疾患詳細

疾患詳細



指定難病HPより

#614204
Proriasis 14, pustular (PSORS14)
(Interleukin 36 receptor antagonist deficiency; DITRA)
(Generalized pustular psoriasis; GPS)
(PSORP)
(Acrodermatitis continua of Hallopeau)
(Palmoplantar pustuosis)

乾癬14, 膿疱性
(Interleukin 36 receptor antagonist 欠乏症)
(全身性膿疱性乾癬)
(連続性肢端皮膚炎, Hallopeau)
(掌蹠膿疱症)
指定難病37 膿疱性乾癬(汎発型)

責任遺伝子:605507 Interleukin 36 receptor antagonist (IL36RN) <2q13>
遺伝形式:常染色体劣性

(症状)
(GARD)
 <5%-29%>
 Cholangitis (胆管炎) [HP:0030151] [1212]
 Furrowed tongue (溝のある舌) [HP:0000221] [08104]
 Geographic tongue (地図状舌) [HP:0025252] [08105]
 Nail dysplasia (爪異形成) [HP:0002164] [1901]
 Nail dystrophy (爪ジストロフィー) [HP:0008404] [1901]
 Oligoarthritis (乏関節炎) [HP:0040313] [15115]
 
 
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Epidermal acanthosis (表皮肥厚) [HP:0025092] [18017]
 Erythema (紅斑) [HP:0010783] [18008]
 Fever (発熱) [HP:0001945] [01413]
 Parakeratosis (錯角化) [HP:0001036] [18019]
 Psoriasiform dermatitis (苔癬型皮膚炎) [HP:0003765] [18019]
 Pustule (化膿疹) [HP:0200039]  [18007]

(UR-DBMS)
【一般】高熱
【口】地図状舌 (一部の患者で)
 陰嚢舌 (一部の患者で)
 移動性舌紅斑 (一部の患者で)
【消化器】胆管炎 (一部の患者で)
【皮膚】膿疱性乾癬, 全身性
(皮膚組織学)
 Spongiform pustules
 Acanthosis
 Elongation of rete ridges
 Parakeratosis in stratum corneum
【爪】爪ジストロフィー (一部の患者で)
【検査】血清 CRP 増加
【その他】大多数の患者は発熱を伴う嚢胞性発疹の反復性フレアをもつが,一部の患者は膿疱のない慢性紅斑性局面を生じる

<指定難病37 膿疱性乾癬(汎発型)>
概要
 乾癬には、最も発症頻度の高い尋常性乾癬の他に
 亜型として、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬がある。
 広義の膿疱性乾癬には膿疱性乾癬(汎発型)と限局性膿疱性乾癬(掌蹠膿疱症、アロポー稽留性肢端皮膚炎)があり、本稿で取り扱うのは膿疱性乾癬(汎発型)である。
 膿疱性乾癬(汎発型)には急性汎発性膿疱性乾癬(von Zumbusch 型)、小児汎発性膿疱性乾癬、疱疹性膿痂疹、などが含まれる。
 von Zumbusch 型は急激な発熱とともに全身の皮膚が潮紅し、無菌性膿疱が多発するまれな疾患である。
 その他の型では、全身症状はないか、あっても軽度で紅斑と膿疱を繰り返し、慢性に経過する。
 経過中に、全身炎症反応に伴って臨床検査異常を示し、しばしば、粘膜症状、関節炎を合併するほか、 まれに眼症状、心・循環器不全、呼吸器不全、二次性アミロイドーシスを合併することがある。膿疱性乾癬(汎発型)と鑑別を要する疾患として、膿疱型薬疹(全身性汎発性発疹性膿疱症:AGEP を含む)や角層下膿疱症がある。

原因
 膿疱性乾癬(汎発型)は尋常性乾癬(肉眼的に膿疱を形成することが少ない炎症性角化症の代表的疾患 の一つ)が先行して発症する症例がある一方で、全く尋常性乾癬と関連がない症例もある。尋常性乾癬の HLA(遺伝的背景)解析の結果、わが国および海外において HLA-Cw6 の集積性がみられるが、膿疱性乾癬(汎発型)では関連がなく、両者は異なる遺伝的素因を有することが示唆される。
 近年の膿疱性乾癬(汎発型)の家族内発症例の検討によって、その原因遺伝子として好中球の遊走に重要な IL-8 をはじめとする炎症性サイトカイン産生に関与する IL-36 の働きを制御する IL-36 受容体アンタ ゴニストをコードする IL36RN ( Interleukin 36 receptor antagonist) 遺伝子の変異が相次いで報告され、さらに孤発例においても尋常性乾癬が先行しない膿疱性乾癬(汎発型)の大半は IL36RN遺伝子の変異を有していることが明らかになってきた。

3.症状
 急性期症状は、前駆症状なしに、あるいは尋常性乾癬皮疹が先行し、灼熱感とともに紅斑を生じる。多くは悪寒・戦慄を伴って急激に発熱し、全身皮膚の潮紅、浮腫とともに無菌性膿疱が全身に多発する。膿疱は3~5mm大で、容易に破れたり、融合して環状・連環状配列をとり、ときに膿海を形成する。爪甲肥厚や爪甲下膿疱、爪甲剥離などの爪病変、頬粘膜病変や地図状舌などの口腔内病変がみられる。しばしば全身の浮腫、関節痛を伴い、ときに結膜炎、虹彩炎、ぶどう膜炎などの眼症状、まれに呼吸不全、循環不全や腎不全を併発することがある。
 慢性期には、尋常性乾癬の皮疹や、手足の再発性膿疱の他、非特異的紅斑・丘疹など多様な症状を呈する。急性期皮膚症状が軽快しても、強直性脊椎炎を含むリウマトイド因子陰性関節炎が続くことがある。

4.治療法
 エトレチナートとシクロスポリンはいずれも第一選択薬である。メトトレキサートは、他の全身治療に抵抗性の症例や、関節炎の激しい症例に推奨されるが、副作用(肝障害、骨髄抑制、間質性肺炎など)に留意し、十分なインフォームドコンセントに配慮する必要がある。
 妊娠までの最低限の薬剤中止期間は、エトレチナートでは女性2年間、男性6か月、メトトレキサートでは男女とも3か月とされている。
 TNFα阻害薬は、膿疱性乾癬(汎発型)に対して有効であり、特に重症関節症合併例に対して推奨される。また、IL-17A阻害薬も膿疱性乾癬に有効性が示され適応が追加された。
 顆粒球吸着除去療法は膿疱性乾癬(汎発型)に対して副作用の少ない安全な治療として推奨されている。
 
5.予後
 治癒あるいは膿疱出現が減少した軽快例は、43.0%の患者で認められる。しかし、膿疱出現をくり返す例や、膿疱出現が増加した再発例も多く、これに尋常性乾癬に移行した例と死亡した例を加えると、約半数の症例は同程度の再発をくり返すため、難治といわざるを得ない。また、まれながら不幸な転帰をとる症例が存在する。死亡統計では、4.2例/年で、55歳以上の男性に多い。海外の報告では、死因として心血管系異常、アミロイドーシス、メトトレキサート合併症などの報告がある。

<指定難病診断基準>
DefiniteとProbableを対象とする。

膿疱性乾癬(汎発型)の定義と診断に必要な主要項目(2006 年)
【定義】
 膿疱性乾癬(汎発型)は, 急激な発熟とともに全身の皮膚が潮紅し, 無菌性膿疱が多発する稀な疾患である。病理組織学的に Kogoj 海綿状膿疱を特徴とする角層下膿疱を形成する。尋常性乾癬皮疹が先行する例としない例があるが, 再発を繰り返すことが本症の特徴である。経過中に全身性炎症反応に伴う臨床検査異常 を示し, しばしば粘膜症状, 関節炎を合併するほか, まれに眼症状, 二次性アミロイドーシスを合併することが ある。

1 主要項目
 1) 発熱あるいは全身倦怠感等の全身症状を伴う。
 2) 全身または広範囲の潮紅皮膚面に無菌性膿疱が多発し, ときに融合し膿海を形成する。
 3) 病理組織学的に Kogoj 海綿状膿疱を特徴とする好中球性角層下膿疱を証明する。
 4) 以上の臨床的, 組織学的所見を繰り返し生じること。 ただし, 初発の場合には臨床経過から下記の疾患 を除外できること。

診断のカテゴリー
以上の4項目を満たす場合を膿疱性乾癬(汎発型)(Definite)と診断する。
主要項目2)と3)を満たす場合をProbableと診断する。

2.膿疱性乾癬(汎発型)診断の参考項目
 1)重症度判定および合併症検索に必要な臨床検査所見
  (1)白血球増多, 核左方移動
  (2)赤沈亢進, CRP 陽性
  (3)IgG 又は IgA 上昇
  (4)低蛋白血症, 低カルシウム血症
  (5)扁桃炎, ASLO 高値, その他の感染病巣の検査
  (6)強直性脊椎炎を含むリウマトイド因子陰性関節炎
  (7)眼病変(角結膜炎, ぶどう膜炎, 虹彩炎など)
  (8)肝・腎・尿所見:治療選択と二次性アミロイドーシス評価 
 2)膿疱性乾癬(汎発型)に包括しうる疾患
  (1)急性汎発性膿疱性乾癬(von Zumbusch 型):膿疱性乾癬(汎発型)の典型例。
  (2)疱疹状膿痂疹:妊娠, ホルモンなどの異常に伴う汎発性膿疱性乾癬。
  (3)稽留性肢端皮膚炎の汎発化:厳密な意味での本症は稀であり, 診断は慎重に行う。
  (4)小児汎発性膿疱性乾癬: circinate annular form は除外する。
 3)一過性に膿疱化した症例は原則として本症に包含されないが, 治療が継続されているために再発が抑えられている場合にはこの限りではない。

3.膿疱性乾癬(汎発型)の除外項目
 1) 尋常性乾癬が明らかに先行し, 副腎皮質ホルモン剤などの治療により一過性に膿疱化した症例は原則と して除外するが, 皮膚科専門医が一定期間注意深く観察した結果, 繰り返し容易に膿疱化する症例で, 本 症に含めた方がよいと判断した症例は, 本症に含む。
 2) circinate annular form は, 通常全身症状が軽微なので対象外とするが, 明らかに汎発性膿疱性乾癬に移 行した症例は, 本症に含む。
 3) 一定期間の慎重な観察により角層下膿疱症, 膿疱型薬疹 (acute generalized exanthematous pustulosis を含む) と診断された症例は除く

(Responsible gene) *605507 Interleukin 36 receptor antagonist (IL36RN) <2q13>
.0001 Psoriasis 14, pustular (614204) [IL36RN, LEU27PRO [dbSNP:rs387906914] (Marrakchi et al. 2011)
.0002 Psoriasis 14, pustular [IL36RN, SER113LEU [dbSNP:rs144478519] (Onoufriadis et al. 2011; Setta-Kaffetzi et al. 2013; Korber et al. 2013)
.0003 Psoriasis 14, pustular [IL36RN, ARG48TRP [dbSNP:rs151325121] (Onoufriadis et al. 2011)
.0004 Psoriasis 14, pustular [IL36RN, IVS3, T-C, +6 [dbSNP:rs148755083] (Farooq et al. 2013l Setta-Kaffetzi et al. 2013; Li et al. 2013)
.0005 Psoriasis 14, pustular [IL36RN, THR123ARG [dbSNP:rs397514629] (Farooq et al. 2013)
.0006 Psoriasis 14, pustular [IL36RN, ARG10TER [dbSNP:rs397514630] (Sugiura et al. 2012)
.0007 Psoriasis 14, pustular [IL36RN, LYS35ARG [dbSNP:rs187015338] (Setta-Kaffetzi et al. 2013)
.0008 Psoriasis 14, pustular [IL36RN, ARG102TRP [dbSNP:rs199932303] (Setta-Kaffetzi et al. 2013)

(Note)
A number sign (#) is used with this entry because of evidence that pustular psoriasis-14 (PSORS14) is caused by homozygous or compound heterozygous mutation in the IL36RN gene (605507) on chromosome 2q14.

Generalized pustular psoriasis (GPP) is a life-threatening disease characterized by sudden, repeated episodes of high-grade fever, generalized rash, and disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive protein (123260) (summary by Marrakchi et al., 2011). GPP often presents in patients with existing or prior psoriasis vulgaris (PV; see 177900); however, GPP can develop without a history of PV (Sugiura et al., 2013). Palmoplantar pustulosis and acrodermatitis continua of Hallopeau represent acral forms of pustular psoriasis that have historically been grouped with GPP (summary by Setta-Kaffetzi et al., 2013).

GPP in association with sterile multifocal osteomyelitis and periostitis (612852) is caused by mutation in the IL1RN gene (147679).

Capon (2013) noted that the percentage of GPP patients reported to be negative for mutation in IL36RN ranges from 51 to 84%, indicative of genetic heterogeneity in the generalized pustular form of psoriasis.

For a discussion of genetic heterogeneity of psoriasis, see PSORS1 (177900).

Clinical Features
Marrakchi et al. (2011) studied 9 families from southern Tunisia segregating autosomal recessive generalized pustular psoriasis. All 16 affected individuals fulfilled the clinical and biologic criteria for generalized pustular psoriasis, defined by repeated flares of sudden onset consisting of diffuse erythematous skin eruption characterized by rapid coverage with pustules, high-grade fever, asthenia, marked leukocytosis, and elevated serum levels of C-reactive protein. Five family members had died after septicemia. Disease developed between 1 week of age and 11 years of age in 12 affected individuals; the remaining 4 affected individuals had onset in adulthood. The frequency of flare-ups was highly variable, and the episodes were associated with viral or bacterial infections in 12 patients, withdrawal of retinoid therapy in 7, menstruation in 6, and pregnancy in 2; the latter 2 patients received a diagnosis of impetigo herpetiformis during pregnancy. Some patients developed chronic erythematous plaques without pustules, and 1 patient exhibited the acrodermatitis continua form of pustulosis, characterized by acral pustular lesions of the digits with partial nail destruction. Histopathologic studies performed in 8 patients showed typical spongiform pustules, acanthosis with elongation of rete ridges, and parakeratosis in the stratum corneum. Immunostaining showed infiltration of the skin by CD8 T cells, CD3 T cells, and macrophages.

Farooq et al. (2013) studied 14 Japanese probands with generalized pustular psoriasis, all of whom repeatedly exhibited fresh erythema and pustules on the entire body, accompanied by high fever, high C-reactive protein, and neutrophilia. Skin biopsy showed spongiform pustules of Kogoj in the subcorneal portion of the epidermis. Age at onset of disease ranged from 15 to 74 years; there was no clear history of drug-induced eruption or withdrawal of oral or topical corticosteroids, which the authors noted had been known to precipitate the disease.

Mapping
In a consanguineous Tunisian family segregating autosomal recessive generalized pustular psoriasis, Marrakchi et al. (2011) genotyped chromosomal markers and identified an 11-Mb region of homozygosity on chromosome 2q13-q14. Analysis of 8 additional, similarly affected Tunisian families revealed cosegregation of disease with a common 1.2-Mb haplotype within the 11-Mb region, suggesting a founder effect.

Molecular Genetics
In 9 Tunisian families segregating autosomal recessive generalized pustular psoriasis mapping to chromosome 2q13-q14, Marrakchi et al. (2011) analyzed 9 candidate genes and identified homozygosity for a missense mutation in the IL36RN gene (L27P; 605507.0001) in all affected individuals.

In 5 unrelated probands with generalized pustular psoriasis, Onoufriadis et al. (2011) performed whole-exome sequencing and identified homozygosity for a missense mutation in the IL36RN gene (S113L; 605507.0002) in 2 probands, and compound heterozygosity for S113L and another missense mutation (R42W; 605507.0003) in a third proband. The mutations segregated with disease in the families, and screening of 250 ethnically matched controls revealed 1 heterozygous carrier of S113L. Sequencing of IL36RN in the 2 patients in whom no mutation was found by exome sequencing confirmed wildtype sequence; Onoufriadis et al. (2011) noted that both mutation-negative patients had palmoplantar pustulosis, which was not found in the 3 mutation-positive patients. The authors suggested that mutation of IL36RN is associated with a specific subtype of generalized pustular psoriasis not associated with palmoplantar lesions.

Farooq et al. (2013) analyzed the IL36RN gene in 14 Japanese patients with generalized pustular psoriasis and identified compound heterozygous mutations in 2 patients (605507.0004-605507.0006), 1 of whom also had psoriasis vulgaris.

Setta-Kaffetzi et al. (2013) analyzed the IL36RN gene in 84 patients with generalized pustular psoriasis as well as 148 patients diagnosed with acral forms of the disease, including 9 with acrodermatitis continua of Hallopeau and 139 with palmoplantar pustulosis. They identified homozygosity or compound heterozygosity for IL36RN mutations in 7 patients with generalized disease, 3 with palmoplantar pustulosis, and 2 with acrodermatitis continua (see 605507.0002, 605507.0004, and 605507.0007-605507.0008). In 10 patients, only 1 IL36RN mutation was detected, either S113L (605507.0002) or c.115+6T-C (605507.0004). Setta-Kaffetzi et al. (2013) observed no significant differences in age at onset, prevalence of psoriasis vulgaris, or clinical presentation between the cases bearing 2 mutated IL36RN alleles and the remainder of the study cohort.

Sugiura et al. (2013) screened 28 Japanese probands with GPP, 9 of whom had GPP alone and 19 of whom also had psoriasis vulgaris (PV), for mutations in the IL36RN gene. Of 9 probands with GPP alone, 5 were homozygous for the R10X mutation (605507.0006) and 3 were compound heterozygous for R10X and c.115+6T-C (605507.0004). Among the 19 GPP probands with PV, 1 was compound heterozygous for R10X and c.115+6T-C, whereas in another, only heterozygosity for R10X was detected. Haplotype analysis was consistent with a founder effect for both the R10X and c.115+6T-C mutations in the Japanese population. HLA typing in the compound heterozygous proband with GPP and PV and an affected sib revealed that both carried the PV-susceptible HLA haplotype HLA-A*2606 (see 142800), whereas an unaffected sib did not. Sugiura et al. (2013) suggested that HLA-A*2606 might contribute to the pathogenesis of PV in the affected sibs.

Korber et al. (2013) identified mutations in the IL36RN gene in 8 of 19 patients with GPP (see, e.g., 605507.0002); available unaffected parents from 5 families were all heterozygous carriers of the respective mutations, none of which were found in 190 controls. Analysis of the CARD14 gene (607211) revealed that 3 patients also carried CARD14 variants, including 1 patient who had only GPP and was homozygous for the S113L mutation in IL36RN; 1 who had only GPP in whom no mutation in IL36RN was detected; and 1 patient who had GPP with PV and was heterozygous for the S113L mutation in IL36RN. In the latter patient, who had PV from age 10 years and developed GPP at 55 years of age, Korber et al. (2013) suggested that the CARD14 mutation was likely responsible for the long-standing PV, whereas the IL36RN mutation might have induced the development of GPP.

In a study of 68 Chinese patients with GPP, 113 with PV, and 373 controls, Li et al. (2013) found that mutations of IL36RN were strongly associated with GPP but that there was no significant association between IL36RN mutations and PV. The c.115+6T-C mutation (605507.0004), which was the most common one in the Chinese GPP patients, was also present in 3.6% of controls and was detected in homozygosity in 2 controls who were more than 40 years old. Li et al. (2013) concluded that multiple factors contribute to the pathogenesis of GPP.

Berki et al. (2014) analyzed the IL36RN gene in 349 British patients with PV and a positive family history, as well as 14 unrelated patients with erythrodermic psoriasis. None of the patients harbored recessive IL36RN mutations; although 2 patients were heterozygous for the S113L mutation, the change did not segregate with disease in their respective families. In addition, the S113L variant was not overrepresented among the 726 case chromosomes compared to 2,222 in-house control exomes. Berki et al. (2014) concluded that loss of IL36RN function does not confer susceptibility to psoriasis vulgaris.

Mossner et al. (2018) sequenced the IL36RN, CARD14, and AP1S3 (615781) genes in 61 patients with GPP, 2 with acute generalized exanthematous pustulosis, and 4 with acrodermatitis continua of Hallopeau. The majority of patients with GPP did not carry rare variants in any of the 3 genes, indicating further genetic heterogeneity of generalized pustular psoriasis. Rare nonsynonymous IL36RN variants were identified in 20 patients with GPP, including 15 with biallelic mutations and 5 with heterozygous mutations. A total of 11 different mutations were detected, with the most frequent being S113L (605507.0002) and a P76L change. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. In patients with a single variant, sequencing of noncoding regions of IL36RN did not reveal evidence for any additional mutations. Noting that the frequency of heterozygous carriers among the GPP patients was 15 times higher than the frequency of heterozygous carriers in the general population, and that none of the heterozygous carrier parents of GPP patients had pustular skin disease, Mossner et al. (2018) suggested that IL36RN mutations represent a contributing effect in heterozygous patients with pustular psoriasis, consistent with a more complex inheritance pattern that was likely oligogenic. Additional rare variants in the CARD14 or AP1S3 genes were identified in 15% of patients with IL36RN mutations, further supporting the notion of oligogenicity.

Population Genetics
Based on the size of the homozygous region on chromosome 2q13-q14 in affected individuals from each of 9 Tunisian families segregating autosomal recessive generalized pustular psoriasis, Marrakchi et al. (2011) estimated that the most recent common ancestor of family members carrying the L27P mutation lived 13 generations ago. The L27P mutation was detected in heterozygosity in 3 of 287 Tunisian controls, indicating a carrier prevalence of approximately 1% and an allele prevalence of 0.52% in this population. The mutation was not found in 500 European controls or in available databases.

Nomenclature
Marrakchi et al. (2011) proposed the acronym DITRA for deficiency of interleukin-36 receptor antagonist.

(文献)
(1) Marrakchi, S., Guigue, P., Renshaw, B. R., Puel, A., Pei, X.-Y., Fraitag, S., Zribi, J., Bal, E., Cluzeau, C., Chrabieh, M., Towne, J. E., Douangpanya, J., and 18 others. Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. New Eng. J. Med. 365: 620-628, 2011
(2) Onoufriadis, A., Simpson, M. A., Pink, A. E., Di Meglio, P., Smith, C. H., Pullabhatla, V., Knight, J., Spain, S. L., Nestle, F. O., Burden, A. D., Capon, F., Trembath, R. C., Barker, J. N. Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am. J. Hum. Genet. 89: 432-437, 2011
(3) Capon, F. :IL36RN mutations in generalized pustular psoriasis: just the tip of the iceberg? J. Invest. Derm. 133: 2503-2504, 2013
(4) Farooq, M., Nakai, H., Fujimoto, A., Fujikawa, H., Matsuyama, A., Kariya, N., Aizawa, A., Fujiwara, H., Ito, M., Shimomura, Y. Mutation analysis of the IL36RN gene in 14 Japanese patients with generalized pustular psoriasis. Hum. Mutat. 34: 176-183, 2013
(5) Korber, A., Mossner, R., Renner, R., Sticht, H., Wilsmann-Theis, D., Schulz, P., Sticherling, M., Traupe, H., Huffmeier, U. Mutations in IL36RN in patients with generalized pustular psoriasis. (Letter) J. Invest. Derm. 133: 2634-2637, 2013
(6) Li, M., Han, J., Lu, Z., Li, H., Zhu, K., Cheng, R., Jiao, Q., Zhang, C., Zhu, C., Zhuang, Y., Wang, Y., Shi, J., Guo, Y., Wu, R., Yao, Z. Prevalent and rare mutations in IL-36RN gene in Chinese patients with generalized pustular psoriasis and psoriasis vulgaris. (Letter) J. Invest. Derm. 133: 2637-2639, 2013
(7) Setta-Kaffetzi, N., Navarini, A. A., Patel, V. M., Pullabhatla, V., Pink, A. E., Choon, S.-E., Allen, M. A., Burden, A. D., Griffiths, C. E. M., Seyger, M. M. B., Kirby, B., Trembath, R. C., Simpson, M. A., Smith, C. H., Capon, F., Barker, J. N. Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes. (Letter) J. Invest. Derm. 133: 1366-1369, 2013
(8) Sugiura, K., Takemoto, A., Yamaguchi, M., Takahashi, H., Shoda, Y., Mitsuma, T., Tsuda, K., Nishida, E., Togawa, Y., Nakajima, K., Sakakibara, A., Kawachi, S., and 14 others. The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist. J. Invest. Derm. 133: 2514-2521, 2013
(9) Berki, D. M., Mahil, S. K., Burden, A. D., Trembath, R. C., Smith, C. H., Capon, F., Barker, J. N. Loss of IL36RN function does not confer susceptibility to psoriasis vulgaris. (Letter) J. Invest. Derm. 134: 271-273, 2014
(10) Mossner, R., Wilsmann-Theis, D., Oji, V., Gkogkolou, P., Lohr, S., Schulz, P., Korber, A., Prinz, J. C., Renner, R., Schakel, K., Vogelsang, L., Peters, K. P., and 18 others. The genetic basis for most patients with pustular skin disease remains elusive. Brit. J. Derm. 178: 740-748, 2018

2011/09/02
2011/10/19
2011/10/26
2013/02/16
2014/11/26 変異変更追加, 全面改訂
2015/04/08 SNP
2016/06/23 ノート改訂
2020/12/17 ノート/文献追加