IL36RN mutations define a severe autoinflammatory phenotype of generalized pustular psoriasis
2014; Elsevier BV; Volume: 135; Issue: 4 Linguagem: Inglês
10.1016/j.jaci.2014.09.043
ISSN1097-6825
AutoresSafia Hussain, Dorottya M. Berki, Siew Eng Choon, A. David Burden, Michael H. Allen, Juan I. Aróstegui, Antonio Chaves, Michael Duckworth, Alan D. Irvine, Maja Mockenhaupt, Alexander A. Navarini, Marieke M.B. Seyger, Pere Soler‐Palacín, Christa Prins, L. Valeyrie‐Allanore, María Asunción Vicente‐Villa, Richard C. Trembath, Catherine Smith, Juliet N. Barker, Francesca Capon,
Tópico(s)Asthma and respiratory diseases
ResumoAutoinflammatory diseases are a heterogeneous group of disorders mediated by abnormal activation of the innate immune system, resulting in recurrent episodes of systemic and organ-specific inflammation.1Aksentijevich I. Kastner D.L. Genetics of monogenic autoinflammatory diseases: past successes, future challenges.Nat Rev Rheumatol. 2011; 7: 469-478Crossref PubMed Scopus (86) Google Scholar In recent years, the pace of autoinflammatory disease gene discovery has undergone a dramatic acceleration with the emergence of novel autoinflammatory phenotypes, highlighting the need to establish reliable diagnostic criteria through the analysis of extended case series.1Aksentijevich I. Kastner D.L. Genetics of monogenic autoinflammatory diseases: past successes, future challenges.Nat Rev Rheumatol. 2011; 7: 469-478Crossref PubMed Scopus (86) Google Scholar Generalized pustular psoriasis (GPP) is a rare autoinflammatory condition presenting with recurrent episodes of skin pustulation that are often accompanied by systemic inflammation (acute-phase response with neutrophilia) and concurrent psoriasis vulgaris (PV).2Griffiths C.E.M. Barker J.N. Psoriasis.in: Burns T. Breathnach S. Cox N. Griffiths C.E.M. Rook's textbook of dermatology. Wiley-Blackwell, Chichester2010: 20.1-20.60Crossref Scopus (30) Google Scholar We and others demonstrated that a proportion of GPP cases carry recessive mutations of IL36RN, the gene encoding the IL-36 receptor antagonist.3Marrakchi S. Guigue P. Renshaw B.R. Puel A. Pei X.Y. Fraitag S. et al.Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.N Engl J Med. 2011; 365: 620-628Crossref PubMed Scopus (556) Google Scholar, 4Onoufriadis A. Simpson M.A. Pink A.E. Di Meglio P. Smith C.H. Pullabhatla V. 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: 432-437Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar This anti-inflammatory protein modulates the activity of IL-36 α, β, and γ, a group of IL-1 family cytokines that have repeatedly been shown to be overexpressed in psoriatic lesions. Importantly, studies of animal models and human primary cell cultures indicate that IL-36 molecules induce the activation of keratinocytes and antigen-presenting cells, thus propagating skin inflammation in patients with psoriasis.5Dietrich D. Gabay C. Inflammation: IL-36 has proinflammatory effects in skin but not in joints.Nat Rev Rheumatol. 2014; ([Epub ahead of print])Crossref Scopus (38) Google Scholar Although these discoveries have shed new light on the pathogenesis of GPP, the rarity of the disease has thus far hindered a robust definition of the symptoms associated with deficiency of IL-36 receptor antagonist (DITRA), so that reliable indications for IL36RN screening are still lacking. Here we sought to address this issue by ascertaining an extended patient resource. We examined 233 cases (see Table E1, Table E2, Table E3 in this article's Online Repository at www.jacionline.org) recruited in accordance with the principles of the Declaration of Helsinki and with ethical approval from the relevant committees of participating institutions. This data set originated from 3 sources: (1) 177 cases were ascertained through a systematic literature search based on the terms "IL36RN" and "generalized pustular psoriasis" (see Fig E1 in this article's Online Repository at www.jacionline.org); (2) 45 patients received diagnoses from the coauthors of this study, according to established criteria2Griffiths C.E.M. Barker J.N. Psoriasis.in: Burns T. Breathnach S. Cox N. Griffiths C.E.M. Rook's textbook of dermatology. Wiley-Blackwell, Chichester2010: 20.1-20.60Crossref Scopus (30) Google Scholar; and (3) 11 cases were initially ascertained by the International Registry of Severe Cutaneous Adverse Reaction Consortium. After an in-depth case review, the consortium expert committee proposed the presentation to be consistent with GPP. Thus the key inclusion criterion underlying the 3 ascertainment streams was a clinical diagnosis of GPP. The subsequent identification of patients with systemic flares was based on the criteria established by the American College of Chest Physicians (leukocytosis and fever >38°C).6Bone R.C. Balk R.A. Cerra F.B. Dellinger R.P. Fein A.M. Knaus W.A. et al.Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine.Chest. 1992; 101: 1644-1655Abstract Full Text Full Text PDF PubMed Scopus (7387) Google Scholar To delineate the phenotypic spectrum associated with DITRA, we first determined the frequency of IL36RN mutations in our cohort. We found that 49 (21.0%) of 233 cases carried recessive IL36RN alleles (see Table E1). Because information on age of onset, systemic involvement, and PV concurrence was available for 99.6%, 72.1%, and 86.7% of cases, we compared these features in patients bearing recessive IL36RN mutations (n = 49) and in those without pathogenic alleles at this locus (n = 166, see Table E1 and the Methods section in this article's Online Repository at www.jacionline.org). We found that IL36RN-positive subjects manifested a strikingly more severe clinical phenotype characterized by an earlier age of onset (17 ± 2.4 vs 33 ± 1.5 years, P = 5.9 × 10−7) and a markedly increased risk of systemic inflammation (83.3% vs 55.6%, P = 1.5 × 10−3; Fig 1, A and B). We also observed a very significant reduction in the prevalence of PV in the IL36RN-positive cohort (36.1% vs 68.7%, P = 5.0 × 10−4; Fig 1, C), validating the results of a small Japanese study.7Sugiura 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: 2514-2521Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar We previously reported 6 patients with GPP bearing single heterozygous IL36RN mutations.8Setta-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: 1366-1369Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar In keeping with this observation, we observed 18 cases (including the subjects we had originally described) with a single disease allele. To validate the significance of these findings, we compared the frequency of monoallelic IL36RN mutations in cases versus population-matched control subjects. We found that heterozygous disease alleles were consistently enriched among cases, with statistically significant P values (P < .02; false discovery rate < 0.05) observed in most ethnic groups (Table I). We also performed a meta-analysis of our case-control resources, which demonstrated that monoallelic IL36RN mutations confer a very substantial increase in disease risk (weighted pooled odds ratio, 7.32; 95% CI, 3.02-17.7; P = 1.1 × 10−5).Table IFrequency distribution of heterozygous IL36RN allelesOriginAllele counts (%)P valueORCasesControl subjectsBritish2/22 (9.1%)2/568 (0.3%).00828.3Chinese4/72 (5.6%)8/394 (2.0%).102.8Japanese3/66 (4.5%)0/178 (0%).01919.7Malay5/110 (4.5%)0/192 (0%).00620.1OR, Odds ratio. Open table in a new tab OR, Odds ratio. We next compared disease severity in subjects carrying 1 or 2 mutations. We focused our analysis on age of onset and systemic inflammation because PV concurrence is not considered a reliable indicator of GPP severity.2Griffiths C.E.M. Barker J.N. Psoriasis.in: Burns T. Breathnach S. Cox N. Griffiths C.E.M. Rook's textbook of dermatology. Wiley-Blackwell, Chichester2010: 20.1-20.60Crossref Scopus (30) Google Scholar We observed a high prevalence of systemic inflammation (>80%) in both patient groups (Fig 1, D), but we noted that the mean age of onset in IL36RN heterozygotes exceeded by 2-fold that of patients with biallelic mutations (36 ± 5.5 vs 17 ± 2.4; P = 6.0 × 10−4; Fig 1, E). The aim of our study was to investigate the correlation between IL36RN mutation status and the clinical presentation of GPP to aid the definition of diagnostic criteria for the stratification of patient cohorts. We found that IL36RN alleles define a GPP phenotype characterized by early onset, high risk of systemic inflammation, and low prevalence of PV. Of note, these conclusions were drawn by comparing the IL36RN-positive data set with a heterogeneous cohort that was solely defined by the lack of IL36RN mutations. As further disease genes are identified and systematically genotyped, the designation of more homogeneous patient subgroups will become possible, allowing the development of formal diagnostic algorithms. We recognize that our study design, which combined the analysis of newly recruited cases with a literature review, might have been vulnerable to ascertainment bias. However, we note there was no significant variability in the frequency of IL36RN mutations across data sets (see Table E4 in this article's Online Repository at www.jacionline.org), indicating that our inclusion criteria were sufficiently robust to allow the ascertainment of a reasonably homogeneous resource. Our analysis demonstrated a gene dosage effect whereby GPP onset is significantly delayed in subjects with monoallelic mutations. Intriguingly, we found that these subjects were still at high risk of systemic inflammation. Thus heterozygous patients might require a longer or more intense exposure to environmental triggers to manifest overt disease. Once an abnormal immune response is initiated, however, the presence of a wild-type IL36RN allele does not appear sufficient to prevent the onset of systemic inflammation. This suggests that abnormal cytokine signaling might be propagated by molecules acting downstream of IL36RN. Further ex vivo analyses will be required to validate this model and define the cytokines that sustain abnormal inflammatory responses in patients with GPP. In conclusion, we have defined a clinical triad (early onset, systemic inflammation, and absence of concurrent PV) that could be used to prioritize patients with GPP for IL36RN screening. Importantly, pilot studies indicate that a proportion of patients with IL36RN mutations could be treated with the IL-1 antagonist anakinra.9Rossi-Semerano L. Piram M. Chiaverini C. De Ricaud D. Smahi A. Koné-Paut I. First clinical description of an infant with interleukin-36-receptor antagonist deficiency (DITRA) successfully treated with interleukin-1-receptor antagonist anakinra.Pediatrics. 2013; 132: e1043-e1047Crossref PubMed Scopus (0) Google Scholar, 10Tauber M. Viguier M. Le Gall C. Smahi A. Bachelez H. Is it relevant to use an interleukin-1-inhibiting strategy for the treatment of patients with deficiency of interleukin-36 receptor antagonist?.Br J Dermatol. 2014; 170: 1198-1199Crossref PubMed Scopus (21) Google Scholar Therapeutic agents that specifically target the IL-36 receptor are also being developed.11Wolf J. Ferris L.K. Anti-IL-36R antibodies, potentially useful for the treatment of psoriasis: a patent evaluation of WO2013074569.Expert Opin Ther Pat. 2014; 24: 477-479Crossref PubMed Scopus (16) Google Scholar Thus our work is expected to facilitate the identification of patients who might benefit from personalized treatment with IL-1 or IL-36 blockers. The IL36RN coding region was screened by using primers and conditions reported elsewhere.E1Onoufriadis A. Simpson M.A. Pink A.E. Di Meglio P. Smith C.H. Pullabhatla V. 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: 432-437Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar In those instances in which Sanger sequencing uncovered a single disease allele, the possibility that the second mutation might be accounted for by the insertion/deletion of an entire exon was excluded by amplifying the entire IL36RN gene region, as previously described.E2Setta-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: 1366-1369Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar Nucleotide changes were considered deleterious if (1) experimentally derived evidence was available in the literature or (2) a high-confidence pathogenicity prediction was returned by using at least 4 of the following programs: SIFT,E3Kumar P. Henikoff S. Ng P.C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm.Nat Protoc. 2009; 4: 1073-1081Crossref PubMed Scopus (4848) Google Scholar PolyPhen-2,E4Adzhubei I. Jordan D.M. Sunyaev S.R. Predicting functional effect of human missense mutations using PolyPhen-2.Curr Protoc Hum Genet. 2013; Chapter 7 (Unit 7.20)Crossref PubMed Scopus (1922) Google Scholar Provean,E5Choi Y. Sims G.E. Murphy S. Miller J.R. Chan A.P. Predicting the functional effect of amino acid substitutions and indels.PLoS One. 2012; 7: e46688Crossref PubMed Scopus (1823) Google Scholar MutPred,E6Li B. Krishnan V.G. Mort M.E. Xin F. Kamati K.K. Cooper D.N. et al.Automated inference of molecular mechanisms of disease from amino acid substitutions.Bioinformatics. 2009; 25: 2744-2750Crossref PubMed Scopus (571) Google Scholar and MutationTaster.E7Schwarz J.M. Rodelsperger C. Schuelke M. Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations.Nat Methods. 2010; 7: 575-576Crossref PubMed Scopus (2042) Google Scholar The sequence of the IL36RN transcript ENST00000393200 was used as a reference in all bioinformatics analyses. Differences in the frequency distribution of dichotomous clinical findings (presence/absence of PV or systemic inflammation) and mean ages of disease onset were assessed with the Fisher exact test and Student unpaired t test, respectively. Both were implemented with the online tools available at http://graphpad.com/quickcalcs/. The combined frequency of heterozygous IL36RN alleles was compared in cases versus control subjects by using the Fisher exact test. Control allele frequencies were determined in the following resources: 284 British subjects sequenced by the 1000 Genomes Project (n = 89) and TwinsUK (n = 195), 89 Japanese and 197 Han Chinese subjects sequenced by the 1000 Genomes Project, and 96 subjects sequenced by the Singapore Sequencing Malay Project.E10Wong L.P. Ong R.T. Poh W.T. Liu X. Chen P. Li R. et al.Deep whole-genome sequencing of 100 southeast Asian Malays.Am J Hum Genet. 2013; 92: 52-66Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, E8Abecasis G.R. Auton A. Brooks L.D. DePristo M.A. Durbin R.M. Handsaker R.E. et al.An integrated map of genetic variation from 1,092 human genomes.Nature. 2012; 491: 56-65Crossref PubMed Scopus (5546) Google Scholar, E9Williams F.M. Scollen S. Cao D. Memari Y. Hyde C.L. Zhang B. et al.Genes contributing to pain sensitivity in the normal population: an exome sequencing study.PLoS Genet. 2012; 8: e1003095Crossref PubMed Scopus (46) Google Scholar The meta-analysis of multiple case-control data sets was implemented with Review Manager 5.2.E11Review Manager (RevMan). The Nordic Cochrane Centre, the Cochrane Collaboration, Copenhagen2012Google Scholar P values of less than .05 were deemed statistically significant.Table E1Study cohort summary statisticsSexEthnicityIL36RN mutation countMaleFemaleEuropeanAsianAfrican012Patients, no. (%)92/233 (39.5%)141/233 (60.5%)49/233 (21.0%)172/233 (73.8%)12/233 (5.2%)166/233 (71.3%)18/233 (7.7%)49/233 (21.0%) Open table in a new tab Table E2Clinical presentation of GPP in cases bearing IL36RN mutationsStudyStudy no.OriginSexAge of onset (y)IL36RN mutations∗The details of subjects bearing a single disease allele are shown in boldface.PVFever (>38°C)LeukocytosisSystemic inflammationMarrakchi et al, 2011E12Marrakchi S. Guigue P. Renshaw B.R. Puel A. Pei X.Y. Fraitag S. et al.Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.N Engl J Med. 2011; 365: 620-628Crossref PubMed Scopus (668) Google ScholarV.4TunisianM2p.Leu27Prop.Leu27ProUnknownYYYIV.2TunisianF0 (1 wk)p.Leu27Prop.Leu27ProYYYYV.2TunisianM4p.Leu27Prop.Leu27ProUnknownYYYV.3TunisianM0 (2 mo)p.Leu27Prop.Leu27ProUnknownYYYII.1TunisianM5p.Leu27Prop.Leu27ProUnknownYYYV.1TunisianF0 (2 wk)p.Leu27Prop.Leu27ProYYYYIV.1TunisianF25p.Leu27Prop.Leu27ProUnknownYYYV.4TunisianF20p.Leu27Prop.Leu27ProUnknownYYYV.1TunisianF22p.Leu27Prop.Leu27ProUnknownYYYOnoufriadis et al, 2011E1Onoufriadis A. Simpson M.A. Pink A.E. Di Meglio P. Smith C.H. Pullabhatla V. 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: 432-437Abstract Full Text Full Text PDF PubMed Scopus (373) Google ScholarGPP-01 II:5BritishF51p.Ser113Leup.Ser113LeuNYYYGPP-02 II:1BritishM5p.Ser113Leup.Ser113LeuNYYYGPP-03 II:2BritishF7p.Ser113Leup.Arg48TrpNYYYFarooq et al, 2013E13Farooq M. Nakai H. Fujimoto A. Fujikawa H. Matsuyama A. Kariya N. et al.Mutation analysis of the IL36RN gene in 14 Japanese patients with generalized pustular psoriasis.Hum Mutat. 2013; 34: 176-183Crossref PubMed Scopus (101) Google ScholarJPP12JapaneseF51p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1p.Thr123ArgNYYYJPP14JapaneseM16p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1p.Arg10XYYYYLi et al, 2013E14Li M. Lu Z. Cheng R. Li H. Guo Y. Yao Z. IL36RN gene mutations are not associated with sporadic generalized pustular psoriasis in Chinese patients.Br J Dermatol. 2013; 168: 426-460Crossref PubMed Scopus (7) Google ScholarPatient 3ChineseF8p.Pro76Leu—NYYYSetta-Kaffetzi et al, 2013E2Setta-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: 1366-1369Abstract Full Text Full Text PDF PubMed Scopus (125) Google ScholarGLA-IBritishM29p.Ser113Leu—NYYYGLA-IIBritishM26p.Ser113Leup.Ser113LeuNYYYGLA-IIIBritishM39p.Ser113Leu—NYYYMAL-IMalayF37p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1YNNNMAL-IIChineseF21p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1YYYYMAL-IIIMalayF9p.Arg10Argfs*The details of subjects bearing a single disease allele are shown in boldface.1—NYYYMAL-IVMalayM42p.Arg10Argfs*The details of subjects bearing a single disease allele are shown in boldface.1—YYYYMAL-VMalayF12p.Arg10Argfs*The details of subjects bearing a single disease allele are shown in boldface.1—YYNNMAL-VIChineseM12p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1NYUnknownUnknownMAL-VIIMalayM8p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1p.Ser113LeuYYYYMAL-VIIIMalayF2p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1YYYYMAL-IXChineseF40p.Arg10Argfs*The details of subjects bearing a single disease allele are shown in boldface.1—YNYNMAL-XChineseM12p.Arg10Argfs*The details of subjects bearing a single disease allele are shown in boldface.1—YNNNP01TurkishM0 (4 mo)p.Pro76Leup.Pro76LeuNUnknownUnknownUnknownP02German/IraqiF1p.Ser113Leup.Ser113LeuNUnknownUnknownUnknownKörber et al, 2013E15Körber A. Mössner R. Renner R. Sticht H. Wilsmann-Theis D. Schulz P. et al.Mutations in IL36RN in patients with generalized pustular psoriasis.J Invest Dermatol. 2013; 133: 2634-2637Abstract Full Text Full Text PDF PubMed Scopus (78) Google ScholarP04GermanF16p.Glu94Xp.Ser113LeuNUnknownUnknownUnknownP05German/PolishF17p.Ser113Leup.Ser113LeuNNUnknownNP06GermanF40p.Arg48Trpp.Ser113LeuYYYYP07German/CzechF0 (4 mo)p.Pro76Leup.Ser113LeuNUnknownUnknownUnknownP08GermanM55p.Ser113Leu—YUnknownUnknownUnknownSugiura et al, 2013E16Sugiura 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: 2514-2521Abstract Full Text Full Text PDF PubMed Scopus (211) Google ScholarPatient 1JapaneseM34p.Arg10Xp.Arg10XNYYYPatient 2JapaneseM2p.Arg10Xp.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1NYYYPatient 4JapaneseF5p.Arg10Xp.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1NYYYPatient 5JapaneseF65p.Arg10Xp.Arg10XNYYYPatient 6JapaneseF40p.Arg10Xp.Arg10XNYYYPatient 7JapaneseF21p.Arg10Xp.Arg10XNYYYPatient 8JapaneseM6p.Arg10Xp.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1NYYYPatient 9JapaneseM8p.Arg10Xp.Arg10XNYYYPatient 25JapaneseF20p.Arg10Xp.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1YYYYPatient 29JapaneseM50p.Arg10X—YYYYKanazawa et al, 2013E17Kanazawa N. Nakamura T. Mikita N. Furukawa F. Novel IL36RN mutation in a Japanese case of early onset generalized pustular psoriasis.J Dermatol. 2013; 40: 749-751Crossref PubMed Scopus (62) Google Scholar—JapaneseM3p.Arg10Xp.Thr123MetYYUnknownUnknownRossi-Semerano et al, 2013E18Rossi-Semerano L. Piram M. Chiaverini C. De Ricaud D. Smahi A. Koné-Paut I. First clinical description of an infant with interleukin-36-receptor antagonist deficiency successfully treated with anakinra.Pediatrics. 2013; 132: e1043-e1047Crossref PubMed Scopus (80) Google Scholar—TunisianM0 (2 wk)p.Leu27Prop.Leu27ProUnknownNYNAbbas et al, 2013E18Rossi-Semerano L. Piram M. Chiaverini C. De Ricaud D. Smahi A. Koné-Paut I. First clinical description of an infant with interleukin-36-receptor antagonist deficiency successfully treated with anakinra.Pediatrics. 2013; 132: e1043-e1047Crossref PubMed Scopus (80) Google Scholar—LebaneseF21p.Ser113Leup.Ser113LeuUnknownYYYSugiura et al, 2014E20Sugiura K. Oiso N. Iinuma S. Matsuda H. Minami-Hori M. Ishida-Yamamoto A. et al.il36rn mutations underlie impetigo herpetiformis.J Invest Dermatol. 2014; 9: 1-12Google ScholarCase 1JapaneseF23p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1UnknownYNNCase 2JapaneseF8p.Arg10X—UnknownYYYRenert-Yuval et al, 2014E21Renert-Yuval Y. Horev L. Babay S. Tams S. Ramot Y. Zlotogorski A. et al.IL36RN mutation causing generalized pustular psoriasis in a Palestinian patient.Int J Dermatol. 2014; 53: 866-868Crossref PubMed Scopus (13) Google Scholar—PalestinianM0 (1 mo)p.Arg10Xp.Arg10XNYYYSugiura et al, 2014E22Sugiura K. Endo K. Akasaka T. Akiyama M. Successful treatment with infliximab of sibling cases with generalized pustular psoriasis caused by deficiency of interleukin-36 receptor antagonist.J Eur Acad Dermatol Venereol. 2014; 9: 1-2Google ScholarPatient 3JapaneseM6p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1NYYYPatient 4JapaneseF53p.Arg10Argfs*The details of subjects bearing a single disease allele are shown in boldface.1—YUnknownUnknownUnknownSong et al, 2014E23Song H.S. Yun S.J. Park S. Lee E.S. Gene mutation analysis in a Korean patient with early-onset and recalcitrant generalized pustular psoriasis.Ann Dermatol. 2014; 26: 424-425Crossref PubMed Scopus (9) Google Scholar—KoreanF4p.Arg10Argfs*The details of subjects bearing a single disease allele are shown in boldface.1—UnknownYYYThis study—SwissM40p.Ser113Leup.Ser113LeuNYYY78GPP1MalayF57p.Arg10Argfs*The details of subjects bearing a single disease allele are shown in boldface.1—YYYY82GPP1MalayF19p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1YYNN89GPP1MalayF40p.Arg10Argfs*The details of subjects bearing a single disease allele are shown in boldface.1—YYYY96GPP1ChineseF7p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1YYUnknownUnknown101GPP1ChineseF30p.Arg10Argfs*The details of subjects bearing a single disease allele are shown in boldface.1—NYYY103GPP1ChineseM5p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1p.Arg10Argfs∗The details of subjects bearing a single disease allele are shown in boldface.1NNNNSCAR1646GermanF43p.Ser113Leup.Ser113LeuUnknownYYYSCAR1690GermanF68p.Ser113Leu—UnknownYYYSCAR2074GermanF53p.Ser113Leup.Ser113LeuUnknownNYNSCAR2548PolishM84p.Ser113Leu—NYYY—AlgerianM0 (5 mo)p.Leu27Prop.Leu27ProYYYY—SpanishF0 (6 mo)p.Gly141Metfs∗The details of subjects bearing a single disease allele are shown in boldface.29p.Gly141Metfs∗The details of subjects bearing a single disease allele are shown in boldface.29UnknownYYYF, Female; M, male.∗ The details of subjects bearing a single disease allele are shown in boldface. Open table in a new tab Table E3Clinical presentation of GPP in patients who do not harbor IL36RN mutationsStudyStudy mo.OriginSexAge of onset (y)Psoriasis vulgarisFever (>38°C)LeukocytosisSystemic inflammationOnoufriadis et al, 2011E1Onoufriadis A. Simpson M.A. Pink A.E. Di Meglio P. Smith C.H. Pullabhatla V. 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: 432-437Abstract Full Text Full Text PDF PubMed Scopus (373) Google ScholarGPP-04 I:1BritishF10NYYYGPP-05 I:1BritishF45NNNNFarooq et al, 2013E13Farooq M. Nakai H. Fujimoto A. Fujikawa H. Matsuyama A. Kariya N. et al.Mutation analysis of the IL36RN gene in 14 Japanese patients with generalized pustular psoriasis.Hum Mutat. 2013; 34: 176-183Crossref PubMed Scopus (101) Google ScholarJPP1JapaneseM74NYNNJPP2JapaneseM72YYNNJPP3JapaneseM72YYYYJPP4JapaneseM20YNNNJPP5JapaneseM45NYYYJPP6JapaneseF43NYYYJPP7JapaneseF73NYYYJPP8JapaneseM42NYYYJPP9JapaneseF58NYYYJPP10JapaneseM36YYYYJPP11JapaneseM48NYYYJPP13JapaneseF17NNNNLi et al, 2013E14Li M. Lu Z. Cheng R. Li H. Guo Y. Yao Z. IL36RN gene mutations are not associated with sporadic generalized pustular psoriasis in Chinese patients.Br J Dermatol. 2013; 168: 426-460Crossref PubMed Scopus (7) Google ScholarPatient 1ChineseM16NNUnknownNPatient 2ChineseM1.5NYNNPatient 4ChineseM2.5NYNNPatient 5ChineseF8NYNNPatient 6ChineseM3NYNNPatient 7ChineseM0 (4 mo)NYNNPatient 8ChineseM6YYNNPatient 9ChineseF5NYNNPatient 10ChineseF9NYNNSetta-Kaffetzi et al, 2013E2Setta-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: 1366-1369Abstract Full Text Full Text PDF PubMed Scopus (125) Google ScholarT009361BritishF45NUnknownUnknownUnknown10167Dutch-RomaniF9YYYY20368Dutch–North AfricanUnknown6YNYN20299Dutch-HispanicM2YNUnknownN2GPP1IndianM28YYYY3GPP1IndianF24YYYY4GPP1MalayF44YUnknownYUnknown5GPP1MalayM26YYYY6GPP1MalayF24YUnknownYUnknown7GPP1ChineseF29YYYY8GPP1ChineseF30YUnknownYUnknown9GPP1MalayF45YYYY10GPP1MalayM36YUnknownYUnknown11GPP1MalayM21YYYY12GPP1IndianF28YUnknownYUnknown13GPP1ChineseF30YNYN14GPP1ChineseF25YYYY16GPP1ChineseF25YYYY17GPP1IndianF2YYYY18GPP1MalayM28YNNN19GPP1MalayM30NNNN20GPP1ChineseF46YNYN21GPP1MalayF46YYYY22GPP1ChineseM38YYNN23GPP1MalayF31YYYY24GPP1MalayF38YYYY25GPP1MalayF42YYUnknownUnknown26GPP1MalayF31YYYY28GPP1MalayF5YYNN29GPP1Chinese/IndianF24YNNN30GPP1MalayF37NYYY31GPP1MalayM4YNYN32GPP1MalayF55NYYY33GPP1IndianF59NUnknownYUnknown36GPP1ChineseF30NUnknownYUnknown37GPP1MalayF56YYYY38GPP1MalayM27YYYY39GPP1IndianF15YNNN41GPP1MalayF52YNNN42GPP1MalayM15YNNN43GPP1MalayM42YYYY45GPP1ChineseM41YYYY46GPP1MalayM34YYUnknownUnknown47GPP1ChineseF17YYYY48GPP1IndianF37YUnknownYUnknown49GPP1MalayF26YUnknownYUnknown51GPP1MalayF14YNNN52GPP1MalayM25YYYY53GPP1ChineseF30YNNN54GPP1MalayF29YYNN56GPP1MalayF12NYNN57GPP1MalayM30NYYY58GPP1MalayF23YYYY59GPP1MalayF17YYYY60GPP1ChineseM63NYYY61GPP1MalayF48YYYY62GPP1MalayM43YYYY63GPP1MalayF43NUnknownYUnknown65GPP1MalayM6YUnknownYUnknown66GPP1ChineseF28YYYY67GPP1IndianM29YYYY68GPP1MalayF31YNNN69GPP1MalayF12YYYY70GPP1ChineseM23YNNN71GPP1MalayF54YUnknownYUnknown72GPP1MalayF30NYYY73GPP1MalayF20YYYY75GPP1IndianF42NNNN76GPP1IndianF26NNNN77GPP1MalayF38YYYYKörber et al, 2013E15Körber A. Mössner R. Renner R. Sticht H. Wilsmann-Theis D. Schulz P. et al.Mutations in IL36RN in patients with generalized pustular psoriasis.J Invest Dermatol. 2013; 133: 2634-2637Abstract Full Text Full Text PDF PubMed Scopus (78) Google ScholarP03IraqiM14NUnknownUnknownUnknownP09GermanF3NUnknownUnknownUnknownP10TurkishF5NUnknownUnknownUnknownP11GermanF9YUnknownUnknownUnknownP12German/PolishF16YUnknownUnknownUnknownP13GermanM17NUnknownUnknownUnknownP14GermanF27NUnknownUnknownUnknownP15GermanF41YNUnknownNP16GermanM45NUnknownUnknownUnknownP17German/FinnishF49NUnknownUnknownUnknownP18GermanF69NUnknownUnknownUnknownP19GermanM72YUnknownUnknownUnknownSugiura et al, 2013E16Sugiura 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: 2514-2521Abstract Full Text Full Text PDF PubMed Scopus (211) Google ScholarPatient 11JapaneseM2NYYYPatient 12JapaneseF9YYYYPatient 13JapaneseF15YYYYPatient 14JapaneseF75YYYYPatient 15JapaneseF58YYYYPatient 16JapaneseM45YYYYPatient 17JapaneseF32YYYYPatient 18JapaneseF27YYYYPatient 19JapaneseM22YYYYPatient 20JapaneseM59YYYYPatient 21JapaneseF72YYYYPatient 22JapaneseM28YYYYPatient 23JapaneseM20YYYYPatient 26JapaneseF42YYYYPatient 27JapaneseM59YYYYPatient 28JapaneseM78YYYYPatient 30JapaneseM24YYYYPatient 31JapaneseM38YYYYThis studyT002229BritishF19YUnknownYUnknownT003673BritishF29YUnknownYUnknownT009359BritishF49NNNNT009360BritishF40NUnknownUnknownUnknown81GPP1ChineseF13YNNN83GPP1IndianM23YNNN84GPP1MalayM41YYYY85GPP1MalayF54NYNN86GPP1MalayM34YYYY87GPP1MalayF15YNNN88GPP1IndianM27YYUnknownUnknown90GPP1IndianF36YUnknownYUnknown91GPP1MalayM10NUnknownYUnknown92GPP1ChineseM30YNNN93GPP1ChineseF61YYNN94GPP1MalayF49YNNN95GPP1ChineseM20YNNN97GPP1MalayM7YYUnknownUnknown98GPP1MalayF5YYNN99GPP1IndianF26YUnknownYUnknown100GPP1ChineseF25YNNN102GPP1IndianF51YUnknownNN104GPP1MalayF21YYYY105GPP1ChineseF57NUnknownYUnknown106GPP1IndianF62YNNN107GPP1ChineseM67NYYY108GPP1ChineseM38YUnknownYUnknown109GPP1ChineseM68YNNN110GPP1IndianF16YUnknownYUnknown111GPP1MalayF23NNNNT018712EthiopianF22NUnknownYUnknownT011497IndianF31YUnknownUnknownUnknownT002189BritishFUnknownYUnknownUnknownUnknownT023653British/IrishM15YYYYT025165PolishF0 (4 mo)YNNNT024653BangladeshiM9YYYYSCAR659ItalianF75YYYYSCAR673ItalianF69NNYNSCAR1789GermanF58NNYNSCAR1798GermanF47YNYNSCAR2082GermanM46YYYYSCAR2479GermanF70NYYYSCAR2540Sri LankanF41NNYNF, Female; M, male. Open table in a new tab Table E4IL36RN mutation frequencies across patient cohorts∗Frequencies were only calculated in data sets that included more than 10 patients.StudyCases with ≥1 IL36RN mutation (%)Farooq et al, 2012E13Farooq M. Nakai H. Fujimoto A. Fujikawa H. Matsuyama A. Kariya N. et al.Mutation analysis of the IL36RN gene in 14 Japanese patients with generalized pustular psoriasis.Hum Mutat. 2013; 34: 176-183Crossref PubMed Scopus (101) Google Scholar2/14 (14.3%)Sugiura et al, 2013E16Sugiura 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: 2514-2521Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar10/28 (35.7%)Setta-Kaffetzi et al, 2013E2Setta-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: 1366-1369Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar13/84 (15.5%)Körber et al, 2013E15Körber A. Mössner R. Renner R. Sticht H. Wilsmann-Theis D. Schulz P. et al.Mutations in IL36RN in patients with generalized pustular psoriasis.J Invest Dermatol. 2013; 133: 2634-2637Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar7/19 (36.8%)This study13/56 (23.2%)Significance of frequency variationP = .22∗ Frequencies were only calculated in data sets that included more than 10 patients. Open table in a new tab F, Female; M, male. F, Female; M, male.
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