The Journal of craniofacial surgery · 2026
Genetic Etiology and Neurodevelopmental Outcomes in Children With Craniosynostosis: A 15-Year Single-Center Retrospective Study.
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Joo Sunyoung, Kang Jeon-Woong, Yang Si Won, Jang Dae-Hyun, Kim Jaewon
Аннотация
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.
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.