Pityriasis Rubra Pilaris Type V as an Autoinflammatory Disease by CARD14 Mutations

Abstract

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.

Pityriasis rubra pilaris-like erythroderma secondary to phosphoinositide 3-kinase inhibition

“…PRP is a rare papulosquamous disorder of unknown aetiology. It has been associated with impaired cell‐mediated immunity, and familial variants have been linked to genetic mutations relevant to other autoinflammatory skin disorders . Clinical findings include orange/red plaques with follicular hyperkeratosis and characteristic ‘islands of sparing’, palmoplantar hyperkeratosis, and frequent progression to erythroderma with pityriasiform scale…”

“…It has been associated with impaired cellmediated immunity, and familial variants have been linked to genetic mutations relevant to other autoinflammatory skin disorders. [7][8][9] Clinical findings include orange/red plaques with follicular hyperkeratosis and characteristic 'islands of sparing', palmoplantar hyperkeratosis, and frequent progression to erythroderma with pityriasiform scale. 10 P110d blockade in mice and humans results in decreased regulatory T-cell (Treg) function and increased effector T-cell activity.…”

Pityriasis rubra pilaris: algorithms for diagnosis and treatment

“…24 Different CARD14 mutations were found, mostly in type V PRP, which does not exclude that polymorphisms of CARD14 are also implicated in the pathophysiology of other forms of PRP. 25,26…”

008 Beneficial effect of ustekinumab in familial pityriasis rubra pilaris with a new missense mutation in CARD14

“…This amino acid substitution is located adjacent to other gain-of-function mutations between the CARD and coiled-coil domain. 1,9 The functional effect of this missense mutation, assessed with various programs, [10][11][12][13][14] (Fig. 1c), which persisted for a total of 24 weeks.…”