IMPORTANCEWe found CARD14 mutations (2 de novo novel mutations and another previously reported mutation) in 3 of 3 patients with pityriasis rubra pilaris (PRP) type V, but not in patients with PRP of other types. Our findings, combined with the published literature, suggest that type V PRP, both familial and sporadic, can be caused by CARD14 mutations. Detailed clinical observation revealed that all 3 patients displayed unique patchy macular brown hyperpigmentation. OBJECTIVE To further determine how often patients with PRP have pathogenic mutations in CARD14 and to elucidate which clinical subtype of PRP is caused by CARD14 mutations. DESIGN, SETTING, AND PARTICIPANTSWe sequenced the entire coding regions of CARD14 in genomic DNA from patients with 5 clinical subtypes of PRP. The detailed clinical features were analyzed in all the patients. The pathogenicity of each mutation was evaluated by several computational predictions. PRP was classified into 6 subgroups, types I to VI, based on clinical criteria. We categorized all the patients with PRP into the clinical subtypes using the classic PRP classification; 22 cases of PRP with varying subtypes were studied. MAIN OUTCOMES AND MEASURESThe prevalence of CARD14 mutations in each subtype of PRP was evaluated. Clinical features and characteristics of patients with PRP with CARD14 mutations were analyzed. RESULTSOverall 22 patients with PRP were included in our study (12 men, 10 women; mean [SD] age, 26 [18] years). Among 3 patients with PRP type V, all were found to have CARD14 mutations: 2 de novo novel mutations (p.Cys127Ser and p.Gln136Leu), and another previously reported mutation (p.Gly117Ser). All were close to the reported pathogenic domains. In silico analysis of all 3 mutations suggested that they are functionally relevant to pathogenesis. All 3 patients displayed unique patchy macular brown hyperpigmentation additionally to other typical features of PRP. Patients with PRP type I and type IV, 1 patient each, had the rare variants in CARD14.CONCLUSIONS AND RELEVANCE Pityriasis rubra pilaris type V is a distinct variant of PRP that is caused by CARD14 mutations. In addition, a rare variant of CARD14 might also be implicated in the pathophysiology of other forms of PRP.

To study the temporal and spatial relationship between infiltrating T-cell subsets or eosinophils and cell adhesion molecules on endothelial cells in skin lesions of atopic dermatitis (AD), we undertook immunohistochemical analysis using monoclonal antibodies against surface markers of T cells, eosinophil granule proteins and cell adhesion molecules. Predominant mononuclear cells in acute and chronic skin lesions were CD3, CD4 and CD45RO positive helper-inducer/memory T cells. Their number was significantly and strongly correlated with the intensity of E-selectin expression. Eosinophils and deposition of eosinophil-derived granule proteins such as eosinophil cationic protein (ECP), major basic protein (MBP) and eosinophil peroxidase (EPO) were found constantly in acute lesions and only occasionally in chronic lesions. The total number of immunoreactive eosinophils and deposits of MBP, EPO and ECP were significantly and strongly correlated with the staining intensity of VCAM-1. In chronic lesions significant reduction of VCAM-1 expression paralleled occasional infiltration of eosinophils. Our results demonstrate the possibility that E-selectin and VCAM-1 are the critical adhesion molecules for trafficking of memory T cells and eosinophils, respectively, into skin lesion of AD. Persistent expression of the adhesion molecules may be related to prolongation of the skin lesion in AD.

A 2-year-old girl showed exaggerated skin reactions to mosquito bites and associated general symptoms, including a high temperature, lymphadenopathy, and hepatosplenomegaly. Peripheral blood lymphocytes contained a high percentage of CD2+, CD3-, CD4-, CD8-, CD11b+, CD16+, CD38+, CD56+, CD57-, and HLA-DR+ large granular lymphocytes that exhibited a marked natural killer cell activity. Immunohistochemically, biopsy specimens taken from the lesional skin demonstrated an infiltrate of the cells bearing the natural killer cell phenotype, indicating a role of these cells in the development of the abnormal skin reactions to mosquito bites and other systemic manifestations. Our case suggests that natural killer cell lymphocytosis may show severe hypersensitivity to mosquito bites as the most outstanding manifestation.

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