P124 Severe psoriasiform phenotype in CARMIL2 deficiency and successful therapy with dupilumab

Abstract A 22-year-patient with consanguineous parents presented with a diagnosis of severe psoriasis with erythroderma and recurrent episodes of fever that had been present since childhood. Neither systemic treatment with methotrexate, ciclosporin A, acitretin, apremilast nor tildrakizumab had led to a significant improvement. Clinically, there was persistent erythroderma with coarse lamellar scaling on the entire integument and pronounced lichenification. Histopathologically, the skin biopsy revealed regular acanthosis, raised papillary tips with inflammatory infiltrate, slight para- and hyperkeratosis, hypogranulosis and a strong expression of NOS2 and CCL27. Immunophenotypically, a reduced number of CD4+ and CD8+ memory cells in line with increased numbers of naïve T cells was found. The proportion of FOXP3+ Treg cells was also reduced and there was an increased number of naive B cells and insufficient conversion into memory B cells. Whole exome sequencing identified a novel homozygous frameshift mutation (c.1894del) in the CARMIL2 gene. CARMIL2 deficiency is a recently described autosomal recessive inherited combined immunodeficiency that impairs T- and B-cell activation and maturation through dysfunctional CD28-mediated costimulation and cell motility through impaired cytoskeletal functions. In addition to various skin manifestations, ranging from seborrheic, atopic or psoriasiform dermatitis and an increased susceptibility to bacterial, mycotic and viral skin infections, the majority of affected individuals present with gastrointestinal symptoms, respiratory infections and the occurrence of EBV+-smooth muscle tumours (SMTs). In our patient, the start of treatment with the monoclonal antibody dupilumab, which binds IL-4Rα and inhibits the signalling of IL-4 and IL-13, led to an impressive long-term improvement in the skin condition. Haematopoietic stem cell transplantation could be a therapeutic option for the long-term control of extracutaneous manifestations but requires control of skin inflammation. In refractory psoriasiform manifestations in combination with susceptibility to infection, gastrointestinal inflammation or EBV+-SMTs, CARMIL2 deficiency should be considered in the differential diagnosis. Our case expands the phenotypic spectrum of a newly discovered primary immunodeficiency and proves for the first time that dupilumab may be an effective treatment option for severe psoriasiform cutaneous manifestations in CARMIL2 deficiency.