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The Journal of Clinical Investigation Feb 2024The rediscovery of meningeal lymphatic vessels (MLVs) has sparked research interest in their function in numerous neurological pathologies. Craniosynostosis (CS) is...
The rediscovery of meningeal lymphatic vessels (MLVs) has sparked research interest in their function in numerous neurological pathologies. Craniosynostosis (CS) is caused by a premature fusion of cranial sutures during development. In this issue of the JCI, Matrongolo and colleagues show that Twist1-haploinsufficient mice that develop CS exhibit raised intracranial pressure, diminished cerebrospinal fluid (CSF) outflow, and impaired paravascular CSF-brain flow; all features that were associated with MLV defects and exacerbated pathology in mouse models of Alzheimer's disease. Activation of the mechanosensor Piezo1 with Yoda1 restored MLV function and CSF perfusion in CS models and in aged mice, opening an avenue for further development of therapeutics.
Topics: Mice; Animals; Brain; Lymphatic Vessels; Craniosynostoses; Alzheimer Disease; Disease Models, Animal; Ion Channels
PubMed: 38357924
DOI: 10.1172/JCI176858 -
The Cleft Palate-craniofacial Journal :... Dec 2023To investigate the relationship between perception of craniofacial deformity, geometric head features, and 3D head shape analyzed by statistical shape modeling (SSM).
OBJECTIVE
To investigate the relationship between perception of craniofacial deformity, geometric head features, and 3D head shape analyzed by statistical shape modeling (SSM).
PATIENTS
A total of 18 unoperated patients with scaphocephaly (age = 5.2 ± 1.1m)-6 were followed-up after spring-assisted cranioplasty (SAC) (age = 9.6 ± 1.5m)-and 6 controls (age = 6.7 ± 2.5m).
MAIN OUTCOME MEASURES
3D head shapes were retrieved from 3D scans or computed tomography (CTs). Various geometrical features were measured: anterior and posterior prominence, take-off angle, average anterior and posterior lateral and horizontal curvatures, cranial index (CI) (cranial width over length), and turricephaly index (TI) (cranial height over length). SSM and principal component analysis (PCA) described shape variability. All models were 3D printed; the perception of deformity was blindly scored by 9 surgeons and 1 radiologist in terms of frontal bossing (FB), occipital bulleting (OB), biparietal narrowing (BN), low posterior vertex (LPV), and overall head shape (OHS).
RESULTS
A moderate correlation was found between FB and anterior prominence (r = 0.56, < .01) and take-off angle (r = - 0.57, < .01). OB correlated with average posterior lateral curvature (r = 0.43, < 0.01) similarly to BPN (r = 0.55, < .01) and LPV (r = 0.43, < .01). OHS showed strong correlation with CI (r = - 0.68, < .01) and TI (r = 0.63, < .01). SSM Mode 1 correlated with OHS (r = 0.66, < .01) while Mode 3 correlated with FB (r = - 0.58, < .01).
CONCLUSIONS
Esthetic cranial appearance in craniofacial patients is correlated to specific geometric parameters and could be estimated using automated methods such as SSM.
Topics: Humans; Child, Preschool; Child; Cephalometry; Craniosynostoses; Skull; Jaw Abnormalities; Perception; Esthetics
PubMed: 35786009
DOI: 10.1177/10556656221111307 -
Clinical Genetics Jul 2023The NADSYN1 gene [MIM*608285] encodes the NAD synthetase 1 enzyme involved in the final step of NAD biosynthesis, crucial for cell metabolism and organ embryogenesis....
The NADSYN1 gene [MIM*608285] encodes the NAD synthetase 1 enzyme involved in the final step of NAD biosynthesis, crucial for cell metabolism and organ embryogenesis. Perturbating the role of NAD biosynthesis results in the association of vertebral, cardiac, renal, and limb anomalies (VCRL). This condition was initially characterized as severe with perinatal lethality or developmental delay and complex malformations in alive cases. Sixteen NADSYN1-associated patients have been published so far. This study illustrates the wide phenotypic variability in NADSYN1-associated NAD deficiency disorder. We report the clinical and molecular findings in three novel cases, two of them being siblings with the same homozygous variant and presenting with either a very severe prenatal lethal or a mild phenotypic form. In addition to an exhaustive literature, we validate the expansion of the spectrum of NAD deficiency disorder. Our findings indicate that NAD deficiency disorder should be suspected not only in the presence of the full spectrum of VCRL, but even a single of the aforementioned organs is affected. Decreased plasmatic levels of NAD should then strongly encourage the screening for any of the genes responsible for a NAD deficiency disorder.
Topics: Female; Humans; Pregnancy; Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor; Homozygote; NAD; Spine; Syndrome
PubMed: 36951206
DOI: 10.1111/cge.14328 -
Child's Nervous System : ChNS :... Nov 2023Numerous classification systems of nonsyndromic sagittal craniosynostosis (NSC) are applied but none has gained a wide acceptance, since each classification is focused...
PURPOSE
Numerous classification systems of nonsyndromic sagittal craniosynostosis (NSC) are applied but none has gained a wide acceptance, since each classification is focused on distinct aspects of cranial dysmorphology. The goal of this study was to depict the most common combinations of radiomorphologic characteristics of NSC and to separate groups where the patients were morphologically similar to one another and at the same time significantly different from others.
METHODS
The study was conducted on anonymized thin-cut CT scans of 131 children with NSC aged 1-12 months (mean age 5.42 months). The type of cranial dysmorphology was assessed using four criteria: skull shape, pattern of sagittal suture fusion, morphologic features and cerebrospinal fluid (CSF) spaces alterations. After assigning the categories, an unsupervised k-modes clustering algorithm was applied to identify distinct patients clusters representing radiomorphologic profiles determined by investigated characteristics.
RESULTS
Cluster analysis revealed three distinct radiomorphologic profiles including the most common combinations of features. The profiles were not influenced by sex nor age but were significantly determined by skull shape (V = 0.58, P < 0.0001), morphologic features (V = 0.50, P < 0.0001) and pattern of sagittal suture fusion (V = 0.47, P < 0.0001). CSF alterations did not significantly correlate with the profiles (P = 0.3585).
CONCLUSION
NSC is a mosaic of radiologic and morphologic features. The internal diversity of NSC results in dissimilar groups of patients defined by unique combinations of radiomorphologic characteristics, from which the skull shape is the most differentiating factor. Radiomorphologic profiles support the idea of clinical trials targeted at more selective outcomes assessment.
Topics: Child; Humans; Infant; Craniosynostoses; Skull; Tomography, X-Ray Computed; Head; Outcome Assessment, Health Care
PubMed: 37243812
DOI: 10.1007/s00381-023-05998-x -
NeoReviews May 2024
Topics: Humans; Infant, Newborn; Syndactyly
PubMed: 38688887
DOI: 10.1542/neo.25-5-e282 -
Frontiers in Pediatrics 2023Mandibulo-Facial Dysostosis with Microcephaly (MFDM) is a rare disease with a broad spectrum of symptoms, characterized by zygomatic and mandibular hypoplasia,...
INTRODUCTION
Mandibulo-Facial Dysostosis with Microcephaly (MFDM) is a rare disease with a broad spectrum of symptoms, characterized by zygomatic and mandibular hypoplasia, microcephaly, and ear abnormalities. Here, we aimed at describing the external ear phenotype of MFDM patients, and train an Artificial Intelligence (AI)-based model to differentiate MFDM ears from non-syndromic control ears (binary classification), and from ears of the main differential diagnoses of this condition (multi-class classification): Treacher Collins (TC), Nager (NAFD) and CHARGE syndromes.
METHODS
The training set contained 1,592 ear photographs, corresponding to 550 patients. We extracted 48 patients completely independent of the training set, with only one photograph per ear per patient. After a CNN-(Convolutional Neural Network) based ear detection, the images were automatically landmarked. Generalized Procrustes Analysis was then performed, along with a dimension reduction using PCA (Principal Component Analysis). The principal components were used as inputs in an eXtreme Gradient Boosting (XGBoost) model, optimized using a 5-fold cross-validation. Finally, the model was tested on an independent validation set.
RESULTS
We trained the model on 1,592 ear photographs, corresponding to 1,296 control ears, 105 MFDM, 33 NAFD, 70 TC and 88 CHARGE syndrome ears. The model detected MFDM with an accuracy of 0.969 [0.838-0.999] ( < 0.001) and an AUC (Area Under the Curve) of 0.975 within controls (binary classification). Balanced accuracies were 0.811 [0.648-0.920] ( = 0.002) in a first multiclass design (MFDM vs. controls and differential diagnoses) and 0.813 [0.544-0.960] ( = 0.003) in a second multiclass design (MFDM vs. differential diagnoses).
CONCLUSION
This is the first AI-based syndrome detection model in dysmorphology based on the external ear, opening promising clinical applications both for local care and referral, and for expert centers.
PubMed: 37664547
DOI: 10.3389/fped.2023.1171277 -
Archives of Orthopaedic and Trauma... Dec 2023To analyze the outcome of surgical treatment of tarsal coalition, assess the role of the surgical technique, as well as of coalition size and type on outcomes. (Review)
Review
PURPOSE
To analyze the outcome of surgical treatment of tarsal coalition, assess the role of the surgical technique, as well as of coalition size and type on outcomes.
METHODS
The search followed the Preferred Reporting Items of Systematic Review and Meta-Analysis and was performed in four databases: MEDLINE, Central, Scopus and Web of Science. The protocol has been registered in the international prospective register of systematic reviews. Patient-reported outcomes (PROMs), complications, revisions and radiographic recurrence were collected. Risk of bias was assessed using MINORS criteria. A random-effects model for meta-analysis was applied for analysis of data heterogeneity.
RESULTS
Twenty-five studies including 760 tarsal coalitions were included and had a weighted average follow-up of 44 months. Studies scored fair to poor on the risk of bias assessment with a mean MINORS score of 67% (44-81%). In 77.8% (37.5-100%) of surgically treated tarsal coalitions, good/excellent/non-limiting or improved PROMs were reported. Calculated data heterogeneity was moderate (I = 57%). Open bar resection with material interposition had a clinical success rate of 78.8% (50-100%). Complications occurred in 4.96% of cases. Coalition size did not prove to be a determining factor in postoperative outcome. The influence of the coalition type was not investigated by any of the studies.
CONCLUSION
Data on outcomes of surgical management for tarsal coalitions is limited to retrospective case series with high risk of bias and moderate data heterogeneity. In about ¾ of cases, open resection and interposition of material results in improved PROMs. The arbitrary margin of ≥ 50% of TC coalition size in relation to the posterior facet has little importance in surgical decision-making. None of the studies reported on the influence of the coalition type on postoperative clinical success.
Topics: Humans; Retrospective Studies; Synostosis; Systematic Reviews as Topic; Tarsal Bones; Tarsal Coalition
PubMed: 37462747
DOI: 10.1007/s00402-023-04982-z -
Experimental Biology and Medicine... Nov 2023This review summarizes the current knowledge of fibroblast growth factor 23 signaling in bone and its role in the disease pathology of X-linked hypophosphatemia.... (Review)
Review
This review summarizes the current knowledge of fibroblast growth factor 23 signaling in bone and its role in the disease pathology of X-linked hypophosphatemia. Craniosynostosis is an under-recognized complication of X-linked hypophosphatemia. The clinical implications and potential cellular mechanisms invoked by increased fibroblast growth factor 23 signaling causing craniosynostosis are reviewed. Knowledge gaps are identified and provide direction for future clinical and basic science studies.
Topics: Humans; Familial Hypophosphatemic Rickets; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Signal Transduction; Craniosynostoses
PubMed: 38230523
DOI: 10.1177/15353702231222023 -
Child's Nervous System : ChNS :... Jul 2023Craniosynostosis, which describes premature fusion of one or more cranial sutures, has been associated with a variety of neurocognitive deficits. We sought to explore...
PURPOSE
Craniosynostosis, which describes premature fusion of one or more cranial sutures, has been associated with a variety of neurocognitive deficits. We sought to explore the cognitive profiles of the various types of single-suture, non-syndromic craniosynostosis (NSC).
METHODS
A retrospective review of children 6-18 years old with surgically corrected NSC who underwent neurocognitive testing (Weschler Abbreviated Scale of Intelligence, Beery-Buktenica Developmental Test of Visuomotor Integration) from the years 2014-2022 was conducted.
RESULTS
204 patients completed neurocognitive testing (139 sagittal, 39 metopic, 22 unicoronal, 4 lambdoid suture). 110 (54%) of the cohort was male, and 150 (74%) were White. Mean IQ was 106.10±14.01 and mean age at surgery and testing were 9.0±12.2 months and 10.9±4.0 years, respectively. Sagittal synostosis was associated with higher scores than metopic synostosis, with significant differences in verbal IQ (109.42±15.76 vs 101.37±10.41), full-scale IQ (108.32±14.44 vs 100.05±11.76), visuomotor integration (101.62±13.64 vs 92.44±12.07), visual perception (103.81±12.42 vs 95.87±11.23), and motor coordination (90.45±15.60 vs 84.21±15.44). Sagittal synostosis was associated with significantly higher scores for visuomotor integration (101.62±13.64 vs 94.95±10.24) and visual perception (103.81±12.42 vs 94.82±12.75) than unicoronal synostosis.
CONCLUSIONS
Compared to patients with sagittal synostosis, patients with metopic synostosis exhibited lower scores in verbal IQ, full-scale IQ, visuomotor integration, visual perception, and motor control after surgical correction. Despite surgical correction for premature metopic suture fusion, the effect on the adjacent frontal lobe and white matter connections to other regions of the brain may have a lasting functional impact. Patients with unicoronal synostosis exhibited lower visuomotor integration and visual perception scores.
Topics: Child; Humans; Male; Infant; Adolescent; Craniosynostoses; Cranial Sutures; Brain; Craniotomy; Sutures
PubMed: 36877207
DOI: 10.1007/s00381-023-05908-1 -
The Journal of Gene Medicine Jan 2024Intellectual disability (ID) can be associated with different syndromes such as Rubinstein-Taybi syndrome (RSTS) and can also be related to conditions such as metabolic...
BACKGROUND
Intellectual disability (ID) can be associated with different syndromes such as Rubinstein-Taybi syndrome (RSTS) and can also be related to conditions such as metabolic encephalomyopathic crises, recurrent,with rhabdomyolysis, cardiac arrhythmias and neurodegeneration. Rare congenital RSTS1 (OMIM 180849) is characterized by mental and growth retardation, significant and duplicated distal phalanges of thumbs and halluces, facial dysmorphisms, and an elevated risk of malignancies. Microdeletions and point mutations in the CREB-binding protein (CREBBP) gene, located at 16p13.3, have been reported to cause RSTS. By contrast, TANGO2-related metabolic encephalopathy and arrhythmia (TRMEA) is a rare metabolic condition that causes repeated metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias and encephalopathy with cognitive decline. Clinicians need more clinical and genetic evidence to detect and comprehend the phenotypic spectrum of this disorder.
METHODS
Exome sequencing was used to identify the disease-causing variants in two affected families A and B from District Kohat and District Karak, Khyber Pakhtunkhwa. Affected individuals from both families presented symptoms of ID, developmental delay and behavioral abnormalities. The validation and co-segregation analysis of the filtered variant was carried out using Sanger sequencing.
RESULTS
In the present study, two families (A and B) exhibiting various forms of IDs were enrolled. In Family A, exome sequencing revealed a novel missense variant (NM 004380.3: c.4571A>G; NP_004371.2: p.Lys1524Arg) in the CREBBP gene, whereas, in Family B, a splice site variant (NM 152906.7: c.605 + 1G>A) in the TANGO2 gene was identified. Sanger sequencing of both variants confirmed their segregation with ID in both families. The in silico tools verified the aberrant changes in the CREBBP protein structure. Wild-type and mutant CREBBP protein structures were superimposed and conformational changes were observed likely altering the protein function.
CONCLUSIONS
RSTS and TRMEA are exceedingly rare disorders for which specific clinical characteristics have been clearly established, but more investigations are underway and required. Multicenter studies are needed to increase our understanding of the clinical phenotypes, mainly showing the genotype-phenotype associations.
Topics: Humans; CREB-Binding Protein; Intellectual Disability; Mutation; Mutation, Missense; Phenotype; Rhabdomyolysis; Rubinstein-Taybi Syndrome
PubMed: 37721116
DOI: 10.1002/jgm.3591