Distinct CutaneousManifestations and Cold-Induced Leukocyte Activation AssociatedWith PLCG2Mutations

A lthough themost commoncutaneousmanifestationof primary immunodeficiency (PID) is infection, a varietyofnoninfectiousdermatologic findingsmayoccur.1 Noninfectious cutaneous granulomas, for instance, are relatively frequent in patients with certain PIDs, including commonvariable immunodeficiency (CVID), severe combined immunodeficiency, chronic granulomatous disease (CGD), and ataxia-telangiectasia (A-T).2,3 Althoughnot completelyunderstood, cutaneous granulomas in PIDmaybe a consequence of abnormal antigen processing, aberrant cytokine production, enhanced cell-mediated immune activity in the presence of a defectivehumoral system, abnormalneutrophil activation, or impaired macrophage regulation.2,4-6 Cutaneous granulomas are also a feature of a newly described PID, PLCG2-associated antibody deficiency and immune dysregulation (PLAID), caused by genomic deletions in PLCG2. PLAID is characterized by cold urticaria, autoimmunity, atopy, and humoral immune deficiency, resulting in recurrent sinopulmonary infections.7 PLAIDassociated deletions of PLCG2 cause diminished receptormediated activity at physiologic temperatures in B cells and natural killer cells with enhanced spontaneous signaling in mast cells and B cells at subphysiologic temperatures. The cold-induced signaling in mast cells leads to the characteristic cold urticaria observed in all patients with PLAID. Cutaneous granulomas have also been identified in 2 additional IMPORTANCE PLCG2-associated antibody deficiency and immune dysregulation (PLAID) is a newly characterized immunodeficiency syndrome associated with distinct cutaneous features. Awareness of the cutaneous skin findings associated with PLAIDmay facilitate diagnosis and improve patient care.