Rachelle Lorenz¹, Amy Goldstein², Sulagna Saitta³, Laurence E. Walsh4, Soma Das¹, William B Dobyns5. ¹Department of Human Genetics, University of Chicago, Chicago, IL, USA.  2Division of Child Neurology, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA.  3Children’s Hospital of Philadelphia, Philadelphia, PA, USA.  4Department of Medical Genetics, Indiana University, Indianapolis, IN, USA. 5Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA.

Microcephaly, seizures, hypotonia, mental retardation, dyskinesia and developmental delay are nonspecific findings which when tied together result in developmental encephalopathies for which a growing list of genetic conditions are recognized, such as Angelman, Rett, Pitt-Hopkins, CNTNAP2-associated, NRXN1-associated and SLC9A6-associated syndromes.  FOXG1 is the latest gene implicated in a long list of developmental encephalopathies.

Recent literature has reported on FOXG1-related disorders (including point mutations and deletions) in at least 17 individuals.  These patients have been previously diagnosed with clinical features consistent with a “congenital form” of Rett syndrome (RTT) or developmental encephalopathy.  These features include, severe postnatal microcephaly, postnatal growth deficiency, hypotonia, developmental delays, seizures, no language development, no useful hand function with associated stereotypies, absent eye contact, irritability in the neonatal period, and delayed myelination and hypoplasia of the corpus callosum.

We report on five additional patients identified with FOXG1 mutations ranging in age from 4-11 years.  Three of the patients have frameshift mutations and two have a missense mutation in FOXG1. Three of the patients are male and two are female.  All five patients had severe postnatal microcephaly, severe mental retardation, hypotonia, developmental delay, severe deficits in social reciprocity, poor eye contact and were non-verbal.  A frank dyskinesia was noted in all patients and none were able to walk independently. While one patient had improved hand function the remaining three patients had no purposeful hand movement and had stereotypies reminiscent of RTT.  All four patients have developed epilepsy, three before the age of 2 years and one just prior to 4 years of age.  Simple gyral pattern, reduced white matter volume, and hypogenesis of the corpus callosum were also noted on MRI for all our patients.  No period of normal development after birth was noted for any of our patients.

While the FOXG1 phenotype overlaps with several syndromes including RTT, the presence of frank dyskinesia, specific brain findings and the absence of a period of normal development after birth, distinguish this phenotype from other developmental encephalopathies. We propose that there is a specific and recognizable combination of developmental features unique to FOXG1 mutations that consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia and corpus callosum hypogenesis and propose the term FOXG1 syndrome for this disorder.  

This abstract (#32) will be presented as a platform presentation by Rachelle Lorenz Saturday March 19 at 5:30pm in Ballroom A.