X-linked chondrodysplasia punctata 1 (CDPX1) due to ARSL pathogenic variants and Xp22.33 contiguous gene deletions: a narrative review of genetics, clinical phenotype, neurodevelopmental features, diagnosis, and multidisciplinary management

Background X-linked chondrodysplasia punctata 1 (CDPX1; OMIM #302950) is a rare X-linked recessive skeletal dysplasia caused by pathogenic variants or deletions in the ARSL gene (formerly ARSE ) at Xp22.33. The disorder is characterised by ectopic cartilage calcification (stippled epiphyses), brachytelephalangy, short stature, and nasomaxillary hypoplasia. Larger contiguous Xp22.33 deletions—ranging from approximately 1.3 Mb to greater than 5 Mb—produce expanded phenotypes that vary according to deletion size and gene content. Specifically, deletions encompassing NLGN4X (neuroligin-4 X-linked) additionally manifest with autism spectrum disorder (ASD), mixed receptive-expressive language disorder, phonological disorder, developmental coordination disorder (DCD), and sensory processing difficulties. Broader deletions may additionally encompass genes responsible for X-linked ichthyosis (STS), Kallmann syndrome (KAL1/ANOS1), intellectual disability (VCX), and—in very large deletions—generalised epilepsy, hearing loss, and attention-deficit/hyperactivity disorder (ADHD). Main body This narrative review synthesises current knowledge on the molecular genetics and pathophysiology of CDPX1, including the role of ARSL in sulfated glycosaminoglycan desulfation and the critical function of NLGN4X in postsynaptic adhesion and excitatory/inhibitory (E/I) synaptic balance. We describe the full clinical spectrum from isolated skeletal dysplasia to the expanded neurodevelopmental contiguous gene syndrome, detail diagnostic approaches including chromosomal microarray and whole-genome sequencing, and provide a comprehensive, evidence-based multidisciplinary management framework. Tables summarise genotype–phenotype correlations, recommended neurodevelopmental assessment tools, and evidence-based intervention strategies. Conclusions Early molecular characterisation of deletion boundaries is essential to stratify neurodevelopmental risk. Deletion extent mandates systematic neurodevelopmental surveillance and early referral to intensive, evidence-based interventions—principally Applied Behavior Analysis, the Early Start Denver Model, and naturalistic speech-language therapy—as the primary modifiable determinants of functional outcome. Increased recognition of the NLGN4X-mediated expanded phenotype across genetics, skeletal dysplasia, and developmental paediatrics communities is needed to close the existing diagnostic and therapeutic gap. It should be noted that evidence supporting neurodevelopmental interventions in this population is largely extrapolated from the broader ASD and language disorder literature; condition-specific randomised trial data for Xp22.33 contiguous gene deletion syndrome are not currently available.