Severe Postnatal Microcephaly Research Articles

Delineating FOXG1 syndrome: From congenital microcephaly to hyperkinetic encephalopathy.

ObjectiveTo provide new insights into the FOXG1-related clinical and imaging phenotypes and refine the phenotype-genotype correlation in FOXG1 syndrome.MethodsWe analyzed the clinical and imaging phenotypes of a cohort of 45 patients with a pathogenic or likely pathogenic FOXG1 variant and performed phenotype-genotype correlations.ResultsA total of 37 FOXG1 different heterozygous mutations were identified, of which 18 are novel. We described a broad spectrum of neurodevelopmental phenotypes, characterized by severe postnatal microcephaly and developmental delay accompanied by a hyperkinetic movement disorder, stereotypes and sleep disorders, and epileptic seizures. Our data highlighted 3 patterns of gyration, including frontal pachygyria in younger patients (26.7%), moderate simplified gyration (24.4%) and mildly simplified or normal gyration (48.9%), corpus callosum hypogenesis mostly in its frontal part, combined with moderate-to-severe myelination delay that improved and normalized with age. Frameshift and nonsense mutations in the N-terminus of FOXG1, which are the most common mutation types, show the most severe clinical features and MRI anomalies. However, patients with recurrent frameshift mutations c.460dupG and c.256dupC had variable clinical and imaging presentations.ConclusionsThese findings have implications for genetic counseling, providing evidence that N-terminal mutations and large deletions lead to more severe FOXG1 syndrome, although genotype-phenotype correlations are not necessarily straightforward in recurrent mutations. Together, these analyses support the view that FOXG1 syndrome is a specific disorder characterized by frontal pachygyria and delayed myelination in its most severe form and hypogenetic corpus callosum in its milder form.

Syndromes génétiques mimant les infections congénitales : à propos de 2 cas

Genetic syndromes that mimic congenital infections must be recognized because of the associated risk of recurrence. We describe a male infant who was born with the association of intra-uterine growth retardation, microcephaly, intracranial calcifications, white matter abnormalities, microphtalmy, bilateral cataract, and hearing loss. Congenital cytomegalovirus (CMV) infection was suspected, but serologic CMV markers were not decisive (IgG+/IgM-). His half-sister (same father) presented a similar phenotype. Therefore, the diagnosis of congenital CMV infection was questioned and a genetic hypothesis was suggested. In 1983, Baraitser et al. first described two brothers with microcephaly and intracranial calcifications and negative TORCH analysis. Later, a number of authors reported children in whom detailed investigation failed to objectively confirm an intra-uterine infective agent. Clinical features include severe postnatal microcephaly, seizures, and pronounced developmental arrest. These cases have been considered to define a distinct autosomal recessive disorder first named pseudo-Torch syndrome. The family described herein is different from the cases previously described with a suspected autosomal dominant inheritance, severe ophtalmological abnormalities, and unusual brain imaging.

Phenotypic spectrum associated with CASK loss-of-function mutations

BackgroundHeterozygous mutations in the CASK gene in Xp11.4 have been shown to be associated with a distinct brain malformation phenotype in females, including disproportionate pontine and cerebellar hypoplasia.MethodsThe study characterised...

The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis

BackgroundSubmicroscopic deletions in 14q12 spanning FOXG1 or intragenic mutations have been reported in patients with a developmental disorder described as a congenital variant of Rett syndrome. This study aimed to...

Band‐like intracranial calcification with simplified gyration and polymicrogyria: A distinct “pseudo‐TORCH” phenotype

The combination of intracranial calcification and polymicrogyria is usually seen in the context of intrauterine infection, most frequently due to cytomegalovirus. Rare familial occurrences have been reported. We describe five patients-two male-female sibling pairs, one pair born to consanguineous parents, and an unrelated female-with a distinct pattern of band-like intracranial calcification associated with simplified gyration and polymicrogyria. Clinical features include severe post-natal microcephaly, seizures and profound developmental arrest. Testing for infectious agents was negative. We consider that these children have the same recognizable "pseudo-TORCH" phenotype inherited as an autosomal recessive trait.

The molecular basis of Goodpasture and Alport syndromes: beacons for the discovery of the collagen IV family.

<h3>Objective</h3> To provide new insights into the <i>FOXG1-</i>related clinical and imaging phenotypes and refine the phenotype-genotype correlation in <i>FOXG1</i> syndrome. <h3>Methods</h3> We analyzed the clinical and imaging phenotypes of a cohort of 45 patients with a pathogenic or likely pathogenic <i>FOXG1</i> variant and performed phenotype-genotype correlations. <h3>Results</h3> A total of 37 <i>FOXG1</i> different heterozygous mutations were identified, of which 18 are novel. We described a broad spectrum of neurodevelopmental phenotypes, characterized by severe postnatal microcephaly and developmental delay accompanied by a hyperkinetic movement disorder, stereotypes and sleep disorders, and epileptic seizures. Our data highlighted 3 patterns of gyration, including frontal pachygyria in younger patients (26.7%), moderate simplified gyration (24.4%) and mildly simplified or normal gyration (48.9%), corpus callosum hypogenesis mostly in its frontal part, combined with moderate-to-severe myelination delay that improved and normalized with age. Frameshift and nonsense mutations in the N-terminus of <i>FOXG1</i>, which are the most common mutation types, show the most severe clinical features and MRI anomalies. However, patients with recurrent frameshift mutations c.460dupG and c.256dupC had variable clinical and imaging presentations. <h3>Conclusions</h3> These findings have implications for genetic counseling, providing evidence that N-terminal mutations and large deletions lead to more severe <i>FOXG1</i> syndrome, although genotype-phenotype correlations are not necessarily straightforward in recurrent mutations. Together, these analyses support the view that <i>FOXG1</i> syndrome is a specific disorder characterized by frontal pachygyria and delayed myelination in its most severe form and hypogenetic corpus callosum in its milder form.