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Journal of Medical Systems Jul 2020This paper presents a methodological procedure, based on the anatomical reconstruction and constrained deformation, to design custom-made implants for forehead...
This paper presents a methodological procedure, based on the anatomical reconstruction and constrained deformation, to design custom-made implants for forehead augmentation in people affected by Apert syndrome, experiencing a frontal bone deficiency. According to the anthropometric theory, a cranial landmarks identification procedure was applied to retrieve, from a repository, a healthy skull, used as reference geometry for implant modelling. Then, using constrained deformation and free-form modelling techniques, it was possible to design a patient-specific implant. At last, the implant was realised using a custom mould, specially designed according to the patient's needs to provide an accurate fit of the defect site. The design procedure was tested on a patient suffering from Apert syndrome. Three implants were virtually modelled and 3D-printed for pre-surgical evaluation. Their shapes were 3D compared with a reference one (handcrafted by a surgeon) to test the accuracy. Deviations are negligible, and the customised implant fulfilled the surgeon's requirements.
Topics: Acrocephalosyndactylia; Computer-Aided Design; Forehead; Humans; Imaging, Three-Dimensional; Plastic Surgery Procedures; Tomography, X-Ray Computed
PubMed: 32720066
DOI: 10.1007/s10916-020-01611-9 -
Scientific Reports Apr 2021Midface hypoplasia is a major manifestation of Apert syndrome. However, the tissue component responsible for midface hypoplasia has not been elucidated. We studied mice...
Midface hypoplasia is a major manifestation of Apert syndrome. However, the tissue component responsible for midface hypoplasia has not been elucidated. We studied mice with a chondrocyte-specific Fgfr2 mutation (Col2a1-cre; Fgfr2) to investigate the effect of cartilaginous components in midface hypoplasia of Apert syndrome. In Col2a1-cre; Fgfr2 mice, skull shape was normal at birth, but hypoplastic phenotypes became evident with age. General dimensional changes of mutant mice were comparable with those of mice with mutations in EIIa-cre; Fgfr2, a classic model of Apert syndrome in mice. Col2a1-cre; Fgfr2 mice showed some unique facial phenotypes, such as elevated nasion, abnormal fusion of the suture between the premaxilla and the vomer, and decreased perpendicular plate of the ethmoid bone volume, which are related to the development of the nasal septal cartilage. Morphological and histological examination revealed that the presence of increased septal chondrocyte hypertrophy and abnormal thickening of nasal septum is causally related to midface deformities in nasal septum-associated structures. Our results suggest that careful examination and surgical correction of the nasal septal cartilage may improve the prognosis in the surgical treatment of midface hypoplasia and respiratory problems in patients with Apert syndrome.
Topics: Acrocephalosyndactylia; Animals; Chondrocytes; Collagen Type II; Cranial Sutures; Disease Models, Animal; Face; Hypertrophy; Mice; Mutation; Nasal Septum; Receptor, Fibroblast Growth Factor, Type 2; X-Ray Microtomography
PubMed: 33846505
DOI: 10.1038/s41598-021-87260-5 -
Italian Journal of Pediatrics Mar 2018Pleural effusion is a rare complication of ventriculo-peritoneal (VP) cerebrospinal fluid (CSF) shunting and its diagnosis is difficult in patients with neurological and... (Review)
Review
BACKGROUND
Pleural effusion is a rare complication of ventriculo-peritoneal (VP) cerebrospinal fluid (CSF) shunting and its diagnosis is difficult in patients with neurological and consciousness impairment.
CASE REPORT
Herein we report the case of a child affected by Pfeiffer syndrome and hydrocephalus, shunted at the age of 3 months, who developed acute respiratory failure due to a right-sided pleural effusion 2 years later. Plain chest radiographs and computed tomography (CT) showed the intrathoracic migration of the right VP shunt abdominal tip. Beta-2 transferrin, a marker for CSF, was found in the pleural fluid and the hypothesis of a CSF hydrothorax was confirmed. Effusion was treated with a thoracentesis. Seven days after, the right VP shunt was revised; a ventriculo-atrial (VA) shunt was also placed on the left side to serve as the main CSF shunt and to prevent the recurrence of hydrothorax. We review the pediatric cases of CSF hydrothorax reported in the literature and discuss the mechanisms underlying this complication together with the possible treatments.
CONCLUSION
Pleural effusion due to VP shunt insertion is a rare and potentially life-threatening condition that should be suspected in any patient with a VP shunt and respiratory failure. Signs of hydrothorax may moreover represent the only clinical evidence of a shunt-related complication in case of neurologically severely compromised patients in which neurologic examination cannot help to make a diagnosis.
Topics: Acrocephalosyndactylia; Catheters; Child, Preschool; Device Removal; Female; Follow-Up Studies; Foreign-Body Migration; Humans; Hydrocephalus; Magnetic Resonance Imaging; Pleural Effusion; Reoperation; Risk Assessment; Tomography, X-Ray Computed; Treatment Outcome; Ventriculoperitoneal Shunt
PubMed: 29587815
DOI: 10.1186/s13052-018-0480-2 -
The Journal of Hand Surgery, European... May 2024This study evaluated how Apert hand syndactyly presentations and reconstructive techniques influence reconstruction outcomes. All cases at a major paediatric hospital...
UNLABELLED
This study evaluated how Apert hand syndactyly presentations and reconstructive techniques influence reconstruction outcomes. All cases at a major paediatric hospital between 2007 and 2022 were analysed, including 98 web space reconstructions in 17 patients. Overall, 62% of hands developed complications and 15% required revision surgery. Upton hand type was significantly associated with postoperative complication incidence, specifically including range-of-motion deficits, flexion contracture, web creep and revision surgery. More severe syndactylies may benefit from additional measures to reduce complications. Rectangular commissural flaps showed 1.9 times greater complication risk than interdigitating triangular flaps, including 11.2 times greater risk of web creep. Zigzag volar finger flaps showed 1.8 times greater complication risk than straight-line incisions, including 3.8 times greater risk of web creep. Our study showed that interdigitating triangular commissural flaps and straight-line volar finger incisions are preferable to rectangular commissural and zigzag finger flaps in most cases of Apert hand syndactyly to minimize complications.
LEVEL OF EVIDENCE
III.
Topics: Humans; Male; Female; Postoperative Complications; Surgical Flaps; Risk Factors; Infant; Plastic Surgery Procedures; Acrocephalosyndactylia; Child, Preschool; Reoperation; Retrospective Studies; Syndactyly; Child; Range of Motion, Articular
PubMed: 37987676
DOI: 10.1177/17531934231213516 -
Journal of Medical Genetics Jun 2021Pathogenic DNA variants in the GLI-Kruppel family member 3 ( gene are known to cause multiple syndromes: for example, Greig syndrome, preaxial polydactyly-type 4 (PPD4)...
INTRODUCTION
Pathogenic DNA variants in the GLI-Kruppel family member 3 ( gene are known to cause multiple syndromes: for example, Greig syndrome, preaxial polydactyly-type 4 (PPD4) and Pallister-Hall syndrome. Out of these, Pallister-Hall is a different entity, but the distinction between Greig syndrome and PPD4 is less evident. Using latent class analysis (LCA), our study aimed to investigate the correlation between reported limb anomalies and the reported variants in these GLI3-mediated polydactyly syndromes. We identified two subclasses of limb anomalies that relate to the underlying variant.
METHODS
Both local and published cases were included for analysis. The presence of individual limb phenotypes was dichotomised and an exploratory LCA was performed. Distribution of phenotypes and genotypes over the classes were explored and subsequently the key predictors of latent class membership were correlated to the different clustered genotypes.
RESULTS
297 cases were identified with 127 different variants in the gene. A two-class model was fitted revealing two subgroups of patients with anterior versus posterior anomalies. Posterior anomalies were observed in cases with truncating variants in the activator domain (postaxial polydactyly; hand, OR: 12.7; foot, OR: 33.9). Multivariate analysis supports these results (Beta: 1.467, p=0.013 and Beta: 2.548, p<0.001, respectively). Corpus callosum agenesis was significantly correlated to these variants (OR: 8.8, p<0.001).
CONCLUSION
There are two distinct phenotypes within the GLI3-mediated polydactyly population: anteriorly and posteriorly orientated. Variants that likely produce haploinsufficiency are associated with anterior phenotypes. Posterior phenotypes are associated with truncating variants in the activator domain. Patients with these truncating variants have a greater risk for corpus callosum anomalies.
Topics: Acrocephalosyndactylia; Genetic Association Studies; Genetic Variation; Humans; Latent Class Analysis; Limb Deformities, Congenital; Nerve Tissue Proteins; Polydactyly; Syndrome; Zinc Finger Protein Gli3
PubMed: 32591344
DOI: 10.1136/jmedgenet-2020-106948 -
The Application of Clinical Genetics 2020Pfeiffer syndrome (PS) is an autosomal dominant disorder caused by mutations in fibroblast growth factor receptor FGFR1 and FGFR2 genes, occurring in approximately...
BACKGROUND
Pfeiffer syndrome (PS) is an autosomal dominant disorder caused by mutations in fibroblast growth factor receptor FGFR1 and FGFR2 genes, occurring in approximately 1:100,000 live births. PS has a wide range of clinical expression and severity, so early prenatal diagnosis is difficult and genetic counseling is desirable. We describe a PS newborn with her ultrasound and molecular studies.
CASE REPORT
We describe a female term newborn with cloverleaf-shaped skull, facial hypoplasia, low ears, exophthalmos and wide, broad and deviated thumbs and hallux. The patient was diagnosed by ultrasound at 29 WGA and referred to a tertiary care hospital for her follow-up. Molecular test revealed a heterozygous pathogenic variant in intron 8 of the FGFR2 gene (FGFR2: c.940-1G>C). It was a de-novo mutation. At 17 days of life, craniosynostosis correction and a Lefort-III frontomaxillary advancement were performed.
CONCLUSION
Pfeiffer syndrome is a devastating genetic disorder. Prenatal diagnosis according PS morphological features in prenatal ultrasound allows timely genetic counseling, early referral to third-level centers, and close follow-up in the prenatal and postnatal stages.
PubMed: 32848441
DOI: 10.2147/TACG.S251581 -
Stem Cell Research & Therapy Dec 2020During development, excessive osteogenic differentiation of mesenchymal progenitor cells (MPC) within the cranial sutures can lead to premature suture fusion or...
BACKGROUND
During development, excessive osteogenic differentiation of mesenchymal progenitor cells (MPC) within the cranial sutures can lead to premature suture fusion or craniosynostosis, leading to craniofacial and cognitive issues. Saethre-Chotzen syndrome (SCS) is a common form of craniosynostosis, caused by TWIST-1 gene mutations. Currently, the only treatment option for craniosynostosis involves multiple invasive cranial surgeries, which can lead to serious complications.
METHODS
The present study utilized Twist-1 haploinsufficient (Twist-1) mice as SCS mouse model to investigate the inhibition of Kdm6a and Kdm6b activity using the pharmacological inhibitor, GSK-J4, on calvarial cell osteogenic potential.
RESULTS
This study showed that the histone methyltransferase EZH2, an osteogenesis inhibitor, is downregulated in calvarial cells derived from Twist-1 mice, whereas the counter histone demethylases, Kdm6a and Kdm6b, known promoters of osteogenesis, were upregulated. In vitro studies confirmed that siRNA-mediated inhibition of Kdm6a and Kdm6b expression suppressed osteogenic differentiation of Twist-1 calvarial cells. Moreover, pharmacological targeting of Kdm6a and Kdm6b activity, with the inhibitor, GSK-J4, caused a dose-dependent suppression of osteogenic differentiation by Twist-1 calvarial cells in vitro and reduced mineralized bone formation in Twist-1 calvarial explant cultures. Chromatin immunoprecipitation and Western blot analyses found that GSK-J4 treatment elevated the levels of the Kdm6a and Kdm6b epigenetic target, the repressive mark of tri-methylated lysine 27 on histone 3, on osteogenic genes leading to repression of Runx2 and Alkaline Phosphatase expression. Pre-clinical in vivo studies showed that local administration of GSK-J4 to the calvaria of Twist-1 mice prevented premature suture fusion and kept the sutures open up to postnatal day 20.
CONCLUSION
The inhibition of Kdm6a and Kdm6b activity by GSK-J4 could be used as a potential non-invasive therapeutic strategy for preventing craniosynostosis in children with SCS. Pharmacological targeting of Kdm6a/b activity can alleviate craniosynostosis in Saethre-Chotzen syndrome. Aberrant osteogenesis by Twist-1 mutant cranial suture mesenchymal progenitor cells occurs via deregulation of epigenetic modifiers Ezh2 and Kdm6a/Kdm6b. Suppression of Kdm6a- and Kdm6b-mediated osteogenesis with GSK-J4 inhibitor can prevent prefusion of cranial sutures.
Topics: Acrocephalosyndactylia; Animals; Histone Demethylases; Jumonji Domain-Containing Histone Demethylases; Mice; Molecular Targeted Therapy; Nuclear Proteins; Osteogenesis; Twist-Related Protein 1
PubMed: 33298158
DOI: 10.1186/s13287-020-02051-5 -
Genetics Aug 2023TWIST1 is a basic helix-loop-helix (bHLH) transcription factor in humans that functions in mesoderm differentiation. TWIST1 primarily regulates genes as a...
TWIST1 is a basic helix-loop-helix (bHLH) transcription factor in humans that functions in mesoderm differentiation. TWIST1 primarily regulates genes as a transcriptional repressor often through TWIST-Box domain-mediated protein-protein interactions. The TWIST-Box also can function as an activation domain requiring 3 conserved, equidistant amino acids (LXXXFXXXR). Autosomal dominant mutations in TWIST1, including 2 reported in these conserved amino acids (F187L and R191M), lead to craniofacial defects in Saethre-Chotzen syndrome (SCS). Caenorhabditis elegans has a single TWIST1 homolog, HLH-8, that functions in the differentiation of the muscles responsible for egg laying and defecation. Null alleles in hlh-8 lead to severely egg-laying defective and constipated animals due to defects in the corresponding muscles. TWIST1 and HLH-8 share sequence identity in their bHLH regions; however, the domain responsible for the transcriptional activity of HLH-8 is unknown. Sequence alignment suggests that HLH-8 has a TWIST-Box LXXXFXXXR motif; however, its function also is unknown. CRISPR/Cas9 genome editing was utilized to generate a domain deletion and several missense mutations, including those analogous to SCS patients, in the 3 conserved HLH-8 amino acids to investigate their functional role. The TWIST-Box alleles did not phenocopy hlh-8 null mutants. The strongest phenotype detected was a retentive (Ret) phenotype with late-stage embryos in the hermaphrodite uterus. Further, GFP reporters of HLH-8 downstream target genes (arg-1::gfp and egl-15::gfp) revealed tissue-specific, target-specific, and allele-specific defects. Overall, the TWIST-Box in HLH-8 is partially required for the protein's transcriptional activity, and the conserved amino acids contribute unequally to the domain's function.
Topics: Animals; Female; Humans; Acrocephalosyndactylia; Basic Helix-Loop-Helix Transcription Factors; Caenorhabditis elegans; Mutation; Transcription Factors; Twist-Related Protein 1
PubMed: 37067863
DOI: 10.1093/genetics/iyad066 -
Journal of Medical Case Reports Apr 2019Greig cephalopolysyndactyly syndrome is a rare multiple congenital anomaly syndrome characterized by the triad of polysyndactyly (preaxial or mixed preaxial and...
BACKGROUND
Greig cephalopolysyndactyly syndrome is a rare multiple congenital anomaly syndrome characterized by the triad of polysyndactyly (preaxial or mixed preaxial and postaxial), macrocephaly, and ocular hypertelorism. Little is known about the neuropsychological phenotype and the developmental features of this syndrome.
CASE PRESENTATION
We describe the clinical features of a 7-year-old Italian white boy affected by Greig cephalopolysyndactyly syndrome in comorbidity with autism spectrum disorder and the case of his 45-year-old white father, carrying the same point deletion (c.3677del) in the GLI3 gene and showing subclinical autistic symptoms. We performed a neuropsychiatric assessment of cognitive, adaptive, socio-communicative, and behavioral skills of the child. Concurrently, the father underwent his first psychiatric evaluation of cognitive skills and autistic symptoms.
CONCLUSIONS
We report the first clinical description of an association between autistic symptoms and Greig cephalopolysyndactyly syndrome in two members of the same family with the same genetic point deletion. Further research is required in order to draw an accurate conclusion regarding the association between Greig cephalopolysyndactyly syndrome and autism.
Topics: Acrocephalosyndactylia; Adult; Autism Spectrum Disorder; Behavior Therapy; Child; Chromosome Deletion; Genetic Linkage; Humans; Male; Nerve Tissue Proteins; Neuropsychological Tests; Phenotype; Zinc Finger Protein Gli3
PubMed: 31010437
DOI: 10.1186/s13256-019-2043-6 -
Development (Cambridge, England) Oct 2018Midface dysgenesis is a feature of more than 200 genetic conditions in which upper airway anomalies frequently cause respiratory distress, but its etiology is poorly...
Midface dysgenesis is a feature of more than 200 genetic conditions in which upper airway anomalies frequently cause respiratory distress, but its etiology is poorly understood. Mouse models of Apert and Crouzon craniosynostosis syndromes exhibit midface dysgenesis similar to the human conditions. They carry activating mutations of , which is expressed in multiple craniofacial tissues during development. Magnetic resonance microscopy of three mouse models of Apert and Crouzon syndromes revealed decreased nasal passage volume in all models at birth. Histological analysis suggested overgrowth of the nasal cartilage in the two Apert syndrome mouse models. We used tissue-specific gene expression and transcriptome analysis to further dissect the structural, cellular and molecular alterations underlying midface and upper airway dysgenesis in Apert mutants. Cartilage thickened progressively during embryogenesis because of increased chondrocyte proliferation in the presence of Oral epithelium expression of mutant which resulted in a distinctive nasal septal fusion defect, and premature facial suture fusion contributed to the overall dysmorphology. Midface dysgenesis in -related craniosynostosis is a complex phenotype arising from the combined effects of aberrant signaling in multiple craniofacial tissues.
Topics: Acrocephalosyndactylia; Animals; Cartilage; Cell Cycle; Cell Proliferation; Chondrocytes; Cranial Sutures; Craniofacial Dysostosis; Craniosynostoses; Disease Models, Animal; Embryo, Mammalian; Face; Gene Expression Regulation, Developmental; Mice, Inbred C57BL; Mice, Mutant Strains; Nose; Organ Specificity; Receptor, Fibroblast Growth Factor, Type 2; Respiratory System Abnormalities
PubMed: 30228104
DOI: 10.1242/dev.166488