Atypical Rett syndrome with selective FOXG1 deletion detected by comparative genomic hybridization: case report and review of literature

Abstract

Rett syndrome is a severe neurodegenerative disorder characterized by acquired microcephaly, communication dysfunction, psychomotor regression, seizures and stereotypical hand movements. Mutations in methyl CpG binding protein 2 (MECP2) are identified in most patients with classic Rett syndrome. Genetic studies in patients with a Rett variant have expanded the spectrum of underlying genetic etiologies. Recently, a deletion encompassing several genes in the long arm of chromosome 14 has been associated with the congenital Rett-syndrome phenotype. Using array-based comparative genomic hybridization, we identified a 3-year-old female with a Rett-like syndrome carrying a de novo single-gene deletion of FOXG1. Her presentation included intellectual disability, epilepsy and a Rett-like phenotype. The variant features included microcephaly at birth and prominent synophrys. Our results confirm that congenital Rett syndrome can be caused by copy-number variation in FOXG1 and expand the clinical phenotypic spectrum of FOXG1 defect in humans.

Figure 1

Loss of one copy of FOXG1 leads to a Rett-variant phenotype. (a) Picture of the patient taken at 3 years of age showing the synophrys and a pointed chin. Note the posturing of the hands. (b) Lateral view of the patient. Note the brachycephaly. (c) Occipito–frontal head-circumference measurements show onset of microcephaly before 1 year of age. (d) Sagittal T1-weighted MRI carried out at 6 months of age illustrates the brachycephaly. (e) Axial flair T2-weighted MRI carried out at 6 months of age shows normal myelination for age and absence of cerebral malformation.

Figure 2

Cartoon representation of chromosome 14, region 26 000 000–29 500 000. ^**represents the 2.594-Mb deletion identified in the case report. This region includes both the FOXG1 gene and C14orf23 gene. The genes PRKD1 and NOVA as shown, are not affected by the deletion. The location of the probe RP11-30H9 is also identified. Figure adapted from www.ensemble.org (chromosome 14: 26 000 000–29 500 000).