DIT- generalized pustular psoriasis GPP IL36RN IL- GPP Marrakchi 1 IL-36Ra ~ 8d 1. DOI /j. cjdv

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1 Aug 2014 Vol.28 No.8 CHIN J DERM VENEREOL 771 IL-36Ra IL-36Ra DITRA PCR IL36RN IL36RN c T > C IL36RN c T > C IL36RN c T > C DITRA DITRA IL36RN R DOI /j. cjdv A Mutation Analysis of IL36RN in A Chinese DITRA Family with Cutaneous Squamous Cell Carcinoma SHU Dan JIN Hong-zhong ZUO Ya-gang YAN Yan Department of Dermatology PUMC Hospital CAMS and PUMC Beijing China Corresponding author JIN Hong-zhong jinhongzhong@ 263. net Abstract Objective To report a DITRA family in which the proband developed cutaneous squamous cell carcinoma secondary to DITRA. Methods The blood samples of a Chinese DITRA family and 178 unrelated healthy controls were collected. All the exons and the flanking sequences of IL36RN were amplified by PCR and products analyzed by direct sequencing. Results Histopathological examination of the skin ulcer revealed epithelioid cells with atypia arranged in cords invasive growth of the dermis and mutation analysis of IL36RN revealed homozygous mutation c T > C in the proband. Meanwhile IL36RN mutation a- nalysis was performed in the unaffected family members and 178 healthy controls. All the unaffected family members and eight healthy controls carried heterozygous c T > C mutation in IL36RN. Conclusion Homozygous IL36RN c T > C mutation may be the cause of DITRA and refractory and persistent pustular lesions may be the causes of secondary cutaneous squamous cell carcinoma in the proband. Key words DITRA IL36RN Mutation Cutaneous squamous cell carcinoma generalized pustular psoriasis GPP RA IL36RN DIT- GPP IL36RN IL- 36Ra GPP Marrakchi 1 IL-36Ra 2 DITRA GPP ~ 8d jinhongzhong@ 263. net

2 d ~ 1e X DITRA 12 A 20mg /d A 100mg /d A 100mg /d 25mg 3d 1 37kg 3 1f ~ 1g 3 Ⅳ 2 1a 10cm 8cm AE1 /AE3 3 + EMA + CEA - CK7 1b - 2 1c 2 86mm /h C 3kg mg /LRF HLA-B27 3 PPD DNA 5 X 5mL DNA 178 ~ Clinical manifestations before treatment X-ray manifestation of feet X-ray manifestation of lower right leg ~ Clinical manifestations after treatment Fig. 1 1 X Clinical and X-ray manifestations of the proband

3 773 HE staining bar = 1mm HE staining bar = 100μm AE1 /AE3 3 + SP staining bar = 200μm EMA + SP staining bar = 200μm Fig. 3 3 Fig. 2 2 Histopathological and immunohistochemical examinations of the ulcer Pedigree of the family DNA 1. 3 PCR c T > C 4b ~ IL36RN GenBank NM_ d IL36RN c T > C % IL1RN 3 1 PCR 2. 2 IL36RN mrna RT-PCR 2 PCR 271bpmRNA 3 IL36RN 5a ~ 5b IL36RN c T > C IL-1Ra 1 IL36RN PCR RT-PCR Tab. 1 Primer pairs for IL36RN PCR and RT-PCR amplification DIRA 6 IL1RN 1. 4 PCR RT-PCR IL36RN mrna 1 IL36RN c T > C RT-PCR TaKaRa RNA RNA cd- NA cdna PCR DNA 4a UCSC http genome. ucsc. edu / IL36RN 3 IL36RN c T > C Exon /cdna Forward primer Reverse primer Productsize bp 1 5'-AGTGCTTCTGGCGACTTAGG-3' 5'-GGAGAGAGAGGCTGAGTTGG-3' '-CTGACCCCAGACCCAGAATC-3' 5'-AGCTGGACAACGGGTCTATC-3' '-GTTACTTCTGGCACAGTAGG-3' 5'-CACTTTGCTGAGAGGTGTAG-3' '-TCATGACAGCTGCTGAGAAG-3' 5'-AGCTGCCATCAACAGAATCC-3' '-AGATGCTGAGCCTACTGAAG-3' 5'-TCTGACATCAGCACCTCCTC-3' '-TAGAGTCAGGGATCTATGGC-3' 5'-GTGTCCTCTCCTTTTCATAC-3' '-CAAATTCACATCCTTCTTGG-3' 5'-GGGTAAATGAAGGATAGTTG-3' 917 cdna 5'-GTCCTGAGTGGGGCGCTGTG-3' 5'-GAAGTAGAAGTCTGTGATGGG-3' 450

4 774 RT-PCR 450bpmR- NA 5a 5c 3 GPP IL1RN 7 PsA Rieter GPP DITRA Friedman 8 1 GPP RF HLA-B27 PUVA A 9-10 Gel electrophoresis of amplified IL36RN DNA fragments M DNA Ladder Marker 1 ~ 7 The amplified DNA fragments of IL36RN exon Homozygous IL36RN c T > C mutation Heterozygous IL36RN c T > C mutation Wild type of IL36RN Fig. 4 4 PCR Gel electrophoresis and PCR sequencing of amplified IL36RN DNA fragments PsA Rieter IL-1Ra IL1RN Piepkorn GPP A 4 A A TNF-α IL36RN c T > C DITRA IL36RN c T > C IL36RN IL36RN 155 IL-36Ra 3 10 IL-36Ra /IL- 36R DITRA 4 5 Gel electrophoresis of amplified IL36RN cdna fragments M DNA Ladder Marker 1 Patient 2 Healthy control RT-PCR sequencing in the 8 c T > C proband PTC premature termination condon RT-PCR sequencing in the healthy control IL-36Ra 5 RT-PCR IL-36 /IL-36R Fig. 5 Gel electrophoresis and PCR sequencing of amplified IL36RN cdna fragments IL36RN c T > C 2. 24%

5 775 psoriasis J. Dermatology % 0. 37% IL36RN homozygous deletion of the IL1RN locus J. N Engl J Med c T > C DITRA Marrakchi S Guigue P Renshaw BR et al. Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis J. N Engl J Med 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 J. Am J Hum Genet Farooq M Nakai H Fujimoto A et al. Mutation analysis of the IL36RN gene in 14 japanese patients with generalized pustular psoriasis J. hum Mutat Setta-Kaffetzi N Navarini AA Patel VM et al. Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes J. J Invest Dermatol 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 6 Reddy S Jia S Geoffrey R et al. An autoinflammatory disease due to 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 J. Dermatology Friedman KJ Vollmer RT. Malignant melanoma and squamous cell carcinoma in a patient treated for severe pustular psoriasis J. J Dermatol Surg Oncol Pouplard C Brenaut E Horreau C et al. Risk of cancer in psoriasis a systematic review and meta-analysis of epidemiological studies J. J Eur Acad Dermatol Venereol Suppl Brewer JD Hoverson Schott AR Roenigk RK. Multiple squamous cell carcinomas in the setting of psoriasis treated with etanercept a report of four cases and review of the literature J. Int J Dermatol Piepkorn M Kumasaka B Krieger JN et al. Development of human papillomavirus-associated Buschke-L wenstein penile carcinoma during cyclosporine therapy for generalized pustular psoriasis J. J Am Acad Dermatol Pt HPV cm 0. 1cm HPV 0. 8cm 0. 6cm 1. M J J J. HPV HPV R B DOI /j. cjdv HE