PSORS14

PSORS14 (Psoriasis Susceptibility 14) is a genetic locus associated with psoriasis. PSORS14 is located on chromosome 2q14.1.

This psoriasis susceptibility locus (PSORS14) has been shown to be associated with pustular psoriasis. PSORS14 is caused by a 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, recurrent episodes of high fever, generalized rash and disseminated pustules with hyperleukocytosis and elevated serum levels of C-reactive protein (123260). GPP often occurs in patients with existing or previous psoriasis vulgaris; however, GPP can also develop without a history of PV (Sugiura et al. 2013). Palmoplantar pustulosis and acrodermatitis continua suppurativa of Hallopeau are acral forms of pustular psoriasis that have been associated with GPP in the past (Setta-Kaffetzi et al. 2013). GPP associated with sterile multifocal osteomyelitis and periostitis (612852) is caused by a mutation in the IL1RN gene (147679).

Capon (2013) found that the percentage of GPP patients found to have a mutation in the IL36RN gene ranged from 51 to 84%, indicating genetic heterogeneity in GPP.

Marrakchi et al. (2011) studied 9 families from southern Tunisia in which autosomal recessive generalized pustular psoriasis occurred. All 16 affected individuals met the clinical and biological criteria for generalized pustular psoriasis (recurrent, sudden onset attacks with diffuse erythematous rash characterized by rapid coverage with pustules, high grade fever, asthenia, marked leukocytosis, elevated serum levels of C-reactive protein). Five family members had died of septicemia. In 12 patients, the disease developed between the ages of 1 week and 11 years; in the remaining 4 patients, it began in adulthood. The frequency of relapses was highly variable, and episodes were associated with viral or bacterial infections in 12 patients, discontinuation of retinoid therapy in 7 patients, menstruation in 6 patients, and pregnancy in 2 patients; the latter two patients were diagnosed with impetigo herpetiformis during pregnancy. Some patients developed chronic erythematous plaques without pustules, 1 patient showed acrodermatitis continua suppurativa, with acral pustular lesions on the toes with partial destruction of the nails.

In a consanguineous Tunisian family with 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 other similarly affected Tunisian families revealed cosegregation of the disease with a common 1.2-Mb haplotype within the 11-Mb region, suggesting a founder effect.

In another 9 Tunisian families with autosomal recessive generalized pustular psoriasis, Marrakchi et al. (2011) analyzed 9 candidate genes and identified homozygosity for a missense mutation in the IL36RN gene in all affected individuals.

Onoufriadis et al (2011) performed whole-exome sequencing in five unrelated subjects with generalized pustular psoriasis and identified homozygosity for a missense mutation in the IL36RN gene (S113L; 605507.0002) in two subjects and compound heterozygosity for S113L and another missense mutation (R42W; 605507.0003) in a third subject. Sequencing of IL36RN in the two patients in whom no mutation was found confirmed the wild-type sequence; Onoufriadis et al. (2011) found that both mutation-negative patients had palmoplantar pustulosis, which was not found in the three mutation-positive patients. The authors hypothesized that the mutation of IL36RN is associated with a specific subtype of generalized pustular psoriasis that is not associated with palmoplantar lesions.

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

Setta-Kaffetzi et al (2013) analyzed the IL36RN gene in 84 patients with generalized pustular psoriasis and in 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. Only one IL36RN mutation was detected in 10 patients. Setta-Kaffetzi et al (2013) observed no significant differences in age at onset, prevalence of psoriasis vulgaris or clinical presentation between the cases with two mutant IL36RN alleles and the rest of the study cohort.

Sugiura et al. (2013) examined 28 Japanese subjects with GPP, 9 of whom had only GPP and 19 of whom also had psoriasis vulgaris (PV), for mutations in the IL36RN gene. Of the 9 subjects 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). Of the 19 GPP probands with PV, 1 was heterozygous for R10X and c.115+6T-C, while another was heterozygous for R10X only. Haplotype analysis revealed a founder effect for both the R10X and c.115+6T-C mutations in the Japanese population. HLA typing of the heterozygous proband with GPP and PV and an affected sibling revealed that both carried the PV susceptible HLA haplotype HLA-A*2606 (see 142800), while an unaffected sibling was unaffected. Sugiura et al. (2013) suggested that HLA-A*2606 could contribute to the pathogenesis of PV in the affected siblings.

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

In a study of 68 Chinese patients with GPP, 113 with PV and 373 control subjects, Li et al. (2013) found that IL36RN mutations 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 most common in the Chinese GPP patients, was also present in 3.6% of controls and was detected in homozygosity in 2 controls who were over 40 years of age.

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2. Capon F (2013) IL36RN mutations in generalized pustular psoriasis: just the tip of the iceberg? J Invest Derm 133: 2503-2504.
3. Farooq M et al. (2013) Mutation analysis of the IL36RN gene in 14 Japanese patients with generalized pustular psoriasis. Hum Mutat 34: 176-183.
4. Korber A et al (2013) Mutations in IL36RN in patients with generalized pustular psoriasis. (Letter) J Invest Derm 133: 2634-2637.
5. Li M et al. (2013) 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.
6. Marrakchi S et al (2011) Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. New Eng J Med 365: 620-628.
7. Mossner R et al (2018) The genetic basis for most patients with pustular skin disease remains elusive. Brit J Derm 178: 740-748.
8. Onoufriadis A et al (2011) 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.
9. Setta-Kaffetzi N et al (2013) Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes. (Letter) J Invest Derm 133: 1366-1369.
10. Sugiura K et al. (2013) The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist. J Invest Derm 133: 2514-2521