Atypical Manifestations of Rett Syndrome: Macrocephaly and Hyperostosis Frontalis Interna in a Female Patient

Rett syndrome is a rare neurodevelopmental disorder caused by mutations in the MECP2 gene on the X chromosome, primarily affecting females. It is characterized by developmental regression, stereotypic hand movements, seizures, and microcephaly due to decelerated head growth. However, atypical presentations, such as macrocephaly and hyperostosis frontalis interna (HFI), are rarely reported. HFI, defined as abnormal thickening of the frontal bone, is uncommon in pediatric populations and is often linked to metabolic disturbances, hormonal imbalances, or prolonged anti-seizure medication (ASM) use. We report the case of a 16-year-old girl with genetically confirmed Rett syndrome who presented with macrocephaly (+2.5 SD) and HFI. Genetic testing identified a pathogenic MECP2 mutation (c.882C>T, Arg270Stop), confirming the diagnosis. The patient’s early development was normal until 18 months, when developmental regression occurred, including loss of speech, impaired social interactions, and stereotypic hand movements. She was also diagnosed with central precocious puberty at age 9, treated with leuprorelin acetate for three years, during which her growth in height ceased. By age 16, her height was -2.6 SD. Brain MRI revealed thickening of the frontal bone and enlarged frontal sinuses, consistent with HFI. She experienced intractable epilepsy managed with multiple ASMs. Reduction in ASM doses improved dystonia but led to seizure recurrence. Additional evaluations revealed mild osteopenia and altered hormonal profiles, suggesting systemic effects of MECP2 dysfunction. This case highlights the expanded phenotypic spectrum of Rett syndrome, emphasizing the impact of MECP2 mutations on cranial growth and bone metabolism. Hormonal dysregulation and ASM use may contribute to these anomalies. Comprehensive evaluation and genetic testing are critical for differentiating Rett syndrome from overlapping conditions. A multidisciplinary approach is essential to manage rare manifestations and improve personalized care strategies.