Neurodevelopmental disorders in children with macrocephaly: A prevalence study and PTEN gene analysis

Abstract Purpose To clarify the relationship between macrocephaly and neurodevelopmental disorders, as well as identify the prevalence of PTEN mutations in autism spectrum disorders with macrocephaly in Japan. Subjects and methods Diagnostic and other medical information of children with macrocephaly younger than 4 years (n = 93) were collected for analysis. PTEN gene mutation analysis was conducted in another set of 16 macrocephalic individuals aged 3–22 years. Results Sixteen macrocephalic children were associated with neurodevelopmental disorders, including autism spectrum disorders (ASDs) (n = 6), autistic traits (n = 5), intellectual disability (n = 5), attention deficit hyperactivity disorder (n = 1), developmental coordination disorders (n = 1), and language disorder (n = 1). Male gender was significantly linked to these disorders, whereas a family history and degree of macrocephaly were not significantly linked to the diagnosis. A novel mutation in the PTEN gene was identified in a 16-year-old girl with autism, mental retardation, language delay, extreme macrocephaly (+4.7 SD) with a prominent forehead, and digital minor anomalies. Conclusion Children with macrocephaly, particularly males, are at a higher risk of neurodevelopmental disorders, rather than progressive etiologies, such as hydrocephalus and neurodegenerative disorders. The data provide a basis for routine health checks for young children in Japan, including the follow-up management and possible screening of PTEN mutations in children with ASDs and macrocephaly.