BACKGROUND: The immune abnormalities underlying the ichthyoses are poorly understood. OBJECTIVE: To determine the immunophenotype of an ichthyosis resulting from mutations in the spectrin repeat 6 (SR6) domain of DSP, the gene encoding desmoplakin, and to target therapy based on the molecular pathogenesis. METHODS: Immunophenotyping was performed using the blood and skin of a girl with SR6 region DSP mutations causing erythroderma/ichthyosis and cardiomyopathy. RESULTS: Based on the discovery of Th1 and Th17/IL-23 skewing in the skin and Th17/IL-22 skewing in blood, ustekinumab therapy was initiated. Ustekinumab was also administered to a boy with an SR6 region DSP mutation and ichthyosis without cardiomyopathy. Both children responded, despite previous poor responses to immunosuppressants and retinoids. LIMITATIONS: Small number of patients and immunophenotyping in only one patient CONCLUSION: An understanding of the molecular basis of inflammation in rare cutaneous disorders can lead to targeted therapy, which promises to be more beneficial than broad immunosuppressants.