Congenital variant of Rett syndrome due to a mutation in the FOXG1 gene: a pediatric case report in Amazon

Abstract

Case Presentation: A 2-year-old male patient, born at term at 38 weeks of gestation through vaginal delivery, with Apgar scores of 9/10, and born to non-consanguineous parents, started a condition with postnatal microcephaly, psychomotor agitation, daily seizures, and non-restorative sleep for approximately one year, according by family members. Additionally, during the same period, he developed severe global neuropsychomotor developmental delay, failing to achieve developmental milestones such as sitting, crawling, standing, walking, and word vocalization, as well as impairment in cognitive acquisition and social interactions. His head circumference was 42 centimeters (z-score < −3 SD). Regarding feeding, he only accepts liquid and pasty diet and has shown poor weight gain. The family history was negative for the patient’s clinical phenotype. Neurological examination revealed craniofacial disproportion and grade 4 muscle strength in the lower limbs, with global muscular atrophy and generalized hypotonia, particularly affecting axial musculature. Brain magnetic resonance imaging revealed microcephaly and mild prominence of the lateral ventricles. After informed consent, a molecular analysis using next-generation sequencing was performed, which identified a heterozygous mutation in the gene encoding the Forkhead Box G1 (FOXG1) transcription factor, leading to the diagnosis of FOXG1-related syndrome. Following the diagnosis, the patient was referred for genetic counseling. Discussion: FOXG1 syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant in the FOXG1 gene. It is a rare genetic neurological disorder that comprises a complex constellation of clinical features, including severe postnatal microcephaly, impaired social reciprocity, combined stereotypies and dyskinesias, epilepsy, poor sleep patterns, and unexplained episodes of crying. Approximately 1,500 patients with FOXG1 syndrome have been diagnosed worldwide, with relatively few cases reported in the literature. The diagnosis of FOXG1 syndrome is established through genetic testing, and treatment is mainly focused on symptomatic management. Final Comments: This study describes an uncommon cause of developmental delay, microcephaly, and hyperkinetic movement disorders in pediatric patients, and highlights the importance of considering uncommon genetic etiologies in children presenting with global developmental delay and microcephaly, while also contributing to the existing knowledge of FOXG1-related syndrome. The diagnosis established through genetic sequencing reinforces the essential role of genetic testing in the diagnostic evaluation of neurodevelopmental disorders, enabling more accurate diagnosis and appropriate genetic counseling. Further studies are needed to improve the characterization and understanding of this rare syndrome.