Psychomotor delay and intellectual disability are potential limitations in psoriasis management, due to low compliance, and strict dependence from care givers intervention. We report our successful experience with a 58-year-old woman, who was genetically affected by Cornelia De Lange syndrome, which causes intellectual disability and psychomotor disorders. The patient had been already treated with topical and traditional therapies, without any clinical benefits. Eventually she adhered to guselkumab treatment. The compliance was excellent, significant improvements were observed after only 3 months of treatment, without adverse effects. During follow-up, the COVID-19 pandemic address concern on the possible increased risk of infection due to immunosuppression. In agreement with current Italian recommendations, risk and benefits profile was discussed with the patient's legal tutor and the decision to continue the treatment was taken. Psoriasis complete clarification was maintained during the most difficult period of the Italian outbreak, allowing the patient to remain safely at home. This article is protected by copyright. All rights reserved.