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Palmoplantar 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 1b), indicating a loss-of-function effect. Interestingly, the notion that variants with opposing effects can result in the same clinical phenotype is supported by the characterization of CARD14 alleles associated with plaque psoriasis. This identified both gain- and loss-of-function changes, suggesting that CARD14 activity levels need to be finely balanced to maintain skin immune homeostasis (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 implies that CARD14 might be a problematic therapeutic target. Although CARD14 has been previously investigated in PPP, earlier studies were mostly restricted to the proximal coiled‒coil domain and had in retrospect limited the potential to detect 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; Mössner et al., 2017Mössner R. Wilsmann-Theis D. Oji V. Gkogkolou P. Löhr S. Schulz P. et al.The genetic basis for most patients with pustular skin disease remains elusive.British J Dermatol. 2017; 178: 740-748Crossref Scopus (0) Google Scholar). Of note, evidence gathered in other inflammatory conditions (e.g., pityriasis rubra pilaris and CARD14-associated papulosquamous eruption) indicates that IL-12p40 blockade (ustekinumab) may be effective in individuals with CARD14 mutations (Eytan et al., 2014Eytan O. Sarig O. Sprecher E. van Steensel M.A. Clinical response to ustekinumab in familial Pityriasis rubra pilaris caused by a novel mutation in CARD14.Br J Dermatol. 2014; 171: 420-422Crossref PubMed Scopus (54) 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 context, our work suggests that whole-gene mutational screens could identify patients with CARD14 disease alleles who may benefit from personalized ustekinumab treatment. All the patient allele frequency data are reported in the text and table of this manuscript. Control allele frequency data were retrieved from the gnomAD database. Athanasios Niaouris: http://orcid.org/0000-0002-8407-2014 Ariana Hernández-Cordero: http://orcid.org/0000-0002-4132-1949 Salma Haddad: http://orcid.org/0000-0002-8123-6853 Niina Karoliina Hassi: http://orcid.org/0000-0002-1548-1199 Natashia Benzian-Olsson: http://orcid.org/0000-0002-5287-7707 Carmen Bugarin Diz: http://orcid.org/0000-0001-6257-3734 A. David Burden: http://orcid.org/0000-0001-7395-9931 Hywel L. Cooper: http://orcid.org/0000-0001-8016-706X Christopher E.M. Griffiths: http://orcid.org/0000-0001-5371-4427 Richard Parslew: http://orcid.org/0000-0002-9430-1394 Andrew E. Pink: http://orcid.org/0000-0001-5151-5539 Nick J. Reynolds: http://orcid.org/0000-0002-6484-825X Shyamal Wahie: http://orcid.org/0000-0003-2798-8429 Richard B. Warren: http://orcid.org/0000-0002-2918-6481 Andrew Wright: http://orcid.org/0000-0002-6072-5148 Michael Simpson: http://orcid.org/0000-0002-8539-8753 Patrick Baum: http://orcid.org/0000-0002-1399-8610 Sudha Visvanathan: http://orcid.org/0000-0002-1170-9272 Jonathan N. Barker: http://orcid.org/0000-0002-9030-183X Catherine H. Smith: http://orcid.org/0000-0001-9918-1144 Francesca Capon: http://orcid.org/0000-0003-2432-5793 Conceptualization: FC; Formal Analysis: AN, AHC, CBD, SH, NBO; Funding Acquisition: FC, CHS, PB, SV; Resources: ADB, HLC, CEMG, RP, AEP, NJR, MS, SW, RBW, AW, JNB, CHS; Investigation: AN, NKH; Supervision: FC; Writing - Original Draft Preparation: FC FC has received research funding from Boehringer-Ingelheim. JNB has received research grants and consultation fees from Boehringer-Ingelheim and Anaptyis Bio. CTW, PB, and SV are Boehringer-Ingelheim employees. HLC has received honoraria for participating in advisory boards or sponsorship to attend conferences from AbbVie, Almirall, Janssen, Leo and has received research grants and/or fees from AbbVie, Almirall, Janssen, Sun and has received to attend from AbbVie, Almirall, Janssen, and honoraria for and from and has as an or or received grants from AbbVie, Janssen, Almirall, and Boehringer-Ingelheim. 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 supported 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 work was supported 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 supported 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 Nick 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 All and on an Illumina instrument were to the using and variants were with et al., H. B. A. T. J. N. et al.The 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. M. the of variants the 2019; PubMed Scopus Google Scholar), et al., M. D. potential of sequence PubMed Scopus Google Scholar), and and Y. a to the of amino and 2015; 31: PubMed Scopus Google Scholar). that the can be for the analysis of coding changes, variants were assessed using CADD, and and that sequence in 2012; PubMed Scopus Google Scholar). and variants that were classified as damaging by at least two predictors were considered potentially pathogenic. and variants were considered potentially pathogenic. systematic literature was by the PubMed with the or and or mutations or or The was and that were not written in were The rare variants (minor allele frequency < 1%) described in the studies were classified as they were predicted to be damaging by at least two algorithms and met one of the described in at least two case with inflammatory skin disease in constructs were generated using the and were using (Supplementary Table All constructs were by sequencing the CARD14 coding and the were in with of and of from and United was to with the constructs and by United were were with and then The the protein was and the with the insoluble was in The two were by using a at were with of et al., C.A. to of 2012; PubMed Scopus Google Scholar) to of rare and damaging CARD14 alleles were compared in cases vs. controls using Fisher's exact results were with a or by as P < was Figure of CARD14 missense alleles associated with inflammatory skin The the of the CARD14 mutations through the systematic literature and the rare variants associated with PPP. 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 characterization 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 phenotype 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; Mössner et al., 2017Mössner R. Wilsmann-Theis D. Oji V. Gkogkolou P. Löhr S. Schulz P. et al.The genetic basis for most patients with pustular skin disease remains J Dermatol. 2017; 178: 740-748Crossref 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 CARD14.Br J Dermatol. 178: 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., 2014Eytan O. Sarig O. Sprecher E. van Steensel M.A. Clinical response to ustekinumab in familial pityriasis rubra pilaris caused by a novel mutation in CARD14.Br J Dermatol. 2014; 171: 420-422Crossref PubMed Scopus Google Scholar; et al., S. O. Sarig O. K. Sprecher 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. B. et and high sequencing identify 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; Mössner et al., 2017Mössner R. Wilsmann-Theis D. Oji V. Gkogkolou P. Löhr S. Schulz P. et al.The genetic basis for most patients with pustular skin disease remains J Dermatol. 2017; 178: 740-748Crossref Scopus Google Scholar; et al., K. M. M. CARD14 is a for generalized pustular psoriasis with psoriasis in the Invest Dermatol. 2014; 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 characterization 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 characterization 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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