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Medicina (Kaunas, Lithuania) Jun 2023Heterozygous pathogenic variants in the gene cause impaired intellectual development and distinctive facial features with or without cardiac defects (MIM #616789)....
Heterozygous pathogenic variants in the gene cause impaired intellectual development and distinctive facial features with or without cardiac defects (MIM #616789). This complex neurodevelopmental disorder is characterised by various phenotypic features, including plagiocephaly, strabismus, clubfoot, poor speech, and developmental delay. The aim of this study was to evaluate the clinical significance and consequences of a novel heterozygous intragenic deletion in a proband with clinical features of a -related disorder through extensive clinical, molecular, and functional characterisation. Combined comparative genomic hybridisation and single-nucleotide polymorphism array (SNP-CGH) was used to identify the changes in the proband's gDNA sequence (DECIPHER #430183). Intragenic deletion was specified via quantitative polymerase chain reaction (qPCR) and Sanger sequencing of the proband's cDNA sample. Western blot and bioinformatics analyses were used to investigate the consequences of this copy number variant (CNV) at the protein level. CRISPR-Cas9 technology was used for a -gene-silencing experiment in a culture of the control individual's skin fibroblasts. After the -gene-editing experiment, subsequent functional fibroblast culture analyses were performed. The analysis of the proband's cDNA sample allowed for specifying the regions of the breakpoints and identifying the heterozygous deletion that spanned exons 3 to 10 of , which has not been reported previously. In silico, the deletion was predicted to result in a truncated protein NP_056150.1:p.(Val104Glyfs*5), partly altering the Med13_N domain and losing the MedPIWI and Med13_C domains. After gene editing was performed, reduced cell viability; an accelerated aging process; and inhibition of the , , and gene expression were found to exist. Based on these findings, heterozygous intragenic 12q24.21 deletion in the affected individual resulted in haploinsufficiency due to the premature termination of protein translation, therefore leading to haploinsufficiency syndrome.
Topics: Humans; Haploinsufficiency; Intellectual Disability; Phenotype; DNA, Complementary; Syndrome; Mediator Complex
PubMed: 37512036
DOI: 10.3390/medicina59071225 -
Children (Basel, Switzerland) Jul 2023Omitting the early closure of the cranial sutures in newly born children is not an uncommon practice. We describe the natural history of several unrelated children and...
BACKGROUND
Omitting the early closure of the cranial sutures in newly born children is not an uncommon practice. We describe the natural history of several unrelated children and adults from two unrelated families. These children were born with variable clinical manifestations: craniofacial asymmetry, ocular proptosis, floppiness, and progressive deceleration in cognitive development. None of these children underwent a cranial sutures assessment. False diagnoses of positional plagiocephaly, neonatal thyrotoxicosis, congenital muscular atrophy, and hydrocephalus were given to the parents. This sort of malpractice was the reason behind a sequence of devastating pathological events that occurred in the lifetime of these children and adults.
MATERIAL AND METHODS
This was a multigenerational study of two unrelated families. In total, we studied three children (aged 7-19 years) and three adults (aged 40-52 years) from two families. The children from the first family were referred to our departments because of pre-pubertal scoliosis, kyphoscoliosis, and early-onset osteoarthritis. Reading the clinical histories of these children signified apparent clinical misconceptions. For instance, craniofacial asymmetry was misinterpreted as positional plagiocephaly and treated by means of helmet molding therapy. Ocular proptosis was given the false diagnosis of neonatal thyrotoxicosis. Floppiness (hypotonia) was misdiagnosed as congenital muscular dystrophy. The index case from the second family showed progressive deceleration in his cognitive development, associated with signs of increased intracranial pressure. The only diagnosis was Dandy-Walker malformation. We documented every patient in accordance with the clinical and radiological phenotypic characterizations. The genotype characterization followed accordingly.
RESULTS
All patients in family (I) manifested a phenotype consistent to a certain extent with the clinical phenotype of Shprintzen-Goldberg syndrome (SGS), though the intensity of spine deformities was greater than has been described in the literature. The second family showed a constellation of Marfanoid habitus, craniosynostosis, increased intracranial pressure, hydrocephalus, Dandy-Walker malformation, seizures, and intellectual disability. The overall clinical phenotype was consistent but not fully diagnostic of craniosynostosis-Dandy-Walker-malformation hydrocephalus syndrome. The early closure of the sutures was totally different from one patient to another, including the premature closure of the metopic, coronal, squamosal, and sagittal sutures. One patient from family (II) underwent the implementation of a shunt system at the age of 3 years, unfortunately passing over the pre-existing craniosynostosis. In addition to skeletal deformities, a history of seizures and severe intellectual disability was recorded. The proband underwent chromosomal karyotyping, the FISH test, and whole-exome sequencing.
CONCLUSION
The purpose of this study was fivefold. Firstly, to gain a meticulous understanding in order to differentiate between positional plagiocephaly, hypotonia, and congenital exophthalmos and their connections to abnormal craniofacial contours was and still is our first and foremost concern. Secondly, we aimed to characterize craniosynostosis, seizures, intellectual disabilities, and hydrocephalus associated with Marfanoid habitus, which were clearly demonstrated in our patients. Thirdly, we aimed to address the imperative for interpretations of clinical and radiological phenotypes and relate these tools to etiological understanding, which is an essential basis for diagnosis in the majority of long-term pediatric admissions. Fourthly, we aimed to assess the impacts of the missed early closure by the pediatricians and pediatric neurologists, which added a heavy pathological burden on these patients and their families. Fifthly, we aimed to identify whether early and diligent recognition can assist in cranial vault remodeling via surgical intervention to halt premature cranial suture fusions and can possibly alter the devastating course and the complications of the synostosed sutures.
PubMed: 37508737
DOI: 10.3390/children10071240 -
Children (Basel, Switzerland) Jul 2023The objective of this study is to analyze conservative treatments implemented to manage positional plagiocephaly in infants. (Review)
Review
OBJECTIVE
The objective of this study is to analyze conservative treatments implemented to manage positional plagiocephaly in infants.
METHODS
This is a systematic review conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, performed in the Medline (PubMed), Scopus, Web of Science, and Cochrane databases. Articles were selected according to the eligibility criteria, regarding the effectiveness of conservative treatments in positional plagiocephaly in infants, published in the last 10 years with a score ≥3 in the PEDro Scale.
RESULTS
A total of 318 articles were identified and 9 of them were finally selected.
CONCLUSIONS
Physical therapy treatment is considered as the first line of intervention in plagiocephaly with non-synostotic asymmetries and manual therapy is the method that obtains the best results within this intervention. In cases of moderate or severe plagiocephaly, helmet therapy can be an effective second-line intervention; however, the best way to prevent this condition is through counseling of parents or caregivers, and early treatment is essential for optimal therapeutic outcomes. The review was registered in PROSPERO (CDR42022306466).
PubMed: 37508680
DOI: 10.3390/children10071184 -
Plastic and Reconstructive Surgery.... May 2023Unilateral lambdoid craniosynostosis is differentiated from deformational plagiocephaly primarily by assessing the cranium from posterior and bird's-eye views. Findings...
UNLABELLED
Unilateral lambdoid craniosynostosis is differentiated from deformational plagiocephaly primarily by assessing the cranium from posterior and bird's-eye views. Findings include posterior displacement of the ipsilateral ear, ipsilateral occipitomastoid bossing, ipsilateral occipitoparietal flattening, contralateral parietal bossing, and contralateral frontal bossing. Diagnosis based off facial morphology may be an easier approach because the face is less obstructed by hair and head-coverings, and can easily be assessed when supine. However, frontofacial characteristics of unilateral lambdoid craniosynostosis are not well described.
METHODS
A retrospective cohort review of patients with isolated, unilateral lambdoid craniosynostosis from the Children's Hospital of Pittsburgh and the Children's Hospital of Philadelphia was performed. Preoperative frontal and profile photographs were reviewed for salient characteristics.
RESULTS
Nineteen patients met inclusion criteria. Eleven patients had left lambdoid craniosynostosis, and eight had right lambdoid craniosynostosis. All patients were nonsyndromic. Patients demonstrated contralateral parietal bossing and greater visibility of the ipsilateral ear. Contralateral frontal bossing was mild. The orbits were tall and turricephaly was present in varying severity. Facial scoliosis as a C-shaped deformity was present in varying severity. The nasal root and chin pointed to the contralateral side.
CONCLUSIONS
The combination of greater visibility of the ipsilateral ear, contralateral parietal bossing, and C-shaped convex ipsilateral facial scoliosis are hallmark frontofacial features of unilateral lambdoid craniosynostosis. Although the ipsilateral ear is more posterior, the greater visibility may be attributed to lateral displacement from the mastoid bulge. Evaluation of long-term postoperative results is needed to assess if this pathognomonic facial morphology is corrected following posterior vault reconstruction.
PubMed: 37360231
DOI: 10.1097/GOX.0000000000005011 -
Andes Pediatrica : Revista Chilena de... Apr 2023Since the American Academy of Pediatrics recommended the supine sleeping position for infants to prevent SIDS, positional plagiocephaly (PP) prevalence has increased.... (Review)
Review
Since the American Academy of Pediatrics recommended the supine sleeping position for infants to prevent SIDS, positional plagiocephaly (PP) prevalence has increased. There are great controversies regarding the possible consequences of PP and the degree of severity required for them to manifest. There is no consensus on the efficacy of PP therapies, such as positioning, kinesiology, and cranial orthoses. This review aims to analyze the existing literature to update the causes, main characteristics, and evidence on the treatment of PP. Intervention from the newborn period is important, encompassing both prevention and management education, as well as early screening, evaluating the possible presence of congenital muscular torticollis, to start early treatment. The presence of PP can be a risk marker for psychomotor development.
Topics: Infant; Infant, Newborn; Humans; Child; Plagiocephaly, Nonsynostotic; Sleep; Torticollis; Prevalence
PubMed: 37358106
DOI: 10.32641/andespediatr.v94i2.4665 -
Children (Basel, Switzerland) May 2023The purpose of this study was to investigate changes in cranial shape among preterm neonates aged 1-6 months and the relationship between developmental quotient (DQ) and...
The purpose of this study was to investigate changes in cranial shape among preterm neonates aged 1-6 months and the relationship between developmental quotient (DQ) and cranial shape at 6 months of age. Preterm infants who were hospitalized in our hospital were prospectively followed for 6 months. The cephalic index (CI) and cranial vault asymmetry index (CVAI) were evaluated at 1 (T1), 3 (T2), and 6 months (T3) of age and compared with those of the full-term infants. The relationship between CI or CVAI and DQ at T3 was analyzed using the Enjoji Scale of Infant Analytical Development. A total of 26 participants born at 34.7 ± 1.9 weeks of gestation were included. The CI increased with age (T1: 77.2%, T2: 82.9%, T3: 85.4%, < 0.01). The prevalence of dolichocephaly at T3 did not significantly differ from that in full-term infants (15.4% vs. 4.5%, = 0.08). CVAI did not significantly differ between preterm and full-term infants. The DQ showed no significant correlation with either the CI or CVAI (correlation coefficients: 0.23 for CI, -0.01; CVAI). Dolichocephaly improved over time in preterm infants and no relationship between cranial shape and development was observed in preterm infants at 6 months of age.
PubMed: 37238403
DOI: 10.3390/children10050855 -
Diagnostics (Basel, Switzerland) May 2023This study compared manual and digital measurements of plagiocephaly and brachycephaly in infants and evaluated whether three-dimensional (3D) digital photography...
This study compared manual and digital measurements of plagiocephaly and brachycephaly in infants and evaluated whether three-dimensional (3D) digital photography measurements can be used as a superior alternative in everyday clinical practice. A total of 111 infants (103 with plagiocephalus and 8 with brachycephalus) were included in this study. Head circumference, length and width, bilateral diagonal head length, and bilateral distance from the glabella to the tragus were assessed by manual assessment (tape measure and anthropometric head calipers) and 3D photographs. Subsequently, the cranial index (CI) and cranial vault asymmetry index (CVAI) were calculated. Measured cranial parameters and CVAI were significantly more precise using 3D digital photography. Manually acquired cranial vault symmetry parameters were at least 5 mm lower than digital measurements. Differences in CI between the two measuring methods did not reach significance, whereas the calculated CVAI showed a 0.74-fold decrease using 3D digital photography and was highly significant ( < 0.001). Using the manual method, CVAI calculations overestimated asymmetry, and cranial vault symmetry parameters were measured too low, contributing to a misrepresentation of the actual anatomical situation. Considering consequential errors in therapy choices, we suggest implementing 3D photography as the primary tool for diagnosing deformational plagiocephaly and positional head deformations.
PubMed: 37238192
DOI: 10.3390/diagnostics13101707 -
Clinical and Experimental Pediatrics Jun 2023
PubMed: 37221641
DOI: 10.3345/cep.2023.00108 -
PEC Innovation Dec 2022Demonstrate the benefits of using 3D printed skull models when counseling families regarding disorders of the cranial vault (namely plagiocephaly and craniosynostosis),...
OBJECTIVES
Demonstrate the benefits of using 3D printed skull models when counseling families regarding disorders of the cranial vault (namely plagiocephaly and craniosynostosis), as traditional imaging review and discussion is often insufficient.
METHODS
3D printed skull models of a patient with plagiocephaly were used during clinic appointments to aid in the counseling of parents. Surveys were distributed following the appointment to evaluate the utility of these models during the discussion.
RESULTS
Fifty surveys were distributed (with a 98% response rate). 3D models were both empirically and anecdotally helpful for parents in understanding their child's diagnosis.
CONCLUSION
Advances in 3D printing technology and software have made producing models more accessible. Incorporating physical, disorder-specific models into our discussions has led to improvements in our ability to communicate with our patients and their families.
INNOVATION
Disorders of the cranial can be challenging to describe to the parents and guardians of affected children; using 3D printed models is a useful adjunct in patient-centered discussions. The subject response to the use of these emerging technologies in this setting suggests a major role for 3D models in patient education and counseling for cranial vault disorders.
PubMed: 37213734
DOI: 10.1016/j.pecinn.2022.100077 -
Plastic and Reconstructive Surgery.... May 2023Positional plagiocephaly is a pediatric condition with important cosmetic implications affecting ∼40% of infants under 12 months of age. Early diagnosis and treatment...
UNLABELLED
Positional plagiocephaly is a pediatric condition with important cosmetic implications affecting ∼40% of infants under 12 months of age. Early diagnosis and treatment initiation is imperative in achieving satisfactory outcomes; improved diagnostic modalities are needed to support this goal. This study aimed to determine whether a smartphone-based artificial intelligence tool could diagnose positional plagiocephaly.
METHODS
A prospective validation study was conducted at a large tertiary care center with two recruitment sites: (1) newborn nursery, (2) pediatric craniofacial surgery clinic. Eligible children were aged 0-12 months with no history of hydrocephalus, intracranial tumors, intracranial hemorrhage, intracranial hardware, or prior craniofacial surgery. Successful artificial intelligence diagnosis required identification of the presence and severity of positional plagiocephaly.
RESULTS
A total of 89 infants were prospectively enrolled from the craniofacial surgery clinic (n = 25, 17 male infants [68%], eight female infants [32%], mean age 8.44 months) and newborn nursery (n = 64, 29 male infants [45%], 25 female infants [39%], mean age 0 months). The model obtained a diagnostic accuracy of 85.39% compared with a standard clinical examination with a disease prevalence of 48%. Sensitivity was 87.50% [95% CI, 75.94-98.42] with a specificity of 83.67% [95% CI, 72.35-94.99]. Precision was 81.40%, while likelihood ratios (positive and negative) were 5.36 and 0.15, respectively. The F1-score was 84.34%.
CONCLUSIONS
The smartphone-based artificial intelligence algorithm accurately diagnosed positional plagiocephaly in a clinical environment. This technology may provide value by helping guide specialist consultation and enabling longitudinal quantitative monitoring of cranial shape.
PubMed: 37197011
DOI: 10.1097/GOX.0000000000004985