Abstract
19 min readPalmoplantar pustulosis (PPP) is a severe pustular eruption that affects the palms and/or soles, with detrimental effects on quality of life. The disease is notoriously difficult to treat because its immune and genetic determinants remain poorly defined (Twelves et al., 2019Twelves S. Mostafa A. Dand N. Burri E. Farkas K. Wilson R. et al.Clinical and genetic differences between pustular psoriasis subtypes.J Allergy Clin Immunol. 2019; 143: 1021-1026Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar). Although mutations of the IL36RN and myeloperoxidase MPO genes have been convincingly associated with generalized pustular psoriasis, they are rarely found in patients with PPP (Haskamp et al., 2020Haskamp S. Bruns H. Hahn M. Hoffmann M. Gregor A. Löhr S. et al.Myeloperoxidase modulates inflammation in generalized pustular psoriasis and additional rare pustular skin diseases.Am J Hum Genet. 2020; 107: 527-538Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar; Twelves et al., 2019Twelves S. Mostafa A. Dand N. Burri E. Farkas K. Wilson R. et al.Clinical and genetic differences between pustular psoriasis subtypes.J Allergy Clin Immunol. 2019; 143: 1021-1026Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar; Vergnano et al., 2020Vergnano M. Mockenhaupt M. Benzian-Olsson N. Paulmann M. Grys K. Mahil S.K. et al.Loss-of-function myeloperoxidase mutations are associated with increased neutrophil counts and pustular skin disease.Am J Hum Genet. 2020; 107 ([published correction appears in Am J Hum Genet 2021;108:757]): 539-543Abstract Full Text Full Text PDF PubMed Google Scholar). Further candidate genes therefore need to be examined. CARD14 encodes a keratinocyte scaffold protein that mediates NF-κB signaling downstream of TRAF2 and TRAF6. Activating CARD14 mutations have been documented in a variety of inflammatory skin disorders, including familial psoriasis, erythrodermic psoriasis, generalized pustular psoriasis, pityriasis rubra pilaris, and CARD14-associated papulosquamous eruption (Berki et al., 2015Berki D.M. Liu L. Choon S.E. David Burden A. Griffiths C.E.M. Navarini A.A. et al.Activating CARD14 mutations are associated with generalized pustular psoriasis but rarely account for familial recurrence in psoriasis vulgaris.J Invest Dermatol. 2015; 135: 2964-2970Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar; Fuchs-Telem et al., 2012Fuchs-Telem D. Sarig O. van Steensel M.A. Isakov O. Israeli S. Nousbeck J. et al.Familial Pityriasis rubra pilaris is caused by mutations in CARD14.Am J Hum Genet. 2012; 91: 163-170Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar; Jordan et al., 2012bJordan C.T. Cao L. Roberson E.D. Pierson K.C. Yang C.F. Joyce C.E. et al.PSORS2 is due to mutations in CARD14.Am J Hum Genet. 2012; 90: 784-795Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar; Nieto-Benito et al., 2020Nieto-Benito L.M. Baniandrés-Rodríguez O. Moreno-Torres A. Hernández-Martín A. Torrelo-Fernández A. Campos-Domínguez M. Clinical response to ustekinumab in CARD14-associated papulosquamous eruption (CAPE) with a new missense mutation in CARD14: a case report and systematic review.J Eur Acad Dermatol Venereol. 2020; 34: e728-e730Crossref PubMed Scopus (8) Google Scholar; Signa et al., 2019Signa S. Campione E. Rusmini M. Chiesa S. Grossi A. Omenetti A. et al.Whole exome sequencing approach to childhood onset familial erythrodermic psoriasis unravels a novel mutation of CARD14 requiring unusual high doses of ustekinumab.Pediatr Rheumatol Online J. 2019; 17: 38Crossref PubMed Scopus (15) Google Scholar). More recently, loss-of-function CARD14 alleles have been observed in a small number of patients with severe atopic dermatitis, further extending the spectrum of CARD14-associated diseases (Peled et al., 2019Peled A. Sarig O. Sun G. Samuelov L. Ma C.A. Zhang Y. et al.Loss-of-function mutations in caspase recruitment domain-containing protein 14 (CARD14) are associated with a severe variant of atopic dermatitis.J Allergy Clin Immunol. 2019; 143: 173-181.e10Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). In this study, we investigated the possibility that CARD14 variants might also be associated with PPP. We examined 236 unrelated cases of European descent, recruited through United Kingdom dermatology departments participating in the APRICOT clinical trial (approved by the London Dulwich Research Ethics Committee; reference 16/LO/0436 [Cro et al., 2021Cro S. Cornelius V.R. Pink A.E. Wilson R. Pushpa-Rajah A. Patel P. et al.Anakinra for palmoplantar pustulosis: results from a randomized, double-blind, multicentre, two-staged, adaptive placebo-controlled trial (APRICOT).Br J Dermatol. 2021; 186: 245-256Crossref PubMed Scopus (13) Google Scholar]) or its sister research study PLUM (approved by the London Bridge Research Ethics Committee; reference 16/LO/2190) (Supplementary Table S1). PPP was diagnosed by dermatologists in line with the consensus criteria set by the European Rare And Severe Psoriasis Expert Network (Navarini et al., 2017Navarini A.A. Burden A.D. Capon F. Mrowietz U. Puig L. Köks S. et al.European consensus statement on phenotypes of pustular psoriasis.J Eur Acad Dermatol Venereol. 2017; 31: 1792-1799Crossref PubMed Scopus (235) Google Scholar). The study was undertaken in accordance with the declaration of Helsinki, and all participants granted their written informed consent. CARD14 variants were identified by querying whole-exome sequence profiles generated on an Illumina HiSeq2000 instrument (n = 212) or by Sanger sequencing the gene coding region and exon/intron junctions (n = 24). Rare changes (minor allele frequency < 1%) were assessed using three independent algorithms (see Supplementary Materials and Methods), and those that were classified as damaging by at least two predictors were considered potentially pathogenic. This approach identified eight deleterious variants, affecting 12 unrelated individuals (Table 1). Meanwhile, an analysis of 62,222 controls (non-Finnish European dataset) sequenced by the gnomAD consortium identified 1,123 rare alleles that met the same pathogenicity criteria. Fisher’s exact test showed that the CARD14 mutational burden was significantly different in the two groups (2.5 vs. 0.9%; P = 1.5 × 10‒3; OR = 2.9, 95% confidence interval = 1.5‒5.1), showing an association between rare CARD14 alleles and PPP. Importantly, the frequency of rare and synonymous CARD14 changes was comparable in cases and controls (P > 0.05), showing that there were no systematic differences between our patient population and the external control dataset.Table 1Rare- and Low-Frequency CARD14 Variants Detected in PPP CasesRs NumberAmino Acid SubstitutionMinor Allele Frequency1Frequency among non-Finnish Europeans, gnomAD 2.1.1.Pathogenicity PredictionsOccurrencesCADD Score2Variants with CADD scores > 15 are considered deleterious.PROVEANMutationTasterSplicemanConsensusrs143747620p.Lys78Asn0.000425.0NeutralPolymorphism—Benign1—p.Ile86Met—17.7NeutralPolymorphism—Benign1rs372403419p.Arg182Cys0.0000922.7NeutralDisease causing—Deleterious1rs200790561p.Glu197Lys0.000727.3DeleteriousDisease causing—Deleterious1rs375882704p.Ala367Thr0.0000924.0NeutralPolymorphism—Benign1rs150536049p.Ser378Arg0.00214.8DeleteriousPolymorphism—Benign1rs780034490p.Ser384Phe0.00000923.3DeleteriousPolymorphism—Deleterious2rs200102454p.Thr591Met0.0000824.3NeutralDisease causing—Deleterious1rs73429414p.Arg597Trp0.0000725.8NeutralDisease causing—Deleterious1rs371910172p.Arg610Cys0.0000324.7NeutralDisease causing—Deleterious1rs138833596p.Val774Ile0.000116.9NeutralDisease causing—Deleterious1rs2289541p.Arg883His0.00028.1NeutralPolymorphism—Benign1rs146678380c.2569+4T>C0.0033.0—Disease causingDeleteriousDeleterious4rs61751629p.Glu422Lys0.03314.8NeutralPolymorphism—Benign25rs117918077p.Arg682Trp0.01635.0DeleteriousDisease causing—Deleterious13Low-frequency variants are reported in the two bottom rows. We reported the p.Arg182Cys and p.Thr591Met deleterious alleles in a previous study (Twelves et al., 2019Twelves S. Mostafa A. Dand N. Burri E. Farkas K. Wilson R. et al.Clinical and genetic differences between pustular psoriasis subtypes.J Allergy Clin Immunol. 2019; 143: 1021-1026Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar).Abbreviations: CADD, Combined Annotation Dependent Depletion; PPP, palmoplantar pustulosis.1 Frequency among non-Finnish Europeans, gnomAD 2.1.1.2 Variants with CADD scores > 15 are considered deleterious. Open table in a new tab Low-frequency variants are reported in the two bottom rows. We reported the p.Arg182Cys and p.Thr591Met deleterious alleles in a previous study (Twelves et al., 2019Twelves S. Mostafa A. Dand N. Burri E. Farkas K. Wilson R. et al.Clinical and genetic differences between pustular psoriasis subtypes.J Allergy Clin Immunol. 2019; 143: 1021-1026Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar). Abbreviations: CADD, Combined Annotation Dependent Depletion; PPP, palmoplantar pustulosis. We next examined low-frequency CARD14 variants, identifying multiple occurrences of a known p.Arg682Trp substitution (Jordan et al., 2012aJordan C.T. Cao L. Roberson E.D. Duan S. Helms C.A. Nair R.P. et al.Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.Am J Hum Genet. 2012; 90: 796-808Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar) (Table 1). This change was also more common in cases than in controls (2.7 vs. 1.6%; P = 0.044; OR = 1.7; 95% confidence interval = 1.0‒3.0). Although our dataset was not powered for subgroup analysis, we found that CARD14 mutations were not restricted to a particular demographic (i.e., females or smokers) and were detectable regardless of plaque psoriasis affection status (Supplementary Table S2). Of note, this argues against the suggestion that PPP presenting with concurrent psoriasis might have a distinct genetic etiology (Murakami and Terui, 2020Murakami M. Terui T. Palmoplantar pustulosis: current understanding of disease definition and pathomechanism.J Dermatol Sci. 2020; 98: 13-19Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). To better understand the significance of our association findings, we compared the location of the rare damaging changes detected in PPP cases with that of known CARD14 mutations. We first carried out a systematic literature review, which identified 61 CARD14 genetic studies (Supplementary Figure S1), reporting a total of 65 rare variants. We then assessed the deleterious potential of each change on the basis of their predicted pathogenicity, recurrence, and segregation (see Supplementary Materials and Methods). This identified 18 variants that were likely to be deleterious (Supplementary Table S3). Strikingly, all damaging missense alleles clustered to two specific gene regions (Supplementary Figure S2). The gain-of-function mutations described in familial psoriasis, generalized pustular psoriasis, pityriasis rubra pilaris, and CARD14-associated papulosquamous eruption mapped between amino acids 117 and 197, affecting the CARD14 coiled‒coil and the preceding linker region. Conversely, the recurrent loss-of-function allele documented in atopic dermatitis lies within the PDZ domain (residue 593). Interestingly, the damaging missense changes detected in PPP cases were found in both mutation hot spots. Three variants (p.Arg182Cys, p.Glu197Lys, and p.Ser384Phe) localized to the coiled‒coil and three to the PDZ domain (p.Thr591Met, p.Arg597Trp, p.Arg610Cys), with one substitution mapping to the C-terminal linker region (p.Val774Ile) (Supplementary Figure S2). These data suggest that PPP is associated with both gain- and loss-of-function CARD14 alleles. To further investigate this possibility, we overexpressed mutagenized cDNA constructs harboring representative coiled‒coil (p.Arg182Cys, p.Ser384Phe) and PDZ (p.Thr591Met) variants. We found that the p.Arg182Cys and p.Ser384Phe alleles led to the formation of insoluble CARD14 aggregates (Figure 1a). Because these promote constitutive NF-κB activation (Berki et al., 2015Berki D.M. Liu L. Choon S.E. David Burden A. Griffiths C.E.M. Navarini A.A. et al.Activating CARD14 mutations are associated with generalized pustular psoriasis but rarely account for familial recurrence in psoriasis vulgaris.J Invest Dermatol. 2015; 135: 2964-2970Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar), the two variants are very likely to have gain-of-function properties. Conversely, we observed that the p.Thr591Met substitution was associated with reduced protein accumulation (Figure a loss-of-function Interestingly, the that variants with effects in the same clinical is by the of CARD14 alleles associated with plaque This identified both gain- and loss-of-function that CARD14 need to be to skin immune (Jordan et al., 2012aJordan C.T. Cao L. Roberson E.D. Duan S. Helms C.A. Nair R.P. et al.Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.Am J Hum Genet. 2012; 90: 796-808Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar). Importantly, this that CARD14 might be a Although CARD14 been investigated in PPP, studies were restricted to the coiled‒coil domain and in the potential to disease alleles (Berki et al., 2015Berki D.M. Liu L. Choon S.E. David Burden A. Griffiths C.E.M. Navarini A.A. et al.Activating CARD14 mutations are associated with generalized pustular psoriasis but rarely account for familial recurrence in psoriasis vulgaris.J Invest Dermatol. 2015; 135: 2964-2970Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar; et al., R. D. P. Löhr S. P. et genetic basis for patients with pustular skin disease J Dermatol. 2017; Scopus Google Scholar). Of note, in inflammatory pityriasis rubra pilaris and CARD14-associated papulosquamous that be in individuals with CARD14 mutations et al., O. Sarig O. E. van Steensel M.A. Clinical response to ustekinumab in familial Pityriasis rubra pilaris caused by a novel mutation in J Dermatol. PubMed Scopus Google Scholar; Nieto-Benito et al., 2020Nieto-Benito L.M. Baniandrés-Rodríguez O. Moreno-Torres A. Hernández-Martín A. Torrelo-Fernández A. Campos-Domínguez M. Clinical response to ustekinumab in CARD14-associated papulosquamous eruption (CAPE) with a new missense mutation in CARD14: a case report and systematic review.J Eur Acad Dermatol Venereol. 2020; 34: e728-e730Crossref PubMed Scopus (8) Google Scholar; Signa et al., 2019Signa S. Campione E. Rusmini M. Chiesa S. Grossi A. Omenetti A. et al.Whole exome sequencing approach to childhood onset familial erythrodermic psoriasis unravels a novel mutation of CARD14 requiring unusual high doses of ustekinumab.Pediatr Rheumatol Online J. 2019; 17: 38Crossref PubMed Scopus (15) Google Scholar). In this our that mutational patients with CARD14 disease alleles from ustekinumab the patient allele frequency data are reported in the and table of this allele frequency data were from the gnomAD A. David L. E. J. N. H. research from research and from and and are for participating in or to from and research and/or from Sun and to from and for and from and as an or or from and to for and the and the European for Research with to is an on of in psoriasis and atopic dermatitis with multiple and for research and from in psoriasis, including and of the APRICOT and PLUM study is reported in the Supplementary Materials and This research was by the for and Research Research at and and London United We also from the Research The APRICOT trial was by the and a Research and and This was by the European of and and the Psoriasis and was by an and was by an Research is in by the Research and is an is an is by the Research The are those of the and not those of the the or the of and The of the APRICOT and PLUM the United United United David and United and United United Cornelius United United United and United of United United United United United United Psoriasis United United and and United Patel and and and United and United Wilson and total of individuals were whole-exome sequenced as of a previous study et al., 2020Vergnano M. Mockenhaupt M. Benzian-Olsson N. Paulmann M. Grys K. Mahil S.K. et al.Loss-of-function myeloperoxidase mutations are associated with increased neutrophil counts and pustular skin disease.Am J Hum Genet. 2020; 107 ([published correction appears in Am J Hum Genet 2021;108:757]): 539-543Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). The same and were then to variant profiles for a further 117 were with and on an Illumina instrument were to the using and variants were with et al., H. A. T. J. N. et and PubMed Scopus Google Scholar) and with et al., K. M. H. of genetic variants from sequencing PubMed Scopus Google Scholar). total of additional palmoplantar pustulosis cases were by Sanger sequencing using the in Supplementary Table The rare CARD14 alleles detected in palmoplantar pustulosis cases and gnomAD controls were using the same the of missense variants was assessed with Combined Annotation Dependent et al., P. D. J. 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The allele is in because its frequency in PPP, palmoplantar Figure Table females of onset plaque psoriasis, palmoplantar pustulosis and Open table in a new tab Supplementary Table of the 12 CARD14 females of onset plaque psoriasis, palmoplantar pustulosis and Open table in a new tab Supplementary Table CARD14 with et al., M. Jordan C.T. Cao L. E. A. et in patients with psoriasis and further in European J Dermatol. PubMed Scopus Google Scholar; et al., L.M. R. M. J. G. et papulosquamous a spectrum including of psoriasis and pityriasis rubra Am Acad Dermatol. Full Text Full Text PDF PubMed Scopus Google Scholar; et al., M. L. David M. D. P. et in clinical of Venereol. PubMed Scopus Google Scholar; Jordan et al., C.T. Cao L. Roberson E.D. Pierson K.C. Yang C.F. Joyce C.E. et al.PSORS2 is due to mutations in CARD14.Am J Hum Genet. 2012; 90: 784-795Abstract Full Text Full Text PDF PubMed Scopus Google Scholar; et al., R. D. P. Löhr S. P. et genetic basis for patients with pustular skin disease J Dermatol. 2017; Scopus Google Scholar; et al., T. K. T. T. Y. N. et rubra pilaris as an disease by CARD14 Dermatol. 2017; PubMed Scopus (57) Google et al., 2012Fuchs-Telem D. Sarig O. van Steensel M.A. Isakov O. Israeli S. Nousbeck J. et al.Familial pityriasis rubra pilaris is caused by mutations in CARD14.Am J Hum Genet. 2012; 91: 163-170Abstract Full Text Full Text PDF PubMed Scopus Google Scholar; et al., T. A. E. Y. S. M. et familial generalized pustular psoriasis caused by a CARD14 J Dermatol. 2017; PubMed Scopus Google et al., C.T. Cao L. Roberson E.D. Pierson K.C. Yang C.F. Joyce C.E. et al.PSORS2 is due to mutations in CARD14.Am J Hum Genet. 2012; 90: 784-795Abstract Full Text Full Text PDF PubMed Scopus Google et al., L.M. R. M. J. G. et papulosquamous a spectrum including of psoriasis and pityriasis rubra Am Acad Dermatol. Full Text Full Text PDF PubMed Scopus Google Scholar; et al., Liu L. of ustekinumab in familial pityriasis rubra pilaris with a new missense mutation in J Dermatol. PubMed Scopus Google et al., L.M. R. M. J. G. et papulosquamous a spectrum including of psoriasis and pityriasis rubra Am Acad Dermatol. Full Text Full Text PDF PubMed Scopus Google Scholar; et al., L. et papulosquamous eruption (CAPE) in three additional cases and of the Dermatol. 2021; PubMed Scopus Google et al., L.M. R. M. J. G. et papulosquamous a spectrum including of psoriasis and pityriasis rubra Am Acad Dermatol. Full Text Full Text PDF PubMed Scopus Google Scholar; et al., O. Sarig O. E. van Steensel M.A. Clinical response to ustekinumab in familial pityriasis rubra pilaris caused by a novel mutation in J Dermatol. PubMed Scopus Google Scholar; et al., S. O. Sarig O. K. E. et genes as of familial pityriasis rubra pilaris from a with and psoriasis.J Eur Acad Dermatol Venereol. PubMed Scopus Google et al., L.M. R. M. J. G. et papulosquamous a spectrum including of psoriasis and pityriasis rubra Am Acad Dermatol. Full Text Full Text PDF PubMed Scopus Google Scholar; et al., T. K. T. T. Y. N. et rubra pilaris as an disease by CARD14 Dermatol. 2017; PubMed Scopus (57) Google et al., T. K. T. T. Y. N. et rubra pilaris as an disease by CARD14 Dermatol. 2017; PubMed Scopus (57) Google et al., A. N. N. et and high sequencing a CARD14 mutation in an with erythrodermic pityriasis rubra Venereol. PubMed Scopus Google et al., C.T. Cao L. Roberson E.D. Pierson K.C. Yang C.F. Joyce C.E. et al.PSORS2 is due to mutations in CARD14.Am J Hum Genet. 2012; 90: 784-795Abstract Full Text Full Text PDF PubMed Scopus Google et al., 2012Fuchs-Telem D. Sarig O. van Steensel M.A. Isakov O. Israeli S. Nousbeck J. et al.Familial pityriasis rubra pilaris is caused by mutations in CARD14.Am J Hum Genet. 2012; 91: 163-170Abstract Full Text Full Text PDF PubMed Scopus Google et al., 2019Signa S. Campione E. Rusmini M. Chiesa S. Grossi A. Omenetti A. et al.Whole exome sequencing approach to childhood onset familial erythrodermic psoriasis unravels a novel mutation of CARD14 requiring unusual high doses of ustekinumab.Pediatr Rheumatol Online J. 2019; 17: 38Crossref PubMed Scopus Google et al., D. R. cases of CARD14-associated papulosquamous eruption from Dermatol. 2020; PubMed Scopus Google et al., 2012Fuchs-Telem D. Sarig O. van Steensel M.A. Isakov O. Israeli S. Nousbeck J. et al.Familial pityriasis rubra pilaris is caused by mutations in CARD14.Am J Hum Genet. 2012; 91: 163-170Abstract Full Text Full Text PDF PubMed Scopus Google et al., 2015Berki D.M. Liu L. Choon S.E. David Burden A. Griffiths C.E.M. Navarini A.A. et al.Activating CARD14 mutations are associated with generalized pustular psoriasis but rarely account for familial recurrence in psoriasis vulgaris.J Invest Dermatol. 2015; 135: 2964-2970Abstract Full Text Full Text PDF PubMed Scopus Google Scholar; et al., R. D. P. Löhr S. P. et genetic basis for patients with pustular skin disease J Dermatol. 2017; Scopus Google Scholar; et al., K. M. M. CARD14 is a for generalized pustular psoriasis with psoriasis in the Invest Dermatol. Full Text Full Text PDF PubMed Scopus Google Scholar; et al., T. K. T. T. Y. N. et rubra pilaris as an disease by CARD14 Dermatol. 2017; PubMed Scopus (57) Google et al., M. Jordan C.T. Cao L. E. A. et in patients with psoriasis and further in European J Dermatol. PubMed Scopus Google et al., 2019Peled A. Sarig O. Sun G. Samuelov L. Ma C.A. Zhang Y. et al.Loss-of-function mutations in caspase recruitment domain-containing protein 14 (CARD14) are associated with a severe variant of atopic dermatitis.J Allergy Clin Immunol. 2019; 143: 173-181.e10Abstract Full Text Full Text PDF PubMed Scopus Google et al., M. Jordan C.T. Cao L. E. A. et in patients with psoriasis and further in European J Dermatol. PubMed Scopus Google Open table in a new tab Supplementary Table 12 14 Open table in a new tab Supplementary Table were described by et al., 2015Berki D.M. Liu L. Choon S.E. David Burden A. Griffiths C.E.M. Navarini A.A. et al.Activating CARD14 mutations are associated with generalized pustular psoriasis but rarely account for familial recurrence in psoriasis vulgaris.J Invest Dermatol. 2015; 135: 2964-2970Abstract Full Text Full Text PDF PubMed Scopus Google Open table in a new tab Abbreviations: palmoplantar pustulosis and Abbreviations: palmoplantar pustulosis and The were described by et al., 2015Berki D.M. Liu L. Choon S.E. David Burden A. Griffiths C.E.M. Navarini A.A. et al.Activating CARD14 mutations are associated with generalized pustular psoriasis but rarely account for familial recurrence in psoriasis vulgaris.J Invest Dermatol. 2015; 135: 2964-2970Abstract Full Text Full Text PDF PubMed Scopus Google
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