Desmosomal-type acantholysis may be a clue to underlying desmoplakin variants, which can be associated with cardiomyopathy. Recognition of this unique and sometimes subtle pattern of acantholysis can be beneficial for patient management and outcomes. Biopsies from three patients with erythrokeratodermia cardiomyopathy and known variants in desmoplakin were examined for the presence of desmosomal-type acantholysis. Biopsies from all three patients had findings of increased space between keratinocytes of the basal and sometimes suprabasal layers, sometimes causing the polygonal keratinocyte border to appear spiky. Desmosomal-type acantholysis may be a clue to an underlying defect in keratinocyte desmosomes.

Erythrokeratodermia cardiomyopathy (EKC) syndrome is a rare autosomal dominant disorder characterized by generalized erythrokeratoderma and progressive dilated cardiomyopathy, caused by pathogenic variants in the SR6 domain of desmoplakin (DSP). We report two cases of EKC with novel de novo missense DSP variants at phenylalanine position 590 (F590S and F590V), expanding the mutational spectrum beyond proline substitutions. Immunostaining demonstrated disrupted desmosomal protein localization. One patient showed significant clinical improvement with ustekinumab therapy. These findings underscore the need for early cardiac monitoring and support IL-12/23p40 inhibition as a potential therapeutic strategy in EKC.

Patients with erythrokeratodermia cardiomyopathy syndrome exhibit congenital, generalised erythrokeratoderma and dilated cardiomyopathy during early childhood. We report a case of erythrokeratodermia cardiomyopathy syndrome in a 15-year-old male patient and focus this report on cardiac features that were present.

Disorders of keratinization (DOK) show marked genotypic and phenotypic heterogeneity. In most cases, disease is primarily cutaneous, and further clinical evaluation is therefore rarely pursued. We have identified subjects with a novel DOK featuring erythrokeratodermia and initially-asymptomatic, progressive, potentially fatal cardiomyopathy, a finding not previously associated with erythrokeratodermia. We show that de novo missense mutations clustered tightly within a single spectrin repeat of DSP cause this novel cardio-cutaneous disorder, which we term erythrokeratodermia-cardiomyopathy (EKC) syndrome. We demonstrate that DSP mutations in our EKC syndrome subjects affect localization of desmosomal proteins and connexin 43 in the skin, and result in desmosome aggregation, widening of intercellular spaces, and lipid secretory defects. DSP encodes desmoplakin, a primary component of desmosomes, intercellular adhesion junctions most abundant in the epidermis and heart. Though mutations in DSP are known to cause other disorders, our cohort features the unique clinical finding of severe whole-body erythrokeratodermia, with distinct effects on localization of desmosomal proteins and connexin 43. These findings add a severe, previously undescribed syndrome featuring erythrokeratodermia and cardiomyopathy to the spectrum of disease caused by mutation in DSP, and identify a specific region of the protein critical to the pathobiology of EKC syndrome and to DSP function in the heart and skin.