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Correspondence
case. Therefore, the development of papular lesions is a distinct phenotypic feature of acquired CL. We recommend that this phenotype should be designated as acquired CL with papular lesions. The condition should be differentiated from mid-dermal elastolysis (MDE), which is another rare acquired disorder of elastic tissue that manifests clinically as either a fine wrinkling of the skin parallel to the skin cleavage or as perifollicular papules. Unlike acquired CL, MDE is characterized histopathologically by a band-like loss of elastic fibers limited to the mid-dermis. The basic pathology common to all forms of CL is a deficiency of elastic fibers. Elastic fibers are composed of two distinct components: an amorphous ELN core and microfibrils. Fibulin-5 localizes to the surface of elastic fibers, which represents an essential determinant of elastic fiber organization.2,3 Molecular defects underlying inherited CL have been well identified. Mutations in ELN and FBLN5 have been shown to be responsible in the majority of cases.4 By contrast, the precise etiology of acquired CL remains unclear, although it has been reported de novo or following cutaneous eruption, antibiotic therapy, or febrile illness. In 2006, Hu et al.1 reported a patient with acquired CL preceded by Toxocara canis parasitism and chronic urticaria. Mutational analysis showed the patient to be heterozygous for an inherited FBLN5 allele G202R, and compound heterozygous for ELN alleles A55V and G773D.1 This would imply that the pathogenesis of acquired CL may also involve an underlying genetic susceptibility and highlights the importance of molecular genetic analysis in patients with acquired CL. The present patient was screened for both ELN and FBLN5, but no mutations were found. It is possible that not only ELN and FBLN5 but also other genes associated with the biosynthesis of elastic fibers may be involved in acquired CL. Further studies are needed to clarify the exact pathogenesis of acquired CL.
Sheng Wang, MD Department of Dermatology West China Hospital Sichuan University Chengdu Sichuan China E-mail: [email protected] References 1 Hu Q, Reymond JL, Pinel N, et al. Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes. J Invest Dermatol 2006; 126: 283–290. International Journal of Dermatology 2015, 54, e56–e69
2 Yanagisawa H, Davis EC, Starcher BC, et al. Fibulin-5 is an elastin-binding protein essential for elastic fiber development in vivo. Nature 2002; 415: 168–171. 3 Nakamura T, Lozano PR, Ikeda Y, et al. Fibulin-5/ DANCE is essential for elastogenesis in vivo. Nature 2002; 415: 171–175. 4 Berk DR, Bentley DD, Bayliss SJ, et al. Cutis laxa: a review. J Am Acad Dermatol 2012; 66: 842.e1–842.e17.
IL36RN gene analysis of two Japanese patients with generalized pustular psoriasis
Recent reports have indicated that generalized pustular psoriasis (GPP) is predominantly caused by defects in IL36RN.1–3 In this study, we performed gene analysis in two patients with GPP and identified homozygous T123M and homozygous 115+6T>C mutations. Case 1 was a 66-year-old man referred to our university clinic (Osaka City University Graduate School of Medicine, Osaka, Japan) 20 years ago with an unremarkable family history and his own history for skin disorders. He developed generalized erythema and pustules in his late 20s and was diagnosed with GPP in 1992; after that, he was treated with topical steroids in addition to oral etretinate and cyclosporine. He had been repeatedly hospitalized due to severe rash with high fever that resulted from upper respiratory tract infection occurring once or twice a year. However, recurrence of this rash was not observed after infliximab treatment was initiated in April 2010. This patient experienced an aggravated episode of the rash after the topical application of vitamin D ointment.4 Direct sequencing of the IL36RN coding exons revealed a homozygous mutation of c.368C>T (p.Thr123Met) (Fig. 1a). Case 2 was a 52-year-old man who visited our university clinic 15 years ago; he did not have an exceptional family or individual medical history. He developed generalized rash at the age of five years and was diagnosed with GPP at the age of 11 years. The patient had been repeatedly hospitalized for this rash until cyclosporine therapy was initiated in 1998. Since then, the clinical course of his condition had relatively stabilized, and no recurrence of the rash was observed. IL36RN gene analysis showed a homozygous splice mutation of 115+6T>C (Fig. 1b). The study protocol has been approved by the ethics committee of Yamagata University Faculty of Medicine, and written informed consents were obtained from the patients. The IL36RN mutations detected in GPP are shown in Figure 2. Although nine mutations have been reported to date, no obvious genotype–phenotype relationship has been detected so far. ª 2014 The International Society of Dermatology
Correspondence
(a)
(b)
Figure 1 Direct sequencing of the IL36RN in Japanese patients with generalized pustular psoriasis showed that, in case 1, the patient has homozygous T123M missense mutation (a) and that, in case 2, the patient has homozygous splice-site mutation, c.115+6T>C (b)
Figure 2 IL36RN mutations reported so far are shown in this map. Among the nine mutations, R10X, T123R, T123M, and 115+6T>C mutations have been reported to be observed in the Japanese population
T123M missense mutation was reported by Kanazawa et al. in a Japanese patient with GPP. The first case reported by Kanazawa et al.5 was that of a compound heterozygous mutation of T123M and R10X, wherein the patient showed a mild phenotype; the condition had been controlled well by topical steroids. The first case discussed in this report is the first of a homozygous T123M mutation, with a severe phenotype resistant to oral etretinate and cyclosporine treatment. The 123rd threonine ª 2014 The International Society of Dermatology
residue has been predicted to play an important role in the functioning of the IL36RN molecule, and functional analysis of the T123R mutation showed that the mutation is pathological.6 Whether the T123M mutation itself has severe functional effects on IL36RN remains to be detected in the future. The 115+6T>C mutation in the second case discussed here has been shown to be a splice mutation that results in exon 3 skipping.5 This mutation was reported in six International Journal of Dermatology 2015, 54, e56–e69
e61
e62
Correspondence
patients in a previous study by Sugiura et al.7 Moreover, four Chinese individuals and six Malaysians have been reported to harbor the same mutation.8 Thus, the mutation appears to be relatively common in Asians. The second case discussed here showed juvenile-onset GPP. After considering the high incidence of such cases, we can hypothesize that this splice-site mutation may result in early-onset GPP. In conclusion, herein we report T123M and 115+6T>C mutations, both homozygous in nature, in two Japanese individuals with Zumbusch type of GPP. Recently, the mutations of the IL36RN gene were shown to be associated with palmoplantar pustulosis, acrodermatitis continua of Hallopeau, and acute generalized exanthematous pustulosis.8,9 Mutation analysis for GPP and these related pustular disorders have been instrumental in the development of specific treatment armamentarium for IL36 signaling.
Takahiro Shiratori, MD Kazuyoshi Fukai, MD Makiko Yasumizu, MD Rieko Taguchi, MD Daisuke Tsuruta, MD Department of Dermatology Osaka City University Graduate School of Medicine Osaka Japan E-mail: [email protected] Yuko Abe, MD Yutaka Hozumi, PhD Tamio Suzuki, MD Department of Dermatology Yamagata University Faculty of Medicine Yamagata Japan Conflicts of interest: None. References 1 Marrakchi S, Guigue P, Renshaw BR, et al. Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med 2011; 365: 620–628. 2 Onoufriadis A, Simpson MA, Pink AE, et al. Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet 2011; 89: 432–437. 3 Navarini AA, Valeyrie-Allanore L, Setta KN, et al. Rare varirations in IL36RN in severe adverse drug reactions manifesting as acute generalized exanthematous pustulosis. J Invest Dermatol 2013; 133: 1904–1907. International Journal of Dermatology 2015, 54, e56–e69
4 Tamiya H, Fukai K, Ishii M, et al. Generalized pustular psoriasis precipitated by topical calcipotriol ointment. Int J Dermatol 2005; 44: 791–792. 5 Kanazawa N, Nakamura T, Mikita N, et al. Novel IL36RN mutation in a Japanese case of early onset generalized pustular psoriasis. J Dermatol 2013; 40: 749– 751. 6 Faroq M, Nakai H, Fujimoto A, et al. Mutation analysis of the IL36RN gene in 14 Japanese patients with generalized pustular psoriasis. Hum Mutat 2013; 34: 176– 183. 7 Sugiura K, Takemoto A, Yamaguchi M, 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– 2521. 8 Setta-Kaffetzi N, Navarini AA, Patel VM, et al. Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes. J Invest Dermatol 2013; 133: 1366–1369. 9 Abbas O, Itani S, Ghosn S, et al. Acrodermatitis continua of Hallopeau is a clinical phenotype of DITRA: evidence that it is a variant of pustular psoriasis. Dermatology 2013; 226: 28–31.
A pediatric case with vasculitis-like viral eruption induced by Epstein–Barr virus
Epstein–Barr virus (EBV) or human herpesvirus 4 is one of the most common human viruses infecting more than 90% of adult population worldwide. Most of the primary infections occur in childhood with no or only nonspecific symptoms. If the infection is acquired in older age, it usually manifests as infectious mononucleosis characterized by sore throat, fever, and lymphadenopathy.1 After primary infection, the virus becomes latent and resides in the lymphocytes, causing the infected patient to be a lifelong EBV carrier. EBV has a high tropism for B cells because of its ability to bind B-lymphocyte surface molecule, CD21. It is also capable of infecting the T cells, natural killer cells, endothelial cells, smooth muscle cells, and monocyte–macrophage group cells. On rare occasions especially in immunosuppression, latent virus becomes active and causes chronic active infection and lymphoproliferative disorders.1 Mucocutaneous findings reported with primary/latent EBV infection include mucocutaneous findings in infectious mononucleosis, Gianotti–Crosti syndrome, hydroa vacciniforme, hypersensitivity to mosquito bites, cutaneous lymphoproliferative disorders, systemic lymphoproliferative disorders, and mucocutaneous ulcers especially in the immunosuppressive state, solid cancers such as nasopharyngeal carcinoma, oral hairy leukoplakia, and rare ª 2014 The International Society of Dermatology
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
Correspondence
case. Therefore, the development of papular lesions is a distinct phenotypic feature of acquired CL. We recommend that this phenotype should be designated as acquired CL with papular lesions. The condition should be differentiated from mid-dermal elastolysis (MDE), which is another rare acquired disorder of elastic tissue that manifests clinically as either a fine wrinkling of the skin parallel to the skin cleavage or as perifollicular papules. Unlike acquired CL, MDE is characterized histopathologically by a band-like loss of elastic fibers limited to the mid-dermis. The basic pathology common to all forms of CL is a deficiency of elastic fibers. Elastic fibers are composed of two distinct components: an amorphous ELN core and microfibrils. Fibulin-5 localizes to the surface of elastic fibers, which represents an essential determinant of elastic fiber organization.2,3 Molecular defects underlying inherited CL have been well identified. Mutations in ELN and FBLN5 have been shown to be responsible in the majority of cases.4 By contrast, the precise etiology of acquired CL remains unclear, although it has been reported de novo or following cutaneous eruption, antibiotic therapy, or febrile illness. In 2006, Hu et al.1 reported a patient with acquired CL preceded by Toxocara canis parasitism and chronic urticaria. Mutational analysis showed the patient to be heterozygous for an inherited FBLN5 allele G202R, and compound heterozygous for ELN alleles A55V and G773D.1 This would imply that the pathogenesis of acquired CL may also involve an underlying genetic susceptibility and highlights the importance of molecular genetic analysis in patients with acquired CL. The present patient was screened for both ELN and FBLN5, but no mutations were found. It is possible that not only ELN and FBLN5 but also other genes associated with the biosynthesis of elastic fibers may be involved in acquired CL. Further studies are needed to clarify the exact pathogenesis of acquired CL.
Sheng Wang, MD Department of Dermatology West China Hospital Sichuan University Chengdu Sichuan China E-mail: [email protected] References 1 Hu Q, Reymond JL, Pinel N, et al. Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes. J Invest Dermatol 2006; 126: 283–290. International Journal of Dermatology 2015, 54, e56–e69
2 Yanagisawa H, Davis EC, Starcher BC, et al. Fibulin-5 is an elastin-binding protein essential for elastic fiber development in vivo. Nature 2002; 415: 168–171. 3 Nakamura T, Lozano PR, Ikeda Y, et al. Fibulin-5/ DANCE is essential for elastogenesis in vivo. Nature 2002; 415: 171–175. 4 Berk DR, Bentley DD, Bayliss SJ, et al. Cutis laxa: a review. J Am Acad Dermatol 2012; 66: 842.e1–842.e17.
IL36RN gene analysis of two Japanese patients with generalized pustular psoriasis
Recent reports have indicated that generalized pustular psoriasis (GPP) is predominantly caused by defects in IL36RN.1–3 In this study, we performed gene analysis in two patients with GPP and identified homozygous T123M and homozygous 115+6T>C mutations. Case 1 was a 66-year-old man referred to our university clinic (Osaka City University Graduate School of Medicine, Osaka, Japan) 20 years ago with an unremarkable family history and his own history for skin disorders. He developed generalized erythema and pustules in his late 20s and was diagnosed with GPP in 1992; after that, he was treated with topical steroids in addition to oral etretinate and cyclosporine. He had been repeatedly hospitalized due to severe rash with high fever that resulted from upper respiratory tract infection occurring once or twice a year. However, recurrence of this rash was not observed after infliximab treatment was initiated in April 2010. This patient experienced an aggravated episode of the rash after the topical application of vitamin D ointment.4 Direct sequencing of the IL36RN coding exons revealed a homozygous mutation of c.368C>T (p.Thr123Met) (Fig. 1a). Case 2 was a 52-year-old man who visited our university clinic 15 years ago; he did not have an exceptional family or individual medical history. He developed generalized rash at the age of five years and was diagnosed with GPP at the age of 11 years. The patient had been repeatedly hospitalized for this rash until cyclosporine therapy was initiated in 1998. Since then, the clinical course of his condition had relatively stabilized, and no recurrence of the rash was observed. IL36RN gene analysis showed a homozygous splice mutation of 115+6T>C (Fig. 1b). The study protocol has been approved by the ethics committee of Yamagata University Faculty of Medicine, and written informed consents were obtained from the patients. The IL36RN mutations detected in GPP are shown in Figure 2. Although nine mutations have been reported to date, no obvious genotype–phenotype relationship has been detected so far. ª 2014 The International Society of Dermatology
Correspondence
(a)
(b)
Figure 1 Direct sequencing of the IL36RN in Japanese patients with generalized pustular psoriasis showed that, in case 1, the patient has homozygous T123M missense mutation (a) and that, in case 2, the patient has homozygous splice-site mutation, c.115+6T>C (b)
Figure 2 IL36RN mutations reported so far are shown in this map. Among the nine mutations, R10X, T123R, T123M, and 115+6T>C mutations have been reported to be observed in the Japanese population
T123M missense mutation was reported by Kanazawa et al. in a Japanese patient with GPP. The first case reported by Kanazawa et al.5 was that of a compound heterozygous mutation of T123M and R10X, wherein the patient showed a mild phenotype; the condition had been controlled well by topical steroids. The first case discussed in this report is the first of a homozygous T123M mutation, with a severe phenotype resistant to oral etretinate and cyclosporine treatment. The 123rd threonine ª 2014 The International Society of Dermatology
residue has been predicted to play an important role in the functioning of the IL36RN molecule, and functional analysis of the T123R mutation showed that the mutation is pathological.6 Whether the T123M mutation itself has severe functional effects on IL36RN remains to be detected in the future. The 115+6T>C mutation in the second case discussed here has been shown to be a splice mutation that results in exon 3 skipping.5 This mutation was reported in six International Journal of Dermatology 2015, 54, e56–e69
e61
e62
Correspondence
patients in a previous study by Sugiura et al.7 Moreover, four Chinese individuals and six Malaysians have been reported to harbor the same mutation.8 Thus, the mutation appears to be relatively common in Asians. The second case discussed here showed juvenile-onset GPP. After considering the high incidence of such cases, we can hypothesize that this splice-site mutation may result in early-onset GPP. In conclusion, herein we report T123M and 115+6T>C mutations, both homozygous in nature, in two Japanese individuals with Zumbusch type of GPP. Recently, the mutations of the IL36RN gene were shown to be associated with palmoplantar pustulosis, acrodermatitis continua of Hallopeau, and acute generalized exanthematous pustulosis.8,9 Mutation analysis for GPP and these related pustular disorders have been instrumental in the development of specific treatment armamentarium for IL36 signaling.
Takahiro Shiratori, MD Kazuyoshi Fukai, MD Makiko Yasumizu, MD Rieko Taguchi, MD Daisuke Tsuruta, MD Department of Dermatology Osaka City University Graduate School of Medicine Osaka Japan E-mail: [email protected] Yuko Abe, MD Yutaka Hozumi, PhD Tamio Suzuki, MD Department of Dermatology Yamagata University Faculty of Medicine Yamagata Japan Conflicts of interest: None. References 1 Marrakchi S, Guigue P, Renshaw BR, et al. Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med 2011; 365: 620–628. 2 Onoufriadis A, Simpson MA, Pink AE, et al. Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet 2011; 89: 432–437. 3 Navarini AA, Valeyrie-Allanore L, Setta KN, et al. Rare varirations in IL36RN in severe adverse drug reactions manifesting as acute generalized exanthematous pustulosis. J Invest Dermatol 2013; 133: 1904–1907. International Journal of Dermatology 2015, 54, e56–e69
4 Tamiya H, Fukai K, Ishii M, et al. Generalized pustular psoriasis precipitated by topical calcipotriol ointment. Int J Dermatol 2005; 44: 791–792. 5 Kanazawa N, Nakamura T, Mikita N, et al. Novel IL36RN mutation in a Japanese case of early onset generalized pustular psoriasis. J Dermatol 2013; 40: 749– 751. 6 Faroq M, Nakai H, Fujimoto A, et al. Mutation analysis of the IL36RN gene in 14 Japanese patients with generalized pustular psoriasis. Hum Mutat 2013; 34: 176– 183. 7 Sugiura K, Takemoto A, Yamaguchi M, 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– 2521. 8 Setta-Kaffetzi N, Navarini AA, Patel VM, et al. Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes. J Invest Dermatol 2013; 133: 1366–1369. 9 Abbas O, Itani S, Ghosn S, et al. Acrodermatitis continua of Hallopeau is a clinical phenotype of DITRA: evidence that it is a variant of pustular psoriasis. Dermatology 2013; 226: 28–31.
A pediatric case with vasculitis-like viral eruption induced by Epstein–Barr virus
Epstein–Barr virus (EBV) or human herpesvirus 4 is one of the most common human viruses infecting more than 90% of adult population worldwide. Most of the primary infections occur in childhood with no or only nonspecific symptoms. If the infection is acquired in older age, it usually manifests as infectious mononucleosis characterized by sore throat, fever, and lymphadenopathy.1 After primary infection, the virus becomes latent and resides in the lymphocytes, causing the infected patient to be a lifelong EBV carrier. EBV has a high tropism for B cells because of its ability to bind B-lymphocyte surface molecule, CD21. It is also capable of infecting the T cells, natural killer cells, endothelial cells, smooth muscle cells, and monocyte–macrophage group cells. On rare occasions especially in immunosuppression, latent virus becomes active and causes chronic active infection and lymphoproliferative disorders.1 Mucocutaneous findings reported with primary/latent EBV infection include mucocutaneous findings in infectious mononucleosis, Gianotti–Crosti syndrome, hydroa vacciniforme, hypersensitivity to mosquito bites, cutaneous lymphoproliferative disorders, systemic lymphoproliferative disorders, and mucocutaneous ulcers especially in the immunosuppressive state, solid cancers such as nasopharyngeal carcinoma, oral hairy leukoplakia, and rare ª 2014 The International Society of Dermatology
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
