Varicella zoster virus–associated generalized pustular psoriasis in a baby with heterozygous IL36RN mutation
Authors: Kazumitsu Sugiura, Ryuhei Uchiyama, Ryuhei Okuyama, Masashi Akiyama
Journal: Journal of the American Academy of Dermatology (2014)

To the Editor: A 2-month-old otherwise healthy boy presented with erythema and pustules without vesicles on the face, trunk, and all limbs. There was no improvement following treatment with oral antibiotics 3 weeks earlier. On admission to our hospital he had a slight fever and a generalized crusted pustular eruption (Fig 1). Laboratory data showed the following abnormal values: white blood cell count 19.14 × 109/L (normal range: 7-15 × 109/L); C-reactive protein level 108.5 mg/L (normal range: <3 mg/L). Bacterial culture of the pustules and microscopy for fungal infection were negative. Histopathologic examination of a skin biopsy specimen revealed spongiosis with neutrophil infiltration in the upper epidermis (Fig 2).Fig 2Varicella zoster virus–induced generalized pustular psoriasis: hematoxylin and eosin staining of the pustules; Bar: 40 μm.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The pustulosis did not improve with application of a potent topical steroid and vitamin D3-containing ointment. Oral cyclosporine was started and gradually increased to 4 mg/kg at 64 days from the disease onset. One week later, the pustules had almost cleared. Administration of 4 mg/kg cyclosporine was continued for more than 9 months. Extensive pustules reappeared with development of an upper respiratory tract infection but subsequently regressed without a change in cyclosporine dosage. There was no family history of a similar eruption. Before the skin manifestations developed, chickenpox was diagnosed in the patient's brother. Serum anti-varicella zoster virus (anti-VZV) immunoglobulin M tested negative in the baby initially but was positive 46 days after the disease onset. Anti-VZV immunoglobulin G antibodies were positive and thought to be derived from the baby's mother. There was no serologic evidence of herpes simplex virus infection. After ethical approval was granted, written informed consent was obtained from the baby's parents in compliance with the Declaration of Helsinki. The entire coding regions of IL36RN including the exon/intron boundaries were sequenced using genome DNA samples from the patient and his parents. The patient and his father had a heterozygous c.28C>T (p.Arg10X) mutation in IL36RN, one of the generalized pustular psoriasis (GPP)-causing founder mutations in the Japanese cohort, whereas his mother did not have an IL36RN mutation (Fig 3).1Sugiura K. Takemoto A. Yamaguchi M. Takahashi H. Shoda Y. Mitsuma T. et al.The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist.J Invest Dermatol. 2013; 133: 2514-2521Crossref PubMed Scopus (235) Google Scholar Diagnosis was VZV-induced GPP, a rare type of psoriasis that periodically recurs. Infection is one of its triggers. Mutation of IL36RN, which encodes interleukin-36 receptor antagonist (IL-36RN), has been associated with GPP in both its heterozygous and homozygous forms.1Sugiura K. Takemoto A. Yamaguchi M. Takahashi H. Shoda Y. Mitsuma T. et al.The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist.J Invest Dermatol. 2013; 133: 2514-2521Crossref PubMed Scopus (235) Google Scholar, 2Navarini A.A. Valeyrie-Allanore L. Setta-Kaffetzi N. Barker J.N. Capon F. Creamer D. et al.Rare variations in IL36RN in severe adverse drug reactions manifesting as acute generalized exanthematous pustulosis.J Invest Dermatol. 2013; 133: 1904-1907Crossref PubMed Scopus (99) Google Scholar, 3Setta-Kaffetzi N. Navarini A.A. Patel V.M. Pullabhatla V. Pink A.E. Choon S.E. et al.Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes.J Invest Dermatol. 2013; 133: 1366-1369Crossref PubMed Scopus (137) Google Scholar IL-36 is not present in normal skin but is induced by inflammatory cytokines including tumor necrosis factor-α (TNF-α).4Carrier Y. Ma H.L. Ramon H.E. Napierata L. Small C. O'Toole M. et al.Inter-regulation of Th17 cytokines and the IL-36 cytokines in vitro and in vivo: implications in psoriasis pathogenesis.J Invest Dermatol. 2011; 131: 2428-2437Crossref PubMed Scopus (323) Google Scholar When functional IL-36RN is underproduced, IL-36 can induce neutrophil-rich infiltration. TNF-α is elevated in the blood of VZV-infected individuals.5Torigo S. Ihara T. Kamiya H. IL-12, IFN-gamma, and TNF-alpha released from mononuclear cells inhibit the spread of varicella-zoster virus at an early stage of varicella.Microbiol Immunol. 2000; 44: 1027-1031Crossref PubMed Scopus (42) Google Scholar It is possible that this patient could not produce enough IL-36RN to antagonize the excessive IL-36 induced by VZV infection, an imbalance that resulted in GPP. To our knowledge, this is the first report of VZV-induced GPP and of GPP triggered by infection in a patient with a heterozygous IL36RN mutation. Clinicians should consider IL-36RN deficiency in the setting of prolonged viral-induced generalized pustulosis.