293 Pityriasis rubra pilaris type V with a heterozygous mutation in CARD14

Abstract

Pityriasis rubra pilaris (PRP) is a rare chronic inflammatory skin disorder clinically characterized by keratotic follicular papules, well-demarcated scaly erythematous plaques interspersed with distinct islands of uninvolved skin, and palmoplantar keratoderma. The autosomal dominant subtype, which is classified as PRP type V (PRPV), is associated with gain-of-function mutations in CARD14. Although around 30 cases with PRPV have been reported in the literature, diagnosis and treatment remain difficult. In this study, we analysed a 60-year-old Japanese male with erythroderma, palmoplantar keratoderma, ectropion and joint contractures of the fingers, all of which had appeared since birth. Notably, he has experienced multiple skin tumours including malignant melanoma and squamous cell carcinoma. Although the patient was initially diagnosed with congenital ichthyosiform erythroderma (CIE), mutation analysis unexpectedly revealed a heterozygous mutation c.356T>C (p.Met119Thr) in CARD14, whereas no pathogenic mutations were detected in any of the 12 genes responsible for CIE. This de novo mutation was absent from available databases. Overexpression of this mutant CARD14 formed aggregations in the cytoplasm, which exhibited a completely different distribution from that of the wild type. Furthermore, the NF-κB luciferase reporter assay revealed that mutant CARD14 showed a 2-fold increase in NF-κB activity compared with the wild type, suggesting the pathogenicity of the mutation. These findings led to the final diagnosis of PRPV. We have treated the present case with ustekinumab, which we have found partially effective. This study further expands our understanding of clinical and genetic features of PRPV. The multiple occurrences of skin tumours with this patient may suggest potential tumorigenesis associated with the disease.