Atypical Rett Syndrome: Is it really more common in females? K. Cusmano-Ozog, P. Tanpaiboon, L. Harris, J. Turner, L. Kehoe, T. Biagi, B. Lanpher Genetics & Metabolism, CNMC, Washington, DC.

   Atypical Rett syndrome is a neurodevelopmental disorder identified in children who exhibit a Rett-like phenotype but do not meet the clinical criteria for Rett syndrome. A variety of genetic alterations have been associated with this phenotype including duplications of MECP2, alterations in another X-linked gene, CDKL5, as well as mutations or deletions of FOXG1 on 14q12. In the last two years at CNMC we have identified 10 probands with a Rett-like phenotype who also had a pathogenic copy number change detected by chromosomal microarray. Five males have a duplication of MECP2, two males have a deletion of FOXG1 and one male and two females have a deletion of CDKL5. Age of diagnosis varied between 1.5 and 19 years with an average age of six. Of the 10 individuals, four have a seizure disorder (infantile spasms, complex partial, myoclonic, multifocal) and is suspected but not proven in a fifth individual. EEG abnormalities with diffuse background slowing suggestive of encephalopathy were noted in four. Brain MRI studies were abnormal in six revealing delayed myelination, posterior periventricular gliosis, bilateral choroid plexus cysts, prominent ventricles and/or volume loss. Three presented with microcephaly; both males with FOXG1 deletions and one female with CDKL5 deletion. None of the males with MECP2 duplication were microcephalic. Asymmetric spasticity was identified in one male with MECP2 duplication, otherwise hypotonia was a common finding. Feeding and swallowing issues with failure to thrive were noted in all but one and six require G-tube feeds; one each also has recurrent pneumonia or sleep apnea. Additional problems identified in single individuals include: cataract, sensory neural hearing loss and coarctation, coronary artery fistula, diaphragmatic hernia, and congenital hip dysplasia. Our findings indicate that atypical Rett syndrome is a common condition that may be readily identified by chromosomal microarray. It has been thought that atypical Rett syndrome occurs more commonly in girls; however, the majority of our cases (80%) are male suggesting this may be under diagnosed in the general population. Additional studies are indicated to better determine prevalence, gender distribution and genotype-phenotype correlations.

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