Abstract: Background：PTEN gene mutation can lead to a variety of syndrome phenotypes. At present, there are many studies on the phenotypic spectrum in adults, but few studies in children. Objective：To summarize the genotypes and clinical phenotypes of children with PTEN gene mutation and their correlation. Design：Case series report. Methods：Children with PTEN gene mutations, rated as being pathogenic or possibly pathogenic, discovered by high-throughput sequencing in the Molecular Medicine Center of the Children's Hospital of Fudan University from January 1, 2016 to January 31, 2023 were included. Their clinical data and gene testing results were intercepted. Main outcome measures：Clinical manifestations and PTEN gene mutations. Results：A total of 51 children with confirmed PTEN gene pathogenic mutations were included, including 33 males. The median age at the time of gene testing was 2 years (1d-13 years), and the median follow-up age was 5.2 years (3.6-6.5 years). The main complaints were developmental delay or communication disorder (24 cases in total, 47.0%). Forty-one pathogenic or suspected pathogenic variants were detected in the PTEN gene, including 28 missense mutations (68.3%), 5 nonsense mutations, 4 frameshift mutations, 3 classical splice site mutations, and 1 initiation codon mutation. Twenty-eight variants were located in the phosphatase domain (68.3%), 11 in the C2 domain (24.4%), and 1 in each of the PIP2 binding motif (PBD) and C-tail domains. c.388C>T(p.R130X) (5 cases) and c.302T>C(p.I101T) (3 cases) were hotspot mutation sites. Twelve mutation sites had not been previously reported. Mutation sources were verified in 22 children, of which 17 (77.3%) were de novo mutations. Macrocephaly was identified in 48 cases (94.1%). Forty-two cases (82.3%) were diagnosed with neurodevelopmental disorders, including language development delay in 36 cases (70%), large motor development delay in 25 cases (49.0%), fine motor development delay in 2 cases, poor balance in 3 cases, ASD in 14 cases (27.4%), intellectual disability in 13 cases (25.5%), attention deficit and hyperactivity disorder in 1 case, learning difficulty in 1 case, and epilepsy in 3 cases (5.8%). Tumor diseases were detected in 11 children (21.6%), with a median age of 4.0(1.0-5.0) years at the time of detection. Eight cases (15.7%) showed skin manifestations including penile freckles, café au lait spots, nevi, and hair follicle keratosis. Thirty-nine patients underwent cranial MRI, and 35 (89.7%) showed abnormalities, mainly including widened perivascular spaces (18 cases), white matter abnormalities (6 cases), and enlarged ventricles (4 cases). There was no significant difference in clinical phenotype, mutation type, and domain distribution of mutation sites. Conclusion：Children with PTEN gene mutations mainly present with macrocephaly with neurodevelopmental disorders such as developmental delay, intellectual disability, and autism spectrum disorder, and may have tumorigenesis, dermatological manifestations, and abnormal cranial MRI findings.

Key words: Macrocephaly, PTEN, Children, Tumor, Neurodevelopmental Disorders