Alternative titles; symbols
SNOMEDCT: 784339002, 83839005; ICD10CM: L40.2; ORPHA: 247353, 404546; DO: 0080474;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q14.1 | Psoriasis 14, pustular | 614204 | Autosomal recessive | 3 | IL36RN | 605507 |
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).
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.
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.
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.
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.
Marrakchi et al. (2011) proposed the acronym DITRA for deficiency of interleukin-36 receptor antagonist.
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. [PubMed: 23792462] [Full Text: https://doi.org/10.1038/jid.2013.285]
Capon, F. :IL36RN mutations in generalized pustular psoriasis: just the tip of the iceberg? J. Invest. Derm. 133: 2503-2504, 2013. [PubMed: 24129779] [Full Text: https://doi.org/10.1038/jid.2013.361]
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. [PubMed: 22903787] [Full Text: https://doi.org/10.1002/humu.22203]
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. [PubMed: 23648549] [Full Text: https://doi.org/10.1038/jid.2013.214]
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. [PubMed: 23863864] [Full Text: https://doi.org/10.1038/jid.2013.267]
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. [PubMed: 21848462] [Full Text: https://doi.org/10.1056/NEJMoa1013068]
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. [PubMed: 28887889] [Full Text: https://doi.org/10.1111/bjd.15867]
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. [PubMed: 21839423] [Full Text: https://doi.org/10.1016/j.ajhg.2011.07.022]
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. [PubMed: 23303454] [Full Text: https://doi.org/10.1038/jid.2012.490]
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. [PubMed: 23698098] [Full Text: https://doi.org/10.1038/jid.2013.230]