BY:  William Dobyns, M.D.

Submicroscopic deletions in 14q12 spanning FOXG1 or intragenic mutations in FOXG1 have been reported in several patients with a developmental disorder described as a congenital variant of Rett syndrome. We sequenced FOXG1 in a cohort of 81 patients (55 females and 26 males) negative for MECP2 mutations in our lab, and detected two  heterozygous mutations. A collaborating research lab identified 4 patients with chromosome translocations affecting FOXG1 and 5 additional patients with intragenic mutations.

When added to 16 reported patients, a clinically recognizable phenotype emerged. The characteristic features of the FOXG1 syndrome include (1) moderate postnatal growth deficiency, (2) decelerating head circumference from 3 months that results in severe postnatal microcephaly, (3) severe mental retardation with (4) absent or minimal language development, (5) deficient social interactions including poor eye contact denoting a syndromic form of autism, (6) combined stereotypies and frank dyskinesias with mixed features of athetosis, chorea and dystonia, (7) epilepsy, (8) poor sleep patterns, (9) irritability especially in infancy, (10) excessive episodes of crying, (11) recurrent aspiration, and (12) frequent gastroesophageal reflux. Brain imaging studies can help with the diagnosis, showing decreased volume of frontal white matter in all patients, hypogenesis of the corpus callosum in most, and mild frontal pachygyria in a few.

The complete syndrome was seen in all patients with chromosome deletions and most with protein truncating mutations, while patients with chromosome translocations affecting enhancer elements and intragenic missense mutations caused a similar but less severe syndrome.