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Journal of Anatomy Mar 2023Syndromic craniosynostosis (CS) patients exhibit early, bony fusion of calvarial sutures and cranial synchondroses, resulting in craniofacial dysmorphology. In this...
Syndromic craniosynostosis (CS) patients exhibit early, bony fusion of calvarial sutures and cranial synchondroses, resulting in craniofacial dysmorphology. In this study, we chronologically evaluated skull morphology change after abnormal fusion of the sutures and synchondroses in mouse models of syndromic CS for further understanding of the disease. We found fusion of the inter-sphenoid synchondrosis (ISS) in Apert syndrome model mice (Fgfr2 ) around 3 weeks old as seen in Crouzon syndrome model mice (Fgfr2c ). We then examined ontogenic trajectories of CS mouse models after 3 weeks of age using geometric morphometrics analyses. Antero-ventral growth of the face was affected in Fgfr2 and Fgfr2c mice, while Saethre-Chotzen syndrome model mice (Twist1 ) did not show the ISS fusion and exhibited a similar growth pattern to that of control littermates. Further analysis revealed that the coronal suture synostosis in the CS mouse models induces only the brachycephalic phenotype as a shared morphological feature. Although previous studies suggest that the fusion of the facial sutures during neonatal period is associated with midface hypoplasia, the present study suggests that the progressive postnatal fusion of the cranial synchondrosis also contributes to craniofacial dysmorphology in mouse models of syndromic CS. These morphological trajectories increase our understanding of the progression of syndromic CS skull growth.
Topics: Mice; Animals; Receptor, Fibroblast Growth Factor, Type 2; Craniosynostoses; Skull; Craniofacial Dysostosis; Acrocephalosyndactylia; Cranial Sutures
PubMed: 36394990
DOI: 10.1111/joa.13790 -
The Cleft Palate-craniofacial Journal :... Apr 2024Head and neck positioning is a key element of craniofacial reconstructive surgery and can become challenging when intervention necessitates broad exposure of the...
Head and neck positioning is a key element of craniofacial reconstructive surgery and can become challenging when intervention necessitates broad exposure of the calvarium. We present a case of craniosynostosis secondary to Apert's syndrome requiring anterior and posterior cranial vault access during surgical correction. A modified sphinx position was used that required significant neck extension. The patient had concurrent Chiari I malformation with brain stem compression so intraoperative neuromonitoring (IONM) was used to ensure that there were no negative effects on the neural elements with positioning. This highlights benefits of IONM in a setting not typically associated with its use.
Topics: Humans; Skull; Acrocephalosyndactylia; Craniosynostoses; Arnold-Chiari Malformation
PubMed: 36357356
DOI: 10.1177/10556656221135284 -
Medicine Oct 2022Fetal skeletal anomalies are one of the most common and potentially pathogenic developmental abnormalities detected by ultrasound screening. Any suspected fetal skeletal...
RATIONALE
Fetal skeletal anomalies are one of the most common and potentially pathogenic developmental abnormalities detected by ultrasound screening. Any suspected fetal skeletal dysplasias often require further comprehensive evaluations.
PATIENT CONCERNS
Here 4 families with adverse fetal skeletal system histories were enrolled, including their histories of gestation, childbirth, familial skeletal abnormalities, and pregnancy outcomes. The corresponding diagnosis were done by whole exome sequencing (WES) combined with dynamic examination.
DIAGNOSIS
All of the families were definitively diagnosed through cytogenetics, molecular genetics, ultrasound, combined with multidisciplinary evaluation. Both of the fetuses in case 1 and case 2 were diagnosed with thanatophoric dysplasia type I, while the neonate in case 3 was diagnosed with Apert syndrome and a 3-years-old proband daughter with Crouzon syndrome in case 4.
INTERVENTIONS
We conducted karyotyping, copy number variation sequencing (CNV-seq), combined with WES to evaluate genetic conditions of abnormal fetus, neonate or proband patient. WES was preferred to obtain a relatively definitive diagnosis.
OUTCOMES
In cases 1 and 2, the families decided to choose termination of pregnancy due to fatal dysplasias. The couple in case 3, delivered a female baby diagnosed with Apert syndrome. Fortunately, in case 4, the family, which had a 3-years-old baby with Crouzon syndrome, gave birth to a healthy baby through prenatal diagnosis.
LESSONS SUBSECTIONS
Invasive prenatal diagnosis and dynamic assessments for the management of fetal skeletal dysplasias could contribute to revealing possible causes of fetal skeletal abnormalities and help clinicians conduct further genetic counseling in clinical practice.
Topics: Pregnancy; Infant, Newborn; Female; Humans; Child, Preschool; Exome Sequencing; DNA Copy Number Variations; Acrocephalosyndactylia; Fetus; Prenatal Diagnosis; Osteochondrodysplasias; Musculoskeletal Abnormalities; Craniofacial Dysostosis; Ultrasonography, Prenatal
PubMed: 36316869
DOI: 10.1097/MD.0000000000031321 -
Pediatric Neurosurgery 2022Prevalence of intracranial aneurysms in children with Apert syndrome has not been described, and development of an aneurysm as a complication secondary to craniofacial...
INTRODUCTION
Prevalence of intracranial aneurysms in children with Apert syndrome has not been described, and development of an aneurysm as a complication secondary to craniofacial surgery has never been reported.
CASE PRESENTATION
We report the rare case of a 10-year-old boy with Apert syndrome who underwent craniofacial reconstruction surgery consisting of subcranial Le Fort III osteotomies, bilateral lateral canthopexies, and nasal nares dilations for midfacial hypoplasia and resultant obstructive sleep apnea, and on routine follow-up magnetic resonance imaging (MRI) 1 year later, he was found to have a large left ophthalmic internal carotid artery (ICA) aneurysm that was not seen on MRI obtained 2 years prior. Immediately after the craniofacial surgery, the patient experienced a severe headache behind his left eye and extraocular movement abnormalities that subsided over the next days to months. Given the new and rapid growth of the aneurysm on follow-up MRI, the patient underwent a diagnostic cerebral angiogram followed by successful flow diversion treatment of the aneurysm with the pipeline embolization device (Medtronic, Dublin, Ireland).
CONCLUSION
Post-procedurally, over the next year, the patient developed word-finding difficulty and stuttering speech. He was found to have in-stent ICA stenosis and middle cerebral artery (MCA) stenosis at the first follow-up and underwent an initial angioplasty. After several weeks, ICA, MCA, and anterior cerebral artery stenoses were identified, and the patient underwent angioplasties for the ICA and MCA stenoses. On follow-up examination after the second procedure, the patient had tremendous improvement in his speech difficulties and was doing well clinically.
Topics: Male; Humans; Child; Carotid Artery, Internal; Constriction, Pathologic; Acrocephalosyndactylia; Embolization, Therapeutic; Intracranial Aneurysm; Carotid Artery Diseases; Cerebral Angiography; Treatment Outcome
PubMed: 36310015
DOI: 10.1159/000527795 -
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 -
The Journal of Craniofacial SurgeryCraniostenosis is a morphological anomaly affecting about 0.5 of 1000 births and one third of the cases are of genetic origin. Among the syndromes responsible for...
Craniostenosis is a morphological anomaly affecting about 0.5 of 1000 births and one third of the cases are of genetic origin. Among the syndromes responsible for craniostenosis, there is the Saethre-Chotzen syndrome due to a mutation of the TWIST 1 gene located on chromosome 7. This polymalformative syndrome classically includes a particular morphology of the auricles. The penetrance is variable and results in a phenotypic variability at the origin of "Saethre-Chotzen like" clinical pictures for which the TWIST 1 gene mutation is sometimes not found. Recently, the TCF 12 gene has been implicated in some of these cases. Among the multiple facial malformations, we have carefully examined the particular morphology of the auricle of these patients. The authors found several abnormalities in patients with a TCF 12 gene mutation, namely a thickened and hammered upper pole of the helix, a narrow concha without crux cymbae and a thickened lobe. These morphological features may guide the diagnosis and allow an earlier search for a TCF 12 gene mutation.
Topics: Humans; Twist-Related Protein 1; Transcription Factors; Mutation; Acrocephalosyndactylia; Craniosynostoses; Basic Helix-Loop-Helix Transcription Factors
PubMed: 35994750
DOI: 10.1097/SCS.0000000000008938 -
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 -
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 -
Journal of Medical Ultrasonics (2001) Oct 2022
Topics: Pregnancy; Female; Humans; Hypoplastic Left Heart Syndrome; Acrocephalosyndactylia; Fetus; Ultrasonography, Prenatal
PubMed: 35917041
DOI: 10.1007/s10396-022-01249-9 -
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