Lauren Head
University of Cincinnati College of Medicine
Introduction: Mutations in the mecp2 gene have been shown to cause a variety of syndromes. The very rare c.925C>T, p.R309W mutation has been reported in one previous multiplex family and several individual cases. We present a family with four children affected by this mutation and compare their findings to previous reports. The clinical features of these patients differentiate this syndrome from the phenomena of Rett Syndrome and offer new insight into its features and treatment. Methods: This was a retrospective case series report of four siblings seen in the Department of Human Genetics at Cincinnati Children’s Hospital Medical Center between November 2011 and November 2018. Review of pertinent literature was summarized for comparison. Results: The three male patients exhibit global developmental delay and intellectual disability. They also have hypothyroidism, hypotonia, recurrent otitis media, aortic dilatation, dysphagia, GERD, macrocephaly, seizures, macroglossia, and coarse facial features. The female patient exhibits hypotonia, recurrent otitis media, macrocephaly, coarse facial features, global developmental delay, and intellectual disability, though to a lesser degree than her brothers. None of the siblings have demonstrated signs of developmental regression. Diagnosis was obtained by a series of genetic and metabolic testing including chromosomal analysis, expanded microarray, PTEN sequencing and an X-Linked Intellectual Disability Panel. They have been treated by an interdisciplinary team using early interventions for disabilities, monitoring of dysphagia and medical management for other complications. Previous reports included information on intellectual disability and seizures, but no description of the presence or absence of the additional medical features seen in our patients. Conclusion: It is evident from these four patients that the c.925C>T, p.R309W mutation results in a phenotype that is distinct from Rett Syndrome, most notably in its compatibility with male survival. The males are severely disabled, have high risk for seizures and may be at risk for dilated aortic root, macroglossia and hypothyroidism. Females have had only mild to moderate intellectual disability along with preserved hand function, speech and other motor skills. Additional study of the functional impact of the mutation in mecp2 and reports of additional affected individuals will be necessary to achieve a more complete understanding of this disorder.
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