Aug 2026· The Journal of craniofacial surgery (Print)· 0 citations· 27 references
Medicine
Abstract
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.
CASK-related disorders may present with severe neurodevelopmental impairment and cerebral palsy–like phenotypes, even in the absence of characteristic neuroimaging findings, which should raise suspicion for CASK-related disorders.
I. Pacheva, Elena Timova, T. Todorov et al.· Frontiers in Psychiatry· 0 citations
Chromosomal microarray analysis (CMA) is a first-tier diagnostic tool for children with neurodevelopmental disorders and congenital anomalies; however, interpretation of variants of uncertain significance (VUS) remains challenging. This study aimed to characterize the copy number variant (CNV) spectrum in pediatric patients with congenital anomalies and/or dysmorphic features, focusing on VUS interpretation through segregation analysis and detailed phenotype–genotype correlation. We retrospectively evaluated 28 pediatric patients with abnormal CMA results referred to two tertiary genetics clinics between 2021 and 2022. Indications included neurodevelopmental delay, intellectual disability, dysmorphism, and/or congenital anomalies. CNVs were classified according to 2020 ACMG/ClinGen standards. Parental segregation analysis was performed for 15 CNVs in 13 families, with particular attention to gene disruption caused by CNV breakpoints. The cohort included 16 males and 12 females, with a mean age of 5.28±4.39 years. Thirty-four CNVs were identified, including 14 deletions and 20 duplications; seven were pathogenic/likely pathogenic and 27 were VUS. Segregation analysis identified five de novo, six maternal, and four paternal variants. A 2q22.2 gain disrupting KYNU at intron 12 was identified in a patient with VACTERL-like features. Three patients had additional karyotypic abnormalities, highlighting the complementary role of CMA. A de novo 4p16.3 duplication disrupting both HTT and ADD1 was also identified. Our findings highlight the importance of detailed phenotyping, breakpoint analysis, and segregation studies in interpreting CNVs, particularly VUS and rare intragenic disruptions. Integrating genomic findings with clinical features and inheritance patterns may improve phenotype–genotype correlation and support the identification of candidate loci.
AIM
To assess neurodevelopmental and neurological features, including neuroimaging abnormalities, in children with molecularly confirmed hypochondroplasia.
METHOD
A retrospective cohort study of children with molecularly confirmed hypochondroplasia seen at Evelina London Children's Hospital skeletal dysplasia service was performed. Data collected included referral characteristics, neuroimaging findings, special educational needs, and diagnosed neurodevelopmental disorders. Statistical comparisons with UK population prevalence were performed using χ2 testing for educational outcomes and exact binomial testing for neurodevelopmental disorders, with Bonferroni-adjusted p-values reported for multiple comparisons.
RESULTS
Forty-four children (24 females and 20 males; median age 9 years 10 months [interquartile range 6 years 7 months-15 years 7 months]) with molecularly confirmed hypochondroplasia were included. Twenty-five had received brain imaging with hippocampal malrotation (HIMAL) identified in 23 (92%). Among school-aged children, 71% required special educational support and 29% had formal education, health, and care plans (EHCPs), statistically higher than both UK population prevalence and previously reported hypochondroplasia prevalence. Formally diagnosed neurodevelopment disorders affected 20.5% of the cohort. Specific learning disorders remained significantly more common than UK population prevalence estimates after Bonferroni correction, with higher observed autism and attention-deficit/hyperactivity disorder rates also identified.
INTERPRETATION
Hypochondroplasia is associated with a substantial burden of neurodevelopmental and neurological abnormalities, including a high prevalence of HIMAL, which exceeds previous estimates. These findings support the need for clinical guidelines, developmental surveillance, and further research into fibroblast growth factor receptor 3 (FGFR3)-related brain development.
Megan F. Baxter, Rhoda Akilapa, Alessandra Cocca et al.· Developmental Medicine & Chi...· 1 citation
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 retrospective multicenter case series of seven previously unreported individuals with heterozygous FBXW7 variants identified through clinical genetic testing expands the phenotypic spectrum associated with FBXW7-related neurodevelopmental disorder and highlights variable expressivity and incomplete penetrance.
Salvatore Savasta, F. Comisi, G. Dell’Isola et al.· Journal of Neurodevelopmenta...· 0 citations
The discovery of variants in PTEN, SRCAP, PQBP1, and NOG identifies novel candidate genes and uncovers potential disease mechanisms in craniosynostosis.
Yufeng Huang, Lingyue Huang, L. Hu et al.· Frontiers in Genetics· 0 citations
