Publication

Abstract : We read with great interest the article by Bai et al., describing three children with FOXG1 syndrome [1]. The authors highlight the deficiencies in the literature on pathogenic FOXG1 variants and present the phenotypes of three representative variants- two intragenic mutations (in Forkhead binding domain and Groucho-binding domain) and one deletion. Here, we report a FOXG1 variant in a girl with developmental delay and unexplained irritability. An 11-month-old girl (with an uneventful perinatal period) presented with excessive irritability and daily episodes of inconsolable crying noted since the age of 7 weeks. These episodes occurred incidentally after a brief febrile period following her vaccination with DPT, Hib, IPV, and OPV. These episodes typically consisted of incessant, high-pitched (Supplemental Video), and inconsolable crying and were associated with poor feeding and disturbed sleep. They were not associated with any abnormal movements and alteration in responsiveness. These episodes persisted throughout infancy with a gradual increase in frequency and duration in the initial six months. Besides, she had a global developmental delay which was apparent by three months of age. At presentation, she could transiently hold her neck, coo, laugh aloud, and recognize her parents. There was a history of a generalized seizure at eight months of age. Her examination revealed microcephaly, spasticity, preserved visual fixation and following, and hearing. She had excessive hand regard and mouthing stereotypies. Brain MRI revealed delayed myelination, a relatively simplified gyral pattern in bilateral frontal and temporal lobes, and callosal agenesis (Fig. 1). Electroencephalography in sleep was unremarkable but it could not be done during one of the episodes of crying. Clinical exome sequencing showed a likely pathogenic, heterozygous, autosomal dominant frameshift insertion(c.454dupG/p.Ala151fs; chr14:29236938) in exon1 (N-terminal domain) of FOXG1 gene. This variation was further validated using Sanger sequencing and was not present in unaffected parents. The involved region is conserved across species, and the predictions by bioinformatics algorithms-SIFT, Mutation Taster, and Phenolyzer were deleterious. This variant is expected to be the same as a recurrent variant (c.460dupG/ p.Glu154fs) due to a stretch of seven guanines (454–460) leading to same variation with duplications at the beginning or end of the stretch [2]. At the last follow-up (28 month-age), she had a persistent developmental delay (some head control, recognized parents, could babble) and infrequent seizures (controlled on valproate; the last seizure at 22 month-age).