Distinct Cutaneous Manifestations and Cold-Induced Leukocyte Activation Associated With PLCG2 Mutations

Abstract

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 PLAID may facilitate diagnosis and improve patient care.

Objectives: To characterize the cutaneous manifestations of PLAID and identify potential cellular mechanisms of the disease.

Design, setting, and participants: In this retrospective analysis of patients with PLAID and PLAID-like disease evaluated at the National Institutes of Health from January 1, 2005, through December 31, 2014, patients with deletions in PLCG2 leading to PLAID and patients with PLAID-like disease for whom a PLAID mutation was not identified were studied.

Main outcomes and measures: Characterization of cutaneous manifestations of PLAID and PLAID-like disease and analysis of PLAID immune cell activation.

Results: Among 36 patients with PLAID and PLAID-like phenotypes, all of whom had evaporative cold urticaria, 8 patients had a history of unique neonatal-onset ulcerative and cutaneous lesions in cold-sensitive regions of the body. Granulomatous skin lesions sparing warm regions (eg, flexural surfaces and skinfolds) were identified in 4 patients. Neutrophils and monocytes from patients with PLAID exhibited enhanced baseline activation in vitro, which was potentiated by ambient temperature exposure.

Conclusions and relevance: Collectively, these findings suggest that early identification of neonatal lesions may help in the diagnosis of PLAID and that leukocyte hyperactivation may underlie cutaneous lesions in patients with PLAID. Further characterization of mechanisms underlying leukocyte hyperactivation may contribute to the fundamental understanding of granuloma formation.

Figure 1. Neonatal Lesions and Granulomatous Skin Disease in Patients With PLCG2-Associated Antibody Deficiency and Immune Dysregulation (PLAID) and PLAID-Like Phenotypes

A, Neonatal nasal lesion showing hemorrhagic ulceration with crust involving the nasal tip and bridge in patient 8 during the first week after birth. B, Resolved nasal lesion in patient 8. C, Granulomatous skin disease in a patient with PLAID (patient 1). Confluent areas of tan to red plaques and nodules on the trunk and extremities with sparing of skinfolds and flexural surfaces. D, Well-demarcated plaque with thick scale and ulceration (patient 2).

Figure 2. Histologic Characterization of PLCG2-Associated Antibody Deficiency and Immune Dysregulation Skin Granulomas

A, Skin biopsy (middle back) showing fairly well-formed granuloma with several scattered eosinophils (patient 1). B, Skin biopsy (lower leg) revealing histiocytic infiltrate with multinucleated giant cells (patient 4) (hematoxylin-eosin, original magnification ×100).

Figure 3. Expression of Surface Activation Markers in Different Temperature Settings

A and B, Mean surface CD11b expression (mean fluorescence intensity [MFI]) in neutrophils (A) and monocytes (B) among healthy controls and patients with PLCG2-associated antibody deficiency and immune dysregulation (PLAID) at ambient temperatures. Error bars indicate SD. C and D, Mean surface CD11b expression (MFI) in neutrophils (C) and monocytes (D) among healthy controls and patients with PLAID at warm temperatures. Error bars indicate SD. E and F, Median relative expression of CD11b in ambient compared with warm temperatures in neutrophils (E) and monocytes (F) from patients with PLAID and healthy controls. Relative MFI of CD11b is calculated as (MFI_ambient/MFI_warm). Error bars indicate interquartile range. G, Basal superoxide production in neutrophils from patients with PLAID compared with healthy controls at 20°C, 30°C, and 37°C. H, Neutrophil superoxide production in response to tumor necrosis factor α in patients with PLAID. ^aP < .05 (unpaired t test and Wilcoxon signed rank test). ^bP < .01 (unpaired t test and Wilcoxon signed rank test). ^cP < .001 (unpaired t test and Wilcoxon signed rank test). ^dP < .33 (unpaired t test and Wilcoxon signed rank test). ^eP = .78 (unpaired t test and Wilcoxon signed rank test).