Tatton-Brown-Rahman Syndrome Due to a Novel DNMT3A Variant Presenting With Autism, Attention-Deficit/Hyperactivity...

Tatton-Brown-Rahman syndrome (TBRS) is a rare overgrowth/intellectual disability disorder caused by DNMT3A variants. It is characterized by tall stature, macrocephaly, and intellectual disability, with an expanding neuropsychiatric spectrum that includes autism spectrum disorder (ASD) and behavioral disturbances. We describe a young adult Saudi male with overgrowth, macrocephaly, coarse facial features, and global developmental delay. Cognitive testing confirmed mild intellectual disability with relative verbal strengths. He was diagnosed with ASD and attention-deficit/hyperactivity disorder (ADHD) and treated with methylphenidate in childhood. In early adulthood, the patient exhibited regression characterized by speech loss, decline in self-care, incontinence, and psychotic-like symptoms, alongside gastrointestinal disease. Genetic testing revealed a novel heterozygous DNMT3A missense variant (c.923G>T, p.Gly308Val) in the PWWP domain, consistent with TBRS. This case illustrates the broadened phenotype of TBRS, including ASD, ADHD, and regression, paralleling prior reports of cognitive unevenness and behavioral vulnerability. Additional findings of eczema, elevated IgE, and anemia suggest possible underrecognized systemic involvement. This case emphasizes the importance of multidisciplinary evaluation and lifelong neuropsychiatric follow-up in TBRS. As the first reported case from Saudi Arabia to our knowledge, it broadens the clinical and geographic spectrum of the disorder and highlights the association between DNMT3A variants, intellectual disability, and ASD.