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Journal of Basic and Clinical... May 2024Genetic disorders involved in skeleton system arise due to the disturbance in skeletal development, growth and homeostasis. Filamin B is an actin binding protein which...
OBJECTIVES
Genetic disorders involved in skeleton system arise due to the disturbance in skeletal development, growth and homeostasis. Filamin B is an actin binding protein which is large dimeric protein which cross link actin cytoskeleton filaments into dynamic structure. A single nucleotide changes in the FLNB gene causes spondylocarpotarsal synostosis syndrome, a rare bone disorder due to which the fusion of carpels and tarsals synostosis occurred along with fused vertebrae. In the current study we investigated a family residing in north-western areas of Pakistan.
METHODS
The whole exome sequencing of proband was performed followed by Sanger sequencing of all family members of the subject to validate the variant segregation within the family. Bioinformatics tools were utilized to assess the pathogenicity of the variant.
RESULTS
Whole Exome Sequencing revealed a novel variant (NM_001457: c.209C>T and p.Pro70Leu) in the gene which was homozygous missense mutation in the gene. The variant was further validated and visualized by Sanger sequencing and protein structure studies respectively as mentioned before.
CONCLUSIONS
The findings have highlighted the importance of the molecular diagnosis in SCT (spondylocarpotarsal synostosis syndrome) for genetic risk counselling in consanguineous families.
Topics: Humans; Synostosis; Filamins; Male; Exome Sequencing; Female; Pedigree; Scoliosis; Abnormalities, Multiple; Mutation, Missense; Pakistan; Homozygote; Lumbar Vertebrae; Musculoskeletal Diseases; Thoracic Vertebrae
PubMed: 38743867
DOI: 10.1515/jbcpp-2024-0031 -
The Journal of Craniofacial Surgery Jun 2024Metopic craniosynostosis (MCS) can be difficult to differentiate from metopic ridge (MR) or normal frontal morphology. This study assess whether the supraorbital...
OBJECTIVE
Metopic craniosynostosis (MCS) can be difficult to differentiate from metopic ridge (MR) or normal frontal morphology. This study assess whether the supraorbital notch-nasion-supraorbital notch (SNS) angle can help identify MCS.
METHODS
Records of 212 patients with preoperative three-dimensional computed tomography scans were examined. The SNS angles, surgeon craniofacial dysmorphology rankings, and CranioRate metopic severity scores (MSSs) were compared with the Spearman rank correlation coefficient. Receiver operating characteristic (ROC) curves with Youden J-statistic and cross-validation of regression models assessed the ability of these measures to predict surgery.
RESULTS
A total of 212 patients were included, consisting of 78 MCS, 37 MR, and 97 controls. Both the mean SNS angle (MCS: 111.7 ± 10.7 degrees, MR: 126.0 ± 8.2 degrees, controls: 130.7 ± 8.8 degrees P < 0.001) and MSS (MCS: 5.9 ± 2.0, MR: 1.4 ± 1.9, controls: 0.2 ± 1.9, P < 0.001) were different among the cohorts. The mean SNS angle (111.5 ± 10.7 versus 129.1 ± 8.8, P < 0.001) was lower in those who had surgery and CranioRate score (5.9 ± 2.1 versus 0.8 ± 2.2, P < 0.001) was higher in those who underwent surgery. SNS angles were positively correlated with surgeon craniofacial dysmorphology rankings ( r = 0.41, P < 0.05) and CranioRate MSS ( r = 0.54, P < 0.05). The ROC curve requiring high sensitivity revealed an SNS angle of 124.8 degrees predicted surgery with a sensitivity of 88.7% and a specificity of 71.3%. A ROC curve using the CranioRate MCC values ≥3.19 predicted surgery with 88.7% sensitivity and 94.7% specificity.
CONCLUSION
Orbital dysmorphology in patients with MCS is well captured by the supraorbital-nasion angle. Both the SNS angle and CranioRate MSS scores accurately predict surgical intervention.
Topics: Female; Humans; Infant; Male; Craniosynostoses; Imaging, Three-Dimensional; Orbit; Reproducibility of Results; Retrospective Studies; ROC Curve; Severity of Illness Index; Tomography, X-Ray Computed
PubMed: 38743289
DOI: 10.1097/SCS.0000000000010302 -
Lancet (London, England) May 2024
Topics: Humans; Bone Diseases, Developmental; Bone Marrow Transplantation; Craniofacial Abnormalities; Hyperostosis; Hypertelorism; Osteochondrodysplasias; Transplantation, Homologous; Female; Child, Preschool
PubMed: 38734477
DOI: 10.1016/S0140-6736(24)00803-1 -
International Journal of Molecular... Apr 2024Hemifacial microsomia (HFM) is a rare congenital genetic syndrome primarily affecting the first and second pharyngeal arches, leading to defects in the mandible,...
Hemifacial microsomia (HFM) is a rare congenital genetic syndrome primarily affecting the first and second pharyngeal arches, leading to defects in the mandible, external ear, and middle ear. The pathogenic genes remain largely unidentified. Whole-exome sequencing (WES) was conducted on 12 HFM probands and their unaffected biological parents. Predictive structural analysis of the target gene was conducted using PSIPRED (v3.3) and SWISS-MODEL, while STRING facilitated protein-to-protein interaction predictions. CRISPR/Cas9 was applied for gene knockout in zebrafish. In situ hybridization (ISH) was employed to examine the spatiotemporal expression of the target gene and neural crest cell (NCC) markers. Immunofluorescence with PH3 and TUNEL assays were used to assess cell proliferation and apoptosis. RNA sequencing was performed on mutant and control embryos, with rescue experiments involving target mRNA injections and specific gene knockouts. was identified as a novel candidate gene for HFM, with four nonsynonymous de novo variants detected in three unrelated probands. Structural predictions indicated significant alterations in the secondary and tertiary structures of . knockout in zebrafish resulted in craniofacial malformation, spine deformity, and cardiac edema, mirroring typical HFM phenotypes. Abnormalities in somatic cell apoptosis, reduced NCC proliferation in pharyngeal arches, and chondrocyte differentiation issues were observed in mutants. mRNA injections and or knockout significantly rescued pharyngeal arch cartilage dysplasia, while mRNA administration partially restored the defective phenotypes. Our findings suggest a functional link between and HFM, primarily through the inhibition of proliferation and disruption of pharyngeal chondrocyte differentiation.
Topics: Animals; Zebrafish; Humans; Male; Female; Goldenhar Syndrome; Apoptosis; Neural Crest; Exome Sequencing; Cell Proliferation; Phenotype; Mutation; Gene Knockout Techniques
PubMed: 38731925
DOI: 10.3390/ijms25094707 -
The Journal of Hand Surgery... Jun 2024Ectodermal dysplasia-syndactyly syndrome 1 (EDSS1) is an exceedingly rare condition associated with mutations in the PVL4 gene. It is characterised by sparse, brittle...
Ectodermal dysplasia-syndactyly syndrome 1 (EDSS1) is an exceedingly rare condition associated with mutations in the PVL4 gene. It is characterised by sparse, brittle hair, eyebrows and eyelashes, abnormal dentition and nails, along with bilateral cutaneous syndactyly involving the fingers and toes. We report a 2-year-old girl who presented to us with bilateral complete simple syndactyly of the third and fourth web spaces of the hands, along with bilateral syndactyly of both feet involving the second to fourth toes. Upon examination, sparse hair and eyebrows, along with abnormal dentition, were noted. Thorough clinical examination and genetic analysis were conducted on the affected child and her father, who exhibited similar clinical features. Genetic analysis revealed a homozygous nonsense mutation in the PVL4 gene in both individuals. According to the literature, EDSS1 has been reported in only 10 families worldwide, and there are no reported cases from India. Level V (Therapeutic).
Topics: Child, Preschool; Female; Humans; Codon, Nonsense; Ectodermal Dysplasia; Syndactyly
PubMed: 38726487
DOI: 10.1142/S242483552472007X -
Annals of Plastic Surgery Jun 2024Posterior vault distraction osteogenesis (PVDO) has been shown to resolve acute intracranial hypertension (AIH) while carrying an acceptable perioperative morbidity...
Posterior vault distraction osteogenesis (PVDO) has been shown to resolve acute intracranial hypertension (AIH) while carrying an acceptable perioperative morbidity profile. PVDO has been associated with symptomatic improvement and fewer surgeries in those requiring ventriculoperitoneal shunts. The authors' experience using PVDO as an acute intervention is presented, demonstrating its safety and efficacy for management of AIH. Four cases of children with craniosynostosis that underwent PVDO in the acute setting are outlined. All patients presented with papilledema and symptoms of AIH. One patient with slit ventricle syndrome (SVS) presented with a nonfunctioning shunt following multiple shunt revisions. No intraoperative complications during distractor placement or removal were reported. Distraction protocol for all patients began on postoperative day 1 at 1-2 mm per day, resulting in an average total distraction of 30.25 mm. For the 3 cases with no shunt, the average length of stay was 7 days. As part of the planned treatment course, the patient with SVS required externalization of the shunt during distraction followed by early distractor removal and planned shunt replacement. One case of surgical site infection (in an immunocompromised patient) required premature distractor removal during the consolidation period. Computed tomography (CT) in all patients indicated increased intracranial volume following distraction, and symptomatic improvement was reported. Six-month follow-up showed resolution of papilledema in all patients. The authors' experience using PVDO in the acute setting is reported, alongside a review of current literature, in order to provide supporting evidence for the efficacy of PVDO as a tool for resolving AIH.
Topics: Humans; Osteogenesis, Distraction; Intracranial Hypertension; Male; Female; Infant; Craniosynostoses; Acute Disease; Child, Preschool; Tomography, X-Ray Computed
PubMed: 38725113
DOI: 10.1097/SAP.0000000000003953 -
The Journal of Craniofacial Surgery Jun 2024This study assesses the level of child-patient satisfaction with the surgical result after scaphocephaly correction and the difference between child-patient and parents'...
OBJECTIVE
This study assesses the level of child-patient satisfaction with the surgical result after scaphocephaly correction and the difference between child-patient and parents' perspectives.
METHODS
A questionnaire was sent out to children between 6 and 18 years old with isolated sagittal synostosis, who had undergone either a frontobiparietal remodeling or extended strip craniotomy, and separately to their parents.
RESULTS
The questionnaire was completed by 96 patients, 81.2% of the patients considered their head to be similar or slightly different from others. Despite the majority being satisfied with the outcome, 33% would change the shape of their head if they could. Patients who underwent extended strip craniotomy wanted to change the back of their head more often ( P = 0.002), whereas patients who underwent frontobiparietal remodeling wanted to change their forehead ( P = 0.005). The patients' own perspective on head shape was independent of the cephalic index (CI). However, patients with a relatively narrow CI received more remarks from others about their heads ( P = 0.038). Parent and child agreement was 49.7% on average. Differences between child-patients and parents were found in reporting adaptive behavior.
CONCLUSION
The majority of patients were satisfied with the outcome of their intervention. The child's perspective seems to be a valuable addition to evaluate sagittal synostosis surgery as it is independent of the CI and differentiates between different surgical techniques. In addition, the patient's perspective is comparable to the parent's perspective, but gives more details on adaptive behavior.
Topics: Humans; Craniosynostoses; Male; Female; Patient Satisfaction; Child; Parents; Adolescent; Surveys and Questionnaires; Craniotomy; Treatment Outcome
PubMed: 38722327
DOI: 10.1097/SCS.0000000000010263 -
The Journal of Craniofacial Surgery Jun 2024VACTERL association is diagnosed based on the non-random co-occurrence of at least 3 out of 6 congenital malformations. The prevalence is thought to be less than 1 in...
VACTERL association is diagnosed based on the non-random co-occurrence of at least 3 out of 6 congenital malformations. The prevalence is thought to be less than 1 in 10,000 to 1 in 40,000. There is no known link between VACTERL association and metopic synostosis in the literature. There were 122 operated cases of metopic synostosis at our institution from 1999 to 2023, with a 2.3:1 male-to-female ratio. The authors describe the co-occurrence of VACTERL association and metopic synostosis in 3 female patients with no identifiable genetic variants. Given that VACTERL association is a diagnosis of exclusion, other rare syndromes were considered but ultimately excluded. This suggests that the co-occurrence of VACTERL association and metopic synostosis is a potentially rare finding, and underlying pathogenic variants are yet to be identified.
Topics: Humans; Female; Craniosynostoses; Limb Deformities, Congenital; Trachea; Heart Defects, Congenital; Anal Canal; Infant; Esophagus; Spine; Male; Kidney
PubMed: 38722317
DOI: 10.1097/SCS.0000000000010268 -
Annals of Plastic Surgery Jun 2024Treatment for polysyndactyly of the toes aims at cosmetic improvement but the lateroplantar rotation of the new fifth toe remains challenging. This study evaluated our...
PURPOSE
Treatment for polysyndactyly of the toes aims at cosmetic improvement but the lateroplantar rotation of the new fifth toe remains challenging. This study evaluated our novel surgical procedure for postaxial polysyndactyly of the toes.
MATERIALS AND METHODS
Patients with postaxial polysyndactyly involving the fourth, fifth, and sixth toes treated in 2007 to 2017 with a minimum follow-up duration of 1 year were retrospectively investigated. Our aims of surgery for this condition were to avoid excessive lateroplantar rotation of the new fifth toe by using a proximally elongated plantar "shark-fin flap" and to make the tip of this toe appear to be naturally pointing inward by using the dog-ear component of the flap on the tip of the toe. The excess skin of the shark-fin flap was grafted onto the lateral surface of the fourth toe. Lateroplantar rotation of the fifth toe in these patients was compared with that in photographs of the feet of 96 normal 4-year-old children.
RESULTS
A total of 11 feet in 10 patients (6 male, 4 female; mean age 1.3 years) were analyzed. Syndactyly between the fourth and fifth toes was complete in 3 feet, incomplete at the level of the distal interphalangeal joint of the fifth toe in 5, and incomplete at the level of the proximal interphalangeal joint of the fifth toe in 3. Lateroplantar rotation of the fifth toe, evaluated by the mean angle between 2 intersecting lines extending from the proximal nail fold of the third and fifth toes, was 25 ± 10° in normal feet and 0 ± 12° in operated feet with polysyndactyly. The absolute left-right difference in this angle was 7 ± 5° in normal children and 22 ± 12° in patients with polysyndactyly. Valgus deformity of the new fifth toe improved in all patients during a mean postoperative follow-up of 3.8 years.
CONCLUSIONS
Using our procedure, no excessive lateroplantar rotation has been observed when the tip of the fifth toe is inclined inward using a dog-ear flap component. This procedure could be useful in patients in whom the cosmetic outcome is a priority.
Topics: Humans; Female; Male; Syndactyly; Retrospective Studies; Child, Preschool; Surgical Flaps; Japan; Infant; Toes; Treatment Outcome; Esthetics; Plastic Surgery Procedures; Follow-Up Studies; East Asian People
PubMed: 38717189
DOI: 10.1097/SAP.0000000000003886 -
Nature Reviews. Drug Discovery Jun 2024
Topics: Humans; Syndactyly; Autistic Disorder; Long QT Syndrome; Primary Immunodeficiency Diseases
PubMed: 38714847
DOI: 10.1038/d41573-024-00075-7