ) in both males and females. We show that dMegf8 localizes to NMJ synapses and is required for proper synaptic growth. mutant larvae and adults show severe motor coordination deficits. At the NMJ, mutants show altered localization of presynaptic and postsynaptic proteins, defects in synaptic ultrastructure, and neurotransmission. Interestingly, mutants have reduced levels of the Type II BMP receptor Wishful thinking (). displays genetic interactions with () and , and in association with Dnrx and Wit plays an essential role in synapse organization. Our studies provide insights into human MEGF8 functions and potentially into mechanisms that may underlie intellectual disabilities observed in Carpenter syndrome as well as MEGF8-related synaptic structural and/or functional deficits in psychiatric disorders. Carpenter syndrome, known for over a century now, is a genetic disorder linked to mutations in () gene and associated with intellectual disabilities among other symptoms. is also associated with psychiatric disorders. Despite the high genetic conservation and clinical relevance, the functions of remain largely uncharacterized. Patients with intellectual disabilities and psychiatric diseases often have an underlying defect in synaptic structure and function. This work defines the role of the fly homolog of human , , in glutamatergic synapse growth, organization, and function and provide insights into potential functions of in human central synapses and synaptic mechanisms that may underlie psychiatric disorders and intellectual disabilities seen in Carpenter syndrome.
Topics: Acrocephalosyndactylia; Animals; Drosophila; Drosophila Proteins; EGF Family of Proteins; Female; Humans; Intellectual Disability; Male; Membrane Proteins; Mutation; Receptors, Cell Surface; Synapses
PubMed: 35944997
DOI: 10.1523/JNEUROSCI.0442-22.2022 -
Genes Oct 2022Objective: To report the clinical and radiographic findings and molecular etiology of the first monozygotic twins affected with Pfeiffer syndrome. Methods: Clinical and...
Objective: To report the clinical and radiographic findings and molecular etiology of the first monozygotic twins affected with Pfeiffer syndrome. Methods: Clinical and radiographic examination and whole exome sequencing were performed on two monozygotic twins with Pfeiffer syndrome. Results: An acceptor splice site mutation in FGFR2 (c.940-2A>G) was detected in both twins. The father and both twins shared the same haplotype, indicating that the mutant allele was from their father’s chromosome who suffered severe upper airway obstruction and subsequent obstructive sleep apnea. Hypertrophy of nasal turbinates appears to be a newly recognized finding of Pfeiffer syndrome. Increased intracranial pressure in both twins were corrected early by fronto-orbital advancement with skull expansion and open osteotomy, in order to prevent the more severe consequences of increased intracranial pressure, including hydrocephalus, the bulging of the anterior fontanelle, and the diastasis of suture. Conclusions: Both twins carried a FGFR2 mutation and were discordant for lambdoid synostosis. Midface hypoplasia, narrow nasal cavities, and hypertrophic nasal turbinates resulted in severe upper airway obstruction and subsequent obstructive sleep apnea in both twins. Hypertrophy of the nasal turbinates appears to be a newly recognized finding of Pfeiffer syndrome. Fronto-orbital advancement with skull expansion and open osteotomy was performed to treat increased intracranial pressure in both twins. This is the first report of monozygotic twins with Pfeiffer syndrome.
Topics: Humans; Acrocephalosyndactylia; Twins, Monozygotic; Sleep Apnea, Obstructive; Airway Obstruction; Hypertrophy
PubMed: 36292735
DOI: 10.3390/genes13101850 -
Journal of Plastic, Reconstructive &... Feb 2022Cerebellar tonsillar herniation (TH) occurs frequently in syndromic craniosynostosis; however, the exact pathogenesis is unknown. This study evaluates the association...
PURPOSE
Cerebellar tonsillar herniation (TH) occurs frequently in syndromic craniosynostosis; however, the exact pathogenesis is unknown. This study evaluates the association between skull base deformities and TH in syndromic craniosynostosis.
METHODS
Retrospective study MRI study comparing syndromic craniosynostosis to controls. Measured parameters included clivus length, skull base angle, Boogard's angle, foramen magnum area, and cerebellar tonsillar position (TP). The association between skull base parameters and TP was evaluated with linear mixed models, correcting for age and risk factors for TH in craniosynostosis (hydrocephalus, intracranial hypertension, craniocerebral disproportion, and lambdoid synostosis).
RESULTS
Two hundred and eighty-two scans in 145 patients were included, and 146 scans in 146 controls. The clivus was smaller at birth, and its growth was retarded in all syndromes. The skull base angle was smaller at birth in Apert and Crouzon syndromes, and the evolution through time was normal. Boogard's angle was smaller at birth in Apert syndrome, and its evolution was disturbed in Apert and Saethre-Chotzen syndromes. The foramen magnum was smaller at birth in Crouzon and Saethre-Chotzen syndromes, and its growth was disturbed in Apert, Crouzon, and Saethre-Chotzen syndromes. TP was higher at birth in Apert syndrome, but lowered faster. In Crouzon syndrome, TP was lower at birth and throughout life. A smaller clivus and larger foramen magnum were associated with a lower TP in controls (p<0.001, p=0.007), and in Crouzon syndrome, this applied to only foramen magnum size (p=0.004).
CONCLUSION
The skull base and its growth are significantly different in syndromic craniosynostosis compared to controls. However, only foramen magnum area is associated with TP in Crouzon syndrome.
Topics: Acrocephalosyndactylia; Craniofacial Dysostosis; Craniosynostoses; Humans; Infant; Infant, Newborn; Retrospective Studies; Skull Base; Syndrome
PubMed: 34799294
DOI: 10.1016/j.bjps.2021.09.066 -
Developmental Medicine and Child... Jan 2021To assess the long-term outcomes of our management protocol for Saethre-Chotzen syndrome, which includes one-stage fronto-orbital advancement.
AIM
To assess the long-term outcomes of our management protocol for Saethre-Chotzen syndrome, which includes one-stage fronto-orbital advancement.
METHOD
All patients born with Saethre-Chotzen syndrome between January 1992 and March 2017 were included. Evaluated parameters included occipital frontal head circumference (OFC), fundoscopy, neuroimaging (ventricular size, tonsillar position, and the presence of collaterals/an abnormal transverse sinus), polysomnography, and ophthalmological outcomes. The relationship between papilledema and its associated risk factors was evaluated with Fisher's exact test.
RESULTS
Thirty-two patients (21 females, 11 males) were included. Median (SD) age at first surgery was 9.6 months (3.1mo) for patients who were primarily referred to our center (range: 3.6-13.0mo), the median (SD) age at last follow-up was 13 years (5y 7mo; range: 3-25y). Seven patients had papilledema preoperatively, which recurred in two. Two patients had papilledema solely after first surgery. Second cranial vault expansion was indicated in 20%. Thirteen patients had an OFC deflection, indicating restricted skull growth, one patient had ventriculomegaly, and none developed hydrocephalus. Eleven patients had emissary veins, while the transverse sinus was aberrant unilaterally in 13 (hypoplastic n=10 and absent n=3). Four patients had mild tonsillar descent, one of which was a Chiari type I malformation. Four patients had obstructive sleep apnoea (two mild, one moderate, and one severe). An aberrant transverse sinus was associated with papilledema (p=0.01).
INTERPRETATION
Single one-stage fronto-orbital advancement was sufficient to prevent intracranial hypertension for 80% of our patients with Saethre-Chotzen syndrome. Follow-up should focus on OFC deflection and venous anomalies.
Topics: Acrocephalosyndactylia; Adolescent; Adult; Child; Child, Preschool; Clinical Protocols; Computed Tomography Angiography; Female; Frontal Bone; Humans; Infant; Intracranial Hypertension; Longitudinal Studies; Magnetic Resonance Imaging; Male; Neuroimaging; Neurosurgical Procedures; Orbit; Outcome Assessment, Health Care; Tomography, Optical Coherence; Young Adult
PubMed: 32909287
DOI: 10.1111/dmcn.14670 -
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 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 -
BMC Musculoskeletal Disorders Nov 2020Apert syndrome is characterised by the presence of craniosynostosis, midface retrusion and syndactyly of hands and feet, thus, synonymously referred to as... (Review)
Review
BACKGROUND
Apert syndrome is characterised by the presence of craniosynostosis, midface retrusion and syndactyly of hands and feet, thus, synonymously referred to as acrocephalosyndactyly type I. Considering these multidisciplinary issues, frequently requiring surgical interventions at an early age, deformities of the feet have often been neglected and seem to be underestimated in the management of Apert syndrome. Typical Apert foot features range from complete fusion of the toes and a central nail mass to syndactyly of the second to fifth toe with a medially deviated great toe; however, no clear treatment algorithms were presented so far. This article reviews the current existing literature regarding the treatment approach of foot deformities in Apert syndrome.
STATE-OF-THE-ART TOPIC REVIEW
Overall, the main focus in the literature seems to be on the surgical approach to syndactyly separation of the toes and the management of the great toe deformity (hallux varus). Although the functional benefit of syndactyly separation in the foot has yet to be determined, some authors perform syndactyly separation usually in a staged procedure. Realignment of the great toe and first ray can be performed by multiple means including but not limited to second ray deletion, resection of the proximal phalanx delta bone on one side, corrective open wedge osteotomy, osteotomy of the osseous fusion between metatarsals I and II, and metatarsal I lengthening using gradual osteodistraction. Tarsal fusions and other anatomical variants may be present and have to be corrected on an individual basis. Shoe fitting problems are frequently mentioned as indication for surgery while insole support may be helpful to alleviate abnormal plantar pressures.
CONCLUSION
There is a particular need for multicenter studies to better elaborate surgical indications and treatment plans for this rare entity. Plantar pressure measurements using pedobarography should be enforced in order to document the biomechanical foot development and abnormalities during growth, and to help with indication setting. Treatment options may include conservative means (i.e. insoles, orthopedic shoes) or surgery to improve biomechanics and normalize plantar pressures.
LEVEL OF EVIDENCE
Level V.
Topics: Acrocephalosyndactylia; Foot Deformities; Hand; Humans; Metatarsal Bones; Osteotomy
PubMed: 33248465
DOI: 10.1186/s12891-020-03812-2 -
Human Genomics Aug 2021The diagnostic process for uncommon disorders with similar manifestations is complicated and requires newer technology, like gene sequencing for a correct diagnosis. (Review)
Review
BACKGROUND
The diagnostic process for uncommon disorders with similar manifestations is complicated and requires newer technology, like gene sequencing for a correct diagnosis.
MAIN BODY
We described two brothers clinically diagnosed with Carpenter syndrome, which is a condition characterized by the premature fusion of certain skull bones (craniosynostosis), abnormalities of the fingers and toes, and other developmental problems, for which they underwent craniotomies. However, whole exome sequencing analysis concluded a novel pathological variation in the ATRX chromatin remodeler gene and protein remodeling demonstrated structural variations that decreased the function, giving a completely different diagnosis to these patients.
CONCLUSION
Our study focuses on the importance of using newer technologies, such as whole exome sequencing analysis, in patients with ambiguous phenotypes.
Topics: Acrocephalosyndactylia; DNA Helicases; Exome; Humans; Mental Retardation, X-Linked; Mutation; Nuclear Proteins; Phenotype; Exome Sequencing; X-linked Nuclear Protein; alpha-Thalassemia
PubMed: 34348791
DOI: 10.1186/s40246-021-00348-x