Naxos disease: current insights from early clinical observations to genetics and precision medicine

Naxos disease is the prototype of the Naxos disease cardiocutaneous spectrum, a group of inherited desmosomal disorders characterised by distinctive hair and skin abnormalities that precede the development of arrhythmogenic cardiomyopathy (ACM). Since its original clinical description in 1986 and the subsequent identification of the first ACM-causing gene (JUP), Naxos disease has provided fundamental insights into the pathogenesis, diagnosis and management of inherited desmosomal cardiomyopathies. This review provides current insights into the evolving clinical spectrum, encompassing the characteristic cutaneous signature, early electrical abnormalities, progressive structural myocardial remodelling, inflammatory ("hot-phase") episodes, ventricular arrhythmias and heart failure. We discuss the expanding genotype-phenotype relationships involving JUP, DSP and DSC2, highlighting how distinct genetic substrates influence ventricular involvement, disease severity and clinical outcomes while sharing common desmosomal mechanisms. Particular emphasis is placed on early clinical recognition, multimodality imaging, genetic diagnosis, risk stratification and lifelong multidisciplinary management. Finally, we discuss the emerging role of international collaborative registries, including NAXCARE, in generating prospective real-world evidence to refine genotype-informed surveillance, improve risk prediction and support precision medicine. Nearly four decades after its original description, Naxos disease has evolved from a rare inherited syndrome into the prototype of desmosomal cardiomyopathy, demonstrating how careful clinical observation can drive molecular discovery, precision medicine and improved patient care.