Jul 2026· Frontiers in child and adolescent psychiatry· Vol 5· 0 citations· 25 references
Medicine
TL;DR
Early-onset psychotic symptoms in adolescents with neurodevelopmental comorbidities may represent a critical clinical indicator of underlying pathogenic copy number variants, including 3q29 deletion syndrome, even in the absence of highly recognizable dysmorphic features.
Abstract
Background 3q29 deletion syndrome is a rare genomic disorder characterized by a broad spectrum of neurodevelopmental and psychiatric manifestations, including developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and a markedly increased lifetime risk of psychosis and schizophrenia. Case presentation We describe a 17-year-old female adolescent with severe congenital heart disease and longstanding neurodevelopmental impairment who developed early-onset recurrent psychotic symptoms. Chromosomal microarray analysis identified a de novo heterozygous 1.6 Mb deletion at the 3q29 locus. The emergence of psychotic symptoms served as the pivotal clinical trigger for genetic investigation in the absence of distinctive dysmorphic findings. Combination therapy with lurasidone and olanzapine led to sustained clinical stabilization over a one-year follow-up period, allowing gradual dose adjustment and functional reintegration through adapted educational and recreational activities. Conclusions Early-onset psychotic symptoms in adolescents with neurodevelopmental comorbidities may represent a critical clinical indicator of underlying pathogenic copy number variants, including 3q29 deletion syndrome, even in the absence of highly recognizable dysmorphic features. Increased clinical awareness may facilitate consideration of early genetic testing in this clinical profile to support precision-informed diagnostic evaluation, treatment planning and multidisciplinary management.
Clinical heterogeneity among children with NRXN1 deletions illustrates clinical heterogeneity among children with autism spectrum disorder and supports the need for larger studies to better define genotype-phenotype relationships.
Samira Said AlHousni, A. Idris, Watfa Al-Mamari et al.· Sultan Qaboos University Med...· 0 citations
A child with refractory epilepsy and behavioral disturbances in whom two rare variants were identified in the SLC2A1 and SMC1A genes illustrates the exceptional coexistence of SLC2A1 and SMC1A variants and underlines the value of early molecular diagnosis even in resource-limited contexts, to guide personalized management.
Kouakou Kouamé Cyprien, Doumbia-Ouattara Mariam, Dainguy Marie Evelyne et al.· Journal of Pediatric Genetic...· 0 citations
Highlights What are the main findings? Juvenile-onset Huntington disease frequently presented with heterogeneous, non-choreic developmental, psychiatric, gait, speech, and movement abnormalities, with a median diagnostic delay of 4 years. Among published patients with ascertainable seizure status, epilepsy was reported in 41.4% and was descriptively more frequent in childhood-onset than adolescent-onset disease. What are the implications of the main findings? Juvenile-onset Huntington disease should be considered when seizures or status epilepticus occur within a progressive multisystem neurological phenotype. HTT repeat-expansion testing should be considered despite absent family history, initially normal imaging, or non-diagnostic metabolic, gene-panel, or exome testing. Abstract Background: Juvenile-onset Huntington disease (JoHD) is a rare form of Huntington disease characterized by symptom onset at or before 20 years of age. Early manifestations are often non-choreic and may be attributed to developmental, psychiatric, movement, metabolic, or epileptic disorders. We described three molecularly confirmed cases and examined early manifestations, diagnostic pathways, and epilepsy. Methods: We conducted a retrospective case series and a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 systematic review of PubMed, Scopus, and Web of Science Core Collection through 5 July 2026. The strict patient-level synthesis required attributable onset at or before 20 years, patient-specific molecular confirmation of a pathogenic HTT repeat expansion, and extractable clinical data. Complementary aggregate or linked reports using closely aligned JoHD criteria were retained for context but excluded from patient-level calculations. Results: The cases included childhood-onset JoHD with drug-resistant epilepsy, adolescent-onset JoHD with progressive motor-cognitive decline and epilepsy in a known Huntington disease pedigree, and childhood-onset JoHD without available family history, in whom status epilepticus prompted renewed diagnostic evaluation. Ninety-three reports were included; of these, 81 contributed 228 unique patients and 12 provided complementary data. Early manifestations were heterogeneous and broadly consistent with previously described childhood-onset JoHD phenotypes. Diagnostic delay was extractable in 180/228 patients; among 172 with point estimates, the median was 4.0 years. Definite epilepsy was reported in 60/145 patients with ascertainable seizure status and was descriptively more frequent in childhood-onset (<10 years) than adolescent-onset (10–20 years) JoHD (49/84 [58.3%] vs. 11/57 [19.3%]). Conclusions: JoHD should be considered in children and adolescents with progressive multisystem neurological involvement, particularly when epilepsy occurs with developmental regression, gait or speech deterioration, pyramidal or extrapyramidal signs, basal-ganglia abnormalities, or a compatible family history.
Mirjana Perkovic Benedik, T. Loboda, Katarina Benedik Kafol et al.· Brain Science· 0 citations
Background: Kabuki syndrome is a rare multisystem neurodevelopmental disorder usually caused by pathogenic KMT2D or KDM6A variants, although a substantial minority of clinically typical patients remain molecularly unresolved. Autism spectrum disorder (ASD) has been reported in this population, but its prevalence and relationship to genotype remain poorly characterized. Case Presentation: We report a 12-year-old Moroccan boy, born to consanguineous parents, referred for severe behavioral disturbances including psychomotor hyperactivity, self-injurious behavior, and marked language delay. Physical examination showed characteristic craniofacial dysmorphism, long palpebral fissures with eversion of the lateral lower eyelids, blue sclerae, broad arched eyebrows, a depressed nasal tip, and a high-arched palate, together with microcephaly, postnatal growth restriction, infantile hypotonia, a waddling gait, and possible scoliosis, fulfilling international consensus criteria on dysmorphology, growth restriction, hypotonia, and musculoskeletal abnormalities for a clinical diagnosis of Kabuki syndrome. He also presented with severe ASD, attention-deficit/hyperactivity disorder, intellectual developmental disorder, and generalized epilepsy, established according to DSM5 criteria. Whole-exome sequencing identified no pathogenic variant in KMT2D or KDM6A, but revealed a heterozygous variant of uncertain significance in YWHAG (NM_012479.3:c.340G>A; p.Glu114Lys), a gene associated with developmental and epileptic encephalopathy. Pharmacological management included extended-release methylphenidate, which was discontinued because of paradoxical worsening of hyperactivity, followed by low-dose aripiprazole, which improved self-injurious behavior and agitation but caused a persistent tremor. Conclusions: This case shows that a well-characterized clinical gestalt remains sufficient to diagnose Kabuki syndrome despite negative first-line genetic testing, and that residual possibilities
M. Nokrou, S. Bounouh, Z. Maataoui et al.· Scholars Journal of Medical...· 0 citations
This case expands the molecular spectrum of KBG syndrome and highlights the importance of genomic testing in children presenting with developmental delay, learning difficulties, and subtle dysmorphic features, particularly when the diagnosis remains uncertain during early childhood.
BACKGROUND
The traditional distinction between syndromic and nonsyndromic craniosynostosis has guided clinical management, but recent genomic advances suggest these categories represent a continuous spectrum rather than discrete entities. Data on genetic etiologies and long-term neurodevelopmental outcomes in Asian populations remain limited.
METHODS
The authors conducted a retrospective cohort study of 68 consecutive children diagnosed with craniosynostosis at a single tertiary center between January 2011 and November 2025. Genetic testing included whole-genome/whole-exome sequencing, targeted next-generation sequencing panels, and chromosomal microarray analysis (CMA). Neurodevelopmental assessments employed the Bayley Scales of Infant Development-III, Social Maturity Scale, Wechsler Intelligence Scales, and Beery-Buktenica Developmental Test of Visual-Motor Integration. Neurodevelopmental disorder (NDD) was defined as the presence of intellectual disability, autism spectrum disorder, or developmental language disorder; a secondary definition additionally included attention-deficit/hyperactivity disorder (ADHD).
RESULTS
Of 68 patients (40 males, 28 females), 39 (57.4%) underwent genetic testing, with pathogenic or likely pathogenic (P/LP) variants identified in 11 (28.2%; genetic-positive group). Identified variants involved chromatin modifiers (DNMT3A, NSD1, KMT2A), transcription factors (TCF12, SOX5), a signaling kinase (TAOK1), and a post-transcriptional regulator (TNRC6B); CMA additionally revealed pathogenic copy number variants (10q26.13-q26.3 deletion, 16p11.2 duplication, 15q11.2-q13.1 duplication, 2q37 deletion). In the primary analysis, NDD was identified in 8 of 11 patients (72.7%) in the genetic-positive group versus 10 of 28 (35.7%) in the genetic-negative group [P = 0.072; odds ratio (OR) 4.80, 95% confidence interval (CI) 1.03-22.29]. In the secondary analysis, including ADHD, NDD was significantly more prevalent in the genetic-positive group (9/11, 81.8% versus 11/28, 39.3%; P = 0.031; OR 6.95, 95% CI 1.26-38.44).
CONCLUSIONS
Comprehensive genetic testing yielded P/LP variants in 28.2% of tested craniosynostosis patients, revealing diverse molecular etiologies. Neurodevelopmental impairment was common and occurred even in genetically negative patients, supporting broad genetic evaluation together with systematic developmental surveillance for all affected children, independent of syndromic classification.
LEVEL OF EVIDENCE
Level III-Retrospective comparative study.
Sunyoung Joo, Jeon-Woong Kang, Si Won Yang et al.· The Journal of craniofacial...· 0 citations
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