Search Results (146)

Copy number variations (CNVs) affecting the chromosomal region 21q21.3–q22.13 are rare and have been increasingly associated with neurodevelopmental abnormalities and multisystemic manifestations. In this study, we aimed to characterize the clinical, genomic, and genotype–phenotype correlations of a Moroccan child carrying a de novo microdeletion in this region. Whole exome sequencing (WES) was performed using sequencing-by-synthesis technology on the GenoLab M platform, and CNV detection was achieved through the SeqOne platform. Variant interpretation was conducted using the Integrative Genomics Viewer (IGV), and a custom gene–phenotype heatmap was generated in R (ComplexHeatmap and pheatmap) based on OMIM, ClinVar, and DECIPHER databases to prioritize candidate genes within the deleted segment. The patient presented with global developmental delay, microcephaly, psychomotor and staturo-ponderal retardation, facial dysmorphism, epilepsy responsive to treatment, and cerebral anomalies, including passive biventricular hydrocephalus and diffuse cortical atrophy. WES-CNV analysis identified a heterozygous de novo microdeletion of approximately 8.2 Mb in 21q21.3–q22.13, encompassing 124 clinically relevant genes. Integrated analysis confirmed the pathogenicity of the deletion and highlighted genotype–phenotype correlations, particularly implicating dosage-sensitive genes such as SON and RUNX1. This case underlines the clinical utility of combining WES, CNV analysis, and phenotype-based bioinformatic tools for diagnosing complex microdeletion syndromes, contributes to understanding genotype–phenotype relationships in 21q21.3–q22.13 deletions, and supports improved clinical interpretation and patient management. Full article

Parental adverse childhood experiences (ACEs) are linked to negative outcomes in children, including emotional and behavioral problems, developmental delays, and higher risk for psychopathology. Most research focuses on school-aged children or community samples, with few studies examining preschool-aged children in child psychiatric care. Understanding parental ACEs in this population is crucial, as early childhood is a sensitive developmental period, and intergenerational effects may be particularly pronounced in children already presenting with psychiatric symptoms. Background/Objectives: The goal of this study was to analyze how parents of patients in an early childhood (0–5.9 yrs) mental health outpatient clinic differ from the general population in terms of the frequency of ACEs. In addition, we investigated the connection between mental health disorders in young children and the specific ACE scores of their parents. Methods: A total of 116 caregivers (34.45 years (SD = 5.28)) and their children (71.6% boys, 28.4% girls) at an average age of 3.99 years (SD = 1.35, range = 0.31–5.95) were included in the analysis. The legal guardians completed the 10-item ACE questionnaire. The young children were diagnosed as part of outpatient treatment using the DC:0–5 classification system. We analyzed the ACE scores and diagnoses descriptively and in comparison to a community sample. Results: An average value of 2.38 parental ACEs was reported by our sample, and 68.1% (n = 79) reported at least one ACE. The high-risk group with four or more ACEs comprised 30.2% (n = 35). The most common diagnosis in young children was the Disorder of Dysregulated Anger and Aggression of Early Childhood, followed by global developmental delay. Adjustment disorder was third in terms of frequency. Among the examined child psychiatric diagnoses, adjustment disorder showed a significant correlation with parents being affected by the ACE category of neglect (OR = 2.54; 95% CI: 1.012–6.369; p = 0.047). Conclusions: Parents who presented their children at an early childhood mental health outpatient clinic reported significantly more ACEs as compared to representative data on ACEs in adulthood. These results highlight the need for further studies with larger samples to enable a more in-depth analysis of the general intergenerational transmission processes and the differential transmission of specific ACEs to specific diagnoses in preschool-aged children. Full article

Background/Objectives: This study aimed at evaluating the association between maternal pre-pregnancy glycemic status and growth delay in offspring using nationwide health screening data. Methods: A retrospective cohort of 258,367 mother–child dyads born between 2014 and 2021 was analyzed. Maternal glycemic status was categorized as normal (<100 mg/dL), impaired fasting glucose (IFG, 100–125 mg/dL), or diabetes mellitus (DM, ≥126 mg/dL). Growth delay was defined as measurements below the 10th percentile of height, weight, and head circumference at 18–24 and 30–36 months. Visual and auditory development were assessed using caregiver questionnaires. Inverse probability of treatment weighting was applied, and weighted relative risks (RRs) were estimated. Results: The prevalence of growth delay was 3.5% for height, 3.8% for weight, and 4.3% for head circumference; visual and auditory problems were reported in 1.2% and 8.2% of children, respectively. Both the DM (1.2%) and IFG (9.3%) groups showed increased risks of growth delay across both age periods. Maternal hyperglycemia was also associated with offspring’s visual and auditory development, with age- and period-specific differences observed. Conclusions: Maternal pre-pregnancy glycemic status was significantly associated with delayed growth in Korean children aged 18–36 months. These findings highlight the importance of optimizing maternal glycemic control prior to pregnancy for favorable child developmental outcomes. Full article

Background: Developmental and Epileptic Encephalopathy (DEE) is a severe and heterogeneous neurological disorder in infancy/early childhood. DEE’s genetic and phenotypic variability complicates diagnosis and treatment. This retrospective study aimed to identify genetic variants and explore genotype–phenotype correlations in children with DEE using a targeted epilepsy gene panel (TGP) and Whole Exome Sequencing (WES). Patients and Methods: Medical records of children who underwent custom-designed 55-gene TGP and WES were reviewed. The diagnostic yield of each method was determined based on the detection of pathogenic (P) and likely pathogenic (LP) variants. Results: A total of 129 patients (66 males, 63 females) underwent TGP, which identified P/LP variants in 29 cases (22.48%). Variants were detected in SCN1A, KCNQ2, STXBP1, CDKL5, PCDH19, PLCB1, WWOX, SCN2A, FGF12, HCN1, SCN8A, and SLC35A2. WES further identified several variants in children with West syndrome. A TSC1 variant was detected in a patient without cutaneous stigmata of tuberous sclerosis complex. The NALCN variant in a patient was linked to Infantile Hypotonia with Psychomotor Retardation and Characteristic Facies 1. A CTBP1 variant associated with extremely rare Hypotonia, Ataxia, Developmental Delay, and Tooth Enamel Defect Syndrome was detected in another patient. A PIEZO2 variant—associated with Marden–Walker syndrome—was found in a child with Early Infantile Developmental and Epileptic Encephalopathy. Conclusions: These findings highlight the extensive genetic heterogeneity and phenotypic variability of DEE. WES demonstrates substantial value in identifying novel gene-disease associations and may be considered as a first-tier diagnostic tool in epilepsy and DEE. Full article

Our study tracks the development of 105 Roma children between 3 and 5 (median age: 51 months), enrolled in an NGO-aided developmental program. Each child undergoes pre- and post-assessment based on the Developmental Assessment of Young Children (DAYC), a standard tool used to track the progress in early childhood development and detect delays. Data are gathered from three sources, teacher, parent/caregiver and specialist, covering four developmental domains and adaptive behavior scale. There are subjective biases; however, in the post-assessment, the teachers’ and parents’ evaluations converge. The test results confirm significant improvement in all areas ($p<0.0001$), with the highest being in cognitive skills $32.2\%$ and the lowest being in physical development $14.4\%$. We also apply machine learning methods to impute missing data and predict the likely future progress for a given student in the program based on the initial input, while also evaluating the influence of environmental factors. Our weighted ensemble regression models are coupled with principal component analysis (PCA) and yield average coefficients of determination $R^2\approx 0.7$ for the features of interest. Also, we perform k-means clustering in the plane cognitive vs. social–emotional progress and consider the classification problem of predicting the group in which a given student would eventually be assigned to, with a weighted $F_1$-score of $0.83$ and a macro-averaged area under the curve (AUC) of $0.94$. This could be useful in practice for the optimized formation of study groups. We explore classification as a means of imputing missing categorical data too, e.g., education, employment or marital status of the parents. Our algorithms provide solutions with the $F_1$-score ranging from $0.92$ to $0.97$ and, respectively, an AUC between $0.99$ and 1. Full article

Background: While attention deficit/hyperactivity disorder (ADHD) is characterized by neurodevelopmental heterogeneity, the influence of familial structural factors—particularly parental age and skipped-generation caregiving—on comorbidity patterns remains insufficiently studied. This study examined the associations between parent–child age gaps, skipped-generation family structures, and psychiatric comorbidities in children with ADHD. Methods: Data came from Taiwan’s NHIRD (2009–2013), including 79,163 ADHD cases and 395,815 matched controls. Key variables included maternal and paternal age at childbirth and grandparent-paid insurance premiums as a proxy for skipped-generation caregiving. Conditional logistic regression was used to estimate odds ratios (ORs) for 20 psychiatric and developmental comorbidities. Results: Children with ADHD exhibited significantly higher odds of various comorbidities, including oppositional defiant disorder (OR = 147.05, 95% CI = 101.0–214.1), somatoform disorder (OR = 25.78, 95% CI = 7.96–83.46), anxiety disorder (OR = 24.49, 95% CI = 17.9–33.5), emotional disturbances during childhood and adolescence (OR = 13.99, 95% CI = 9.15–21.4), and autism spectrum disorder (OR = 8.07, 95% CI = 6.63–9.82). Advanced maternal age (>35 years) was associated with increased odds of autism spectrum disorder (OR = 1.47, 95% CI: 1.29–1.67) and speech/language delay (OR = 1.33, 95% CI: 1.17–1.52), whereas younger maternal age (≤25 years) was linked to higher odds of anxiety disorder (OR = 1.23, 95% CI: 1.13–1.33) and adjustment reaction (OR = 1.41, 95% CI: 0.95–2.11). Maternal age under 20 years showed the highest odds for bipolar disorder (OR = 2.01, 95% CI: 1.04–3.88). For paternal age, older age (>35 years) was associated with increased odds of autism (OR = 1.14, 95% CI: 1.04–1.26) and speech/language delay (OR = 1.15, 95% CI: 1.04–1.27), whereas paternal age ≤20 years was strongly linked to bipolar disorder (OR = 3.58, 95% CI: 1.54–8.32) and anxiety (OR = 1.39, 95% CI: 1.01–1.93). Children from skipped-generation families—defined as grandparent-paid insurance premiums without parental cohabitation—had significantly higher odds of bipolar disorder (OR = 2.88, 95% CI: 1.36–6.11), personality disorder (OR = 9.23, 95% CI: 2.23–38.20), adjustment reaction (OR = 2.23, 95% CI: 1.39–3.59), and emotional disturbances during childhood/adolescence (OR = 1.69, 95% CI: 1.13–2.54). Conclusions: Both extremes of parental age and skipped-generation caregiving are linked to specific associations with certain psychiatric comorbidity patterns in children with ADHD. These findings highlight the importance of integrating family structure into diagnostic assessments and treatment planning and support the development of targeted early interventions. Full article

Autism spectrum disorder (ASD) deals with several symptoms, including language and speech impairment and developmental delays. The main brain regions affected could be the prefrontal cortex (PFC) or the temporal lobe. The detrimental features could include oxidative stress, mitochondrial dysfunction, and neuroinflammation. Most often, these phenomena are interrelated and can lead to one another, creating a vicious cycle. They also influence the regulation of certain genes involved in the pathogenesis of ASD or related behavior. In the brain regions prone to these detrimental features, a cascade of free radicals, inflammatory cytokines, and mitochondrial energy disruptions is initiated. These actions during the prenatal or developmental stage of the child potentially lead to ASD symptomatic features, such as social isolation, communication difficulty, speech and language impairment, cognitive dysfunction, and intellectual disability. The more recent theories, including genetics, epigenetics, and the gut–brain axis, have been demonstrated to play a greater role in ASD pathology, often being associated with the more common ones as mentioned above. We also introduced some of the neurological disorders possessing shared genetic and behavioral traits with ASD. Many genes playing a role in ASD-like features and their potential targeted drugs were explained briefly. However, there are limited therapeutic options, and molecular pathways related to this disorder are less explored. Currently, researchers and therapists are racing to uncover a concrete remedy. This review also provides a brief outline of potential antioxidant, mitochondrial, and anti-inflammatory therapies. We finally included some novel strategies to diagnose and manage autistic pathology and symptoms. Full article

Background/Objectives: Pseudohypoparathyroidism (PHP) is a group of genetic disorders characterized by end-organ resistance to multiple hormones, short stature, brachydactyly, subcutaneous ossifications, obesity, and developmental delays. The tissue specific imprinting of GNAS in the hypothalamus may lead to different eating behavior phenotypes in maternally inherited (PHP1A, PHP1B) vs. paternally inherited (PPHP) variants. In this exploratory study, we aimed to evaluate differences in eating behaviors in a cohort of patients with PHP1A, PPHP and PHP1B. Methods: Assessments included caregiver-reported measures (hyperphagia questionnaire, children’s eating behavior questionnaire, child feeding questionnaire) and self-reported measures (three factor eating behavior questionnaire). Results: A total of 58 patients with PHP1A, 13 patients with PPHP and 10 patients with PHP1B contributed data, along with 124 obese pediatric controls. An increased risk of obesity was found in PHP1A vs. PPHP (adult body mass index (BMI) 39.8 ± 8.7 vs. 30.2 ± 7.4 kg/m², p = 0.03). Parents reported significantly earlier onset of interest in food in children with PHP1A (2.0 ± 2.3 years) and PHP1B (1.1 ± 1.3 years) compared with controls (5.2 ± 3.2 years, p < 0.001). Measures of hyperphagia, satiety and other feeding behaviors were all similar to controls. The highest hyperphagia questionnaire scores were seen prior to adolescence. In a multi-year, longitudinal assessment of 11 pediatric patients with PHP1A, hyperphagia scores were stable and 25% showed an improvement in symptoms. Conclusion: Patients with PHP1A/1B may have hyperphagia symptoms from a young age but they do not worsen over time. Patients may overeat when allowed access to food, but do not usually have disruptive food seeking behaviors. Early diagnosis can give clinicians the opportunity to provide anticipatory diagnosis on the increased risk of obesity in PHP1A/1B and need for scheduled meals and controlled portions. Further studies with larger cohorts are needed to confirm these findings. Full article

Infant motor development has traditionally been studied through child-centered frameworks that often overlook the vital role parents play in shaping early outcomes. This paper provides a renewed ecological approach, foregrounding parental perspectives—knowledge, beliefs, attitudes, theories, and expectations—and examining how they directly and indirectly guide infants’ motor trajectories. Drawing on cross-cultural evidence, we illustrate how differences in parental priorities and caregiving behaviors can either accelerate or delay the emergence of crucial motor skills. We also highlight the reciprocal relationship between parent and child: while parental views shape caregiving practices, children’s developing abilities and behaviors can, in turn, alter their parents’ perspectives. Building on existing theories, including Bronfenbrenner’s ecological systems theory and dynamic systems theory, our integrated model situates the parent–child dyad within broader socioeconomic, cultural, and environmental contexts. This model shows the dynamic, ever-evolving interplay between parents and children and demonstrates the importance of aligning parental cognition with targeted interventions to optimize motor development. By examining how cultural norms, individual experiences, and contextual factors converge, this paper offers both a theoretical framework and practical implications for supporting infants’ growth. This paper will inform future research by encouraging parent-focused developmental studies and guiding practitioners to design culturally informed interventions in the field of motor development. Full article

Background: Joubert syndrome (JS) is a multi-systemic ciliopathy, characterized by intellectual disability and congenital anomalies involving the brain, kidney, heart, and eye. Even if clinical presentation is variable, most authors consider a brain abnormality known as the molar tooth sign (MTS) as mandatory for diagnosis. About 40 genes were identified to be associated with JS, usually with an autosomal recessive pattern. KATNIP variants represent a rare cause of JS; only six families were previously reported. Methods: We performed exome sequencing in a child with a syndromic phenotype, described the clinical features and molecular findings, and performed a review of the literature to identify known individuals with pathogenic variants in KATNIP, highlighting clinical characteristics and gene-phenotype correlations. Results: Using exome sequencing, we identified a homozygous novel frameshift variant c.808del, p.Ser270ValfsTer28 in KATNIP in a 5-year-old male from a consanguineous family of Roma ethnic background. Notable clinical features of the proband include severe developmental delay, hypotonia, and post-axial polydactyly. He did not have MTS, but showed severe anemia and esophageal atresia, which was already reported in association with a KATNIP variant. We collected the phenotypes of all reported patients and discussed common and distinct features with respect to typical JS. Affected individuals shared JS clinical features, although the typical MTS was not always present, polydactyly and renal abnormalities were absent, while pituitary abnormalities were common. Conclusions: Our report provides new data for KATNIP-related JS, expanding the clinical phenotypic spectrum and suggesting a possible role of KATNIP defects in the development of esophageal atresia. Full article

Background: A structure survey conducted by the Department of Health on early childhood development in Thailand indicates that 27.20–32.50% of preschool children have developmental delays. These children require appropriate care and constant stimulation to help them develop normally. Methods: The ChildWeCare innovation system for monitoring children and providing appropriate care for those with developmental delays from birth to 5 years of age has been developed. This is accompanied by qualified personnel providing assistance to parents for their child’s development. Enrollment of participants and provision of services via the system were implemented. Appropriate intervention from the ChildWeCare system will be provided for each specific child, and each parent will be assigned homework for training their children. Results: The database of the ChildWeCare system was developed using MySQL, which can store information about the child, parent, homework, and log usage system, as well as data on each parent’s homework assignments. Our pilot testing shows that parents were satisfied with the ChildWeCare system. Conclusions: The ChildWeCare system could provide guidance on suitable stimulation techniques and strategies for each child’s specific needs. These preliminary results could indicate the advantages of further plans for the system’s implementation in other settings in Health Region 1 or nationwide. Full article

The BCS1L gene encodes a mitochondrial chaperone which inserts the Fe₂S₂ iron–sulfur Rieske protein into the nascent electron transfer complex III. Variants in the BCS1L gene are associated with a spectrum of mitochondrial disorders, ranging from mild to severe phenotypes. Björnstad syndrome, a milder condition, is characterized by sensorineural hearing loss (SNHL) and pili torti. More severe disorders include Complex III Deficiency, which leads to neuromuscular and metabolic dysfunctions with multi-systemic issues and Growth Retardation, Aminoaciduria, Cholestasis, Iron Overload, and Lactic Acidosis syndrome (GRACILE). The severity of these conditions varies depending on the specific BCS1L mutation and its impact on mitochondrial function. This study describes a 27-month-old child with SNHL, proximal renal tubular acidosis, woolly hypopigmented hair, developmental delay, and metabolic alterations. Genetic analysis revealed a homozygous BCS1L variant (c.38A>G, p.Asn13Ser), previously reported in a patient with a more severe phenotype that, however, was not functionally characterized. In this work, functional studies in a yeast model and patient-derived fibroblasts demonstrated that the variant impairs mitochondrial respiration, complex III activity (CIII), and also alters mitochondrial morphology in affected fibroblasts. Interestingly, we unveil a new possible mechanism of pathogenicity for BCS1L mutant protein. Since the interaction between BCS1L and CIII is increased, this suggests the formation of a BCS1L-containing nonfunctional preCIII unable to load RISP protein and complete CIII assembly. These findings support the pathogenicity of the BCS1L c.38A>G variant, suggesting altered interaction between the mutant BCS1L and CIII. Full article

Background/Objectives: Unilateral hearing loss (UHL) is a relatively common disability condition comprising around 20–50% of all congenital hearing loss (HL). The adverse effects of UHL affect the typical development of auditory function with implications for communication, speech and language acquisition, academic development and quality of life. Current literature suggests an early intervention treatment in order to avoid developmental delays, but there is a lack of evidence about the effectiveness and use of hearing devices. The purpose of the present study was to evaluate the benefits of rehabilitative strategies such as hearing aid (HA) and cochlear implant (CI) in UHL children by exploring audiological and parent-reported outcomes. Methods: A total of 18 UHL children, between the ages of 3 and 17, were enrolled in the study designed as a prospective longitudinal study from July 2023 to July 2024. All children were evaluated for speech perception in quiet and noise and subjective benefits before and after rehabilitative treatment with HA in 15 (83.3%) children and with CI in 3 (16.7%) children. Results: The evaluation of audiological outcomes in children with UHL, based on assessment of aided sound field thresholds and speech perception scores assessment versus unaided, shows improvements in audiometric thresholds and how the hearing devices adequately support listening and spoken language. Scores with hearing devices were significantly higher than baseline-only scores when averaging both SSQ and CHILD questionnaires, pointing to an overall rehabilitative benefit. Conclusions: Rehabilitative interventions, particularly HA and CI, offer notable benefits when introduced early, but achieving optimal outcomes requires a multidisciplinary and individualized approach. Full article

The most common way for children with social communication delays to receive intervention before age three in the United States is through Part C early intervention (EI). Part C was designed to take a multidisciplinary approach to address a range of developmental domains. The type of intervention delivered in Part C EI has rarely been examined through direct observation. Our team conducted a mixed-methods analysis to characterize EI sessions by 33 providers across four states. Specifically, we describe the quantity and quality of caregiver coaching based on provider report and researcher coding of EI session content. Eligible providers conducted weekly EI sessions with at least one child with social communication delays. Providers self-reported greater use of caregiver coaching relative to the video coding conducted by researchers. While there were similarities in session topics, presumed goals, and intervention strategies used across providers, differences were observed in session duration, session location, and caregiver engagement in session. This study begins to fill a substantial gap by illuminating the types of interventions children with social communication delays receive in federally mandated Part C. It also highlights the need for more specialized training and standardization in EI practices to ensure that children with social communication delays and their caregivers benefit from the most efficacious interventions during a critical time of increased brain plasticity. Full article

Background: Cerebral cavernous malformations (CCMs) are vascular lesions linked to mutations in the CCM1, CCM2, and CCM3 genes, resulting in angiogenesis dysregulation. This case study highlights the clinical course of a child with severe CCMs and explores the genetic basis of the condition. Methods: We used comprehensive clinical assessment and magnetic resonance imaging (MRI) to monitor the patient’s neurological status and CCM progression and genetic analysis by whole-exome sequencing to identify mutations in CCM-related genes. Results: The patient presented with developmental delays, multiple CCMs, and recurrent hemorrhagic events, requiring five surgical interventions. Genetic analysis revealed a novel frameshift mutation in the PDCD10 gene. Despite surgical efforts, the patient developed significant disability by age 13. Conclusions: This case illustrates the aggressive clinical course associated with CCMs, particularly in patients with CCM3 mutations. It underscores the importance of genetic screening and monitoring in understanding hereditary CCM progression and guiding treatment strategies. Full article