Atopy Beyond the Skin: CARMIL2 Deficiency

Introduction Primary atopic disorders (PADs) are a group of inborn errors of immunity characterized by severe eczema, elevated IgE, eosinophilia, and recurrent infections. Among them, CARMIL2 deficiency is a rare combined immunodeficiency with prominent skin manifestations and dysregulated T cell function. Clinical Case We present a case of a 47-year-old male with a lifelong history of refractory atopic dermatitis, dependent on high-dose systemic corticosteroids, leading to significant sequelae such as tooth loss and osteoporosis. He had recurrent bacterial, fungal, and viral infections, including pneumonia, otitis media with hearing loss, histoplasmosis, molluscum contagiosum, herpes zoster, and chronic skin and nail infections. Over time, he developed chronic diarrhea and was diagnosed with ALK-negative anaplastic large-cell T cell lymphoma (ALCL). Immunological evaluation revealed normal immunoglobulin levels with elevated IgE, eosinophilia, impaired vaccine responses, global lymphopenia, with reduced naive T cells, B-switched and memory impairment. Next-generation sequencing identified two heterozygous variants in CARMIL2 (one likely pathogenic, one of uncertain significance). The patient was put into immunoglobulin replacement and dupilumab, which initially improved his dermatitis. After that, he began chemotherapy (brentuximab, cyclophosphamide, doxorubicin, and corticosteroids) with initial clinical improvement. However, he relapsed with central nervous system involvement and died despite further treatment. Discussion This case illustrates the diagnostic challenge of adult-onset primary immunodeficiencies with predominant atopic features. CARMIL2 deficiency affects actin polymerization and T cell signaling, impairing immune regulation and barrier function. The temporal association between dupilumab use and lymphoma onset raises concern about biologic therapy in immune-dysregulated hosts. While ALCL has not been previously reported in CARMIL2 deficiency, this case suggests potential associations worth further investigation. Whether allogeneic hematopoietic stem cell transplantation should be considered in such cases remains an open question.