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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 Developmental Biology Aug 2022Apert syndrome is a rare genetic disorder characterized by craniosynostosis, midface retrusion, and limb anomalies. Cleft palate occurs in a subset of Apert syndrome... (Review)
Review
Apert syndrome is a rare genetic disorder characterized by craniosynostosis, midface retrusion, and limb anomalies. Cleft palate occurs in a subset of Apert syndrome patients. Although the genetic causes underlying Apert syndrome have been identified, the downstream signaling pathways and cellular mechanisms responsible for cleft palate are still elusive. To find clues for the pathogenic mechanisms of palatal defects in Apert syndrome, we review the clinical characteristics of the palate in cases of Apert syndrome, the palatal phenotypes in mouse models, and the potential signaling mechanisms involved in palatal defects. In Apert syndrome patients, cleft of the soft palate is more frequent than of the hard palate. The length of the hard palate is decreased. Cleft palate is associated most commonly with the S252W variant of FGFR2. In addition to cleft palate, high-arched palate, lateral palatal swelling, or bifid uvula are common in Apert syndrome patients. Mouse models of Apert syndrome display palatal defects, providing valuable tools to understand the underlying mechanisms. The mutations in FGFR2 causing Apert syndrome may change a signaling network in epithelial-mesenchymal interactions during palatogenesis. Understanding the pathogenic mechanisms of palatal defects in Apert syndrome may shed light on potential novel therapeutic solutions.
PubMed: 35997397
DOI: 10.3390/jdb10030033 -
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 -
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 -
Ethiopian Journal of Health Sciences May 2022Bacterial Sepsis is a serious medical problem affecting children with Congenital Heart Disease (CHD). The pattern and factors predicting outcome of bacterial sepsis have...
BACKGROUND
Bacterial Sepsis is a serious medical problem affecting children with Congenital Heart Disease (CHD). The pattern and factors predicting outcome of bacterial sepsis have not been studied in Africa. The study aimed to describe the pattern and outcome of bacterial sepsis among children with CHD in Tikur Anbessa Specialized Hospital (TASH).
METHODS
A cross-sectional study was carried out among children with CHD and sepsis at TASH between May 2017 and July 2020. Structured questionnaires were used for data collection. Statistical significance was set at P value < 0.05, and multivariable logistic regression was used to determine predictors.
RESULTS
This study included 384 CHD children with sepsis. Proportion of culture proven bacterial sepsis was 17.1 % (66) (95% CI: 13.6-21.3). Coagulase negative staphylococcus aureus 7% (27), Staphylococcus aureus 4.4% (17) and Actinobacteria 1.8% (7) were the common isolated bacteriological agents. Death was documented in 25% (96) of study subjects. Down syndrome subjects were 2.4 times [aOR=2.416 (95%CI: 1.367-4.264)] more likely to die from sepsis. Those with associated comorbidities (Apert syndrome, Cerebral palsy, Chiari 2 malformation, Patau syndrome, Noonan syndrome, Congenital Rubella, Portal vein thrombosis, HIV, Scoliosis and VACTERL association) were 4.4 times more likely to die from sepsis [aOR=4.418 (95%CI: 1.617-12.072)].
CONCLUSION
Bacterial sepsis is a common problem among children with CHD. Gram positive bacteria were common causes. Down syndrome and other co morbidities predicted bacterial sepsis mortality. Blood culture and sensitivity tests are recommended to halt the high mortality seen in Down syndrome or those with co morbidities.
Topics: Child; Cross-Sectional Studies; Down Syndrome; Ethiopia; Heart Defects, Congenital; Hospitals; Humans; Sepsis
PubMed: 35813671
DOI: 10.4314/ejhs.v32i3.7 -
Journal of Community Hospital Internal... 2022Sinus of Valsalva aneurysm (SOVA) is a rare anomaly of the aorta that can be congenital or acquired. It can be associated with syndromes such as Marfan syndrome and...
BACKGROUND
Sinus of Valsalva aneurysm (SOVA) is a rare anomaly of the aorta that can be congenital or acquired. It can be associated with syndromes such as Marfan syndrome and Ehlers-Danlos syndrome. However, to our knowledge, it has never been described in a patient with Apert syndrome. Although it often presents as an incidental finding on imaging, SOVA is associated with the risk of serious complications, including rupture. A possible connection between the conditions might be the FGFR2 gene mutation in Apert syndrome and the influence of a mutation in fibroblast growth factor 2 (FGF2) on heart development. Here we report a case of acute heart failure secondary to rupture of SOVA into the right atrium in a patient with Apert syndrome.
CASE PRESENTATION
A 47-year-old Caucasian woman with a history of Apert syndrome and rheumatoid arthritis presented with shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, and progressive bilateral lower extremity edema for 2 weeks. She was diagnosed with acute right heart failure due to ruptured SOVA. The patient underwent surgical repair of the ruptured SOVA. Unfortunately, her postoperative course was complicated by a stroke leading to brain death.
CONCLUSION
Ruptured SOVA is a quite rare but serious condition that can cause life-threatening complications. In this case, SOVA occurred in a patient with Apert syndrome. The case may suggest that these two conditions may be related through the FGFR2 gene mutation associated with Apert syndrome and the related growth factor FGF2 involved in heart development.
PubMed: 35711877
DOI: 10.55729/2000-9666.1013 -
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 -
Journal of Oral Biology and... 2022Apert syndrome (AS) is a rare congenital disorder that correlates with many craniofacial features, like craniosynostosis, midfacial malformation, and symmetrical...
BACKGROUND
Apert syndrome (AS) is a rare congenital disorder that correlates with many craniofacial features, like craniosynostosis, midfacial malformation, and symmetrical syndactyly of the hands and feet.
AIM
This paper describes the facial and oral manifestations in a 20-year-old female previously diagnosed with AS, discusses the complex dental treatment plan and treatments, including the use of a customized toothbrush handle to enhance the patient's brushing ability.
RESULTS
A satisfactory outcome was provided, and the patients quality of life improved significantly due to this comprehensive multi-disciplinary care process.
CONCLUSIONS
Comprehensive examination, extensive medical history reviewed, parental and patient consent are needed to establish a comprehensive treatment plan regarding the special needs of these patients.
PubMed: 35514675
DOI: 10.1016/j.jobcr.2022.04.002