FOXG1 syndrome, historically known as the congenital variant of Rett syndrome, is a severe neurodevelopmental disorder caused by de novo, heterozygous FOXG1 mutations. It is characterized by early-onset developmental impairment and distinctive neurological features. But, unlike classic Rett syndrome, which usually presents after 6–18 months of development, FOXG1 syndrome usually manifests from birth or infancy, and this is why it’s sometimes referred to as “congenital Rett syndrome”.
Key clinical characteristics include:
• Developmental Delay and Intellectual Disability
o Global Developmental Delay is universal, and most individuals have severe intellectual disability with little or no expressive language development. Developmental milestones such as independent sitting or walking are significantly delayed. As well, cognitive and motor functions are underdeveloped in the majority of patients.
• Microcephaly and Brain Abnormalities
o Postnatal microcephaly (emerging within the first year) is a major hallmark. Many children have brain malformations visible through MRI scans, most notably agenesis or hypogenesis of the corpus callosum (partial or complete absence of the corpus callosum). Other common findings are hypomyelination of white matter in the CNS, reduced of the hippocampus and other forebrain structures, and reduced complexity of cortical gyri folding patterns. These neuroanatomical changes reflect the crucial role of FOXG1 in forebrain development.
• Movement Disorders (Hyperkinetic)
o Complex hyperkinetic movements are a core feature. Patients often exhibit abnormal involuntary movements including chorea, dystonia, athetosis, and facial dyskinesias. Intermittent jerking movements and hand stereotypies (repetitive movements) are observed as well. Muscle tone can be variable, with hypotonia in infancy evolving to hypertonia or rigidity in later childhood.
• Epilepsy
o Epileptic seizures occur in approximately 60–80% of diagnosed individuals. Onset most often occurs in infancy. Seizure types range from infantile spasms to generalized tonic-clonic or complex focal seizures.
• Behavioral and Sensory Features
o Irritability and an unsettled demeanor are frequently noted in infancy. Many children demonstrate features associated with autism, such as poor eye contact, lack of social reciprocity, and repetitive behaviors. Nearly all diagnosed individuals lack verbal speech. Additionally, cortical visual impairment is common, and affected infants may be less responsive to their visual environment despite intact ocular structures. This is thought to reflect impaired visual processing in the brain. Other findings can include feeding difficulties (gastroesophageal reflux, aspiration risk), and collectively, these features can lead to a poor quality of life.
FOXG1