Expanding the Phenotypic Spectrum of Raynaud-Claes Syndrome: A Rett-like Presentation with Two New Cases.

Pathogenic variants in the CLCN4 gene are associated with a rare X-linked neurodevelopmental disorder, Raynaud-Claes syndrome, characterized by intellectual disability, epilepsy, language impairment, motor deficits, stereotypies, and structural brain abnormalities. Although heterozygous females are often considered to be only mildly affected, severe phenotypes have also been reported, and the clinical presentation shows considerable heterogeneity. The present study aims to summarize the current knowledge on CLCN4-related neurodevelopmental disorders through a review of the available literature and to describe two additional patients carrying pathogenic CLCN4 variants, one male and one female. The female patient was found to carry a de novo heterozygous variant (c.2152C > T), while the male patient harbored a de novo hemizygous variant (c.949G > A). Clinical data were compared with those reported in the literature in order to identify phenotypic similarities and differences among patients previously described with the same mutations. Furthermore, in light of the literature review and the clinical data collected from our patients, we propose considering Raynaud-Claes syndrome as a Rett-like condition. This perspective expands the scope of differential diagnosis and underscores the importance of multidisciplinary and longitudinal diagnostic evaluation to improve clinical characterization, therapeutic management, and genetic counseling.