IL36RN – Pustular Psoriasis (Psoriasis 14, Pustular)

IL36RN encodes the interleukin-36 receptor antagonist (IL-36Ra) and is the causative gene for deficiency of IL-36Ra (DITRA), manifesting as autosomal recessive pustular psoriasis, classified as Psoriasis 14, Pustular (MONDO:0013626). Patients present with sterile neutrophilic pustules, systemic inflammation, and variable involvement of extremities (e.g., acrodermatitis continua of Hallopeau).

1. Clinical Validity

Biallelic IL36RN variants have been identified in at least 77 probands across multiple cohorts: 58 Chinese patients (PMID:36843341), nine Tunisian families (≥18 affected) (PMID:21848462), and additional independent cases (PMID:21839423; PMID:22903787; PMID:23428889; PMID:24019411). Segregation in consanguineous and nonconsanguineous families, recessive inheritance, and concordant functional assays support a Definitive association.

2. Genetic Evidence

Inheritance is autosomal recessive. Segregation analysis across at least 19 affected relatives in multiplex families demonstrates co-segregation with disease. Case series comprise 58 patients bearing homozygous or compound heterozygous IL36RN variants in DITRA (PMID:36843341). Variant spectrum includes missense, nonsense/frameshift, and splice-site changes. A recurrent founder missense variant, c.80T>C (p.Leu27Pro), reduces IL-36Ra stability and receptor binding (PMID:21848462).

3. Functional Evidence

Mutations such as p.Leu27Pro, p.Ser113Leu, and p.Arg48Trp show loss-of-function in NF-κB reporter assays and reduced protein expression (PMID:27220475). Il36rn⁻/⁻ mice develop exaggerated neutrophil recruitment and pustular lesions, recapitulating human disease and supporting haploinsufficiency of IL-36Ra in pustular psoriasis.

4. Conflicting Evidence

A p.Pro82Leu variant shows preserved mRNA and protein levels without clinical phenotype in a single patient, suggesting benign status and highlighting the need for comprehensive functional validation (PMID:37525499).

5. Integration and Conclusion

IL36RN mutations cause DITRA by abolishing IL-36Ra antagonism, leading to unrestrained IL-36 signaling and neutrophil-driven pustular eruptions. Genetic testing enables definitive diagnosis, informs prognosis (early onset, possible ACH progression), and guides therapy: IL-1 blockade (anakinra) or targeted IL-36R inhibition (spesolimab) achieves clinical remission. Further genotype-phenotype studies may refine risk stratification.

Key Take-home: Biallelic IL36RN variants definitively underlie autosomal recessive pustular psoriasis (Psoriasis 14, Pustular), and molecular diagnosis directs targeted anti-cytokine therapy.

References

• Dermatology (Basel, Switzerland) • 2013 • Acrodermatitis continua of Hallopeau is a clinical phenotype of DITRA: evidence that it is a variant of pustular psoriasis. PMID:23428889
• Pediatrics • 2013 • First clinical description of an infant with interleukin-36-receptor antagonist deficiency successfully treated with anakinra. PMID:24019411
• Experimental Dermatology • 2023 • Deficiency of interleukin-36 receptor antagonist (DITRA): An analysis of 58 Chinese patients in a tertiary hospital in Taiwan. PMID:36843341
• The New England Journal of Medicine • 2011 • Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. PMID:21848462
• American Journal of Human Genetics • 2011 • Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. PMID:21839423
• Human Mutation • 2013 • Mutation analysis of the IL36RN gene in 14 Japanese patients with generalized pustular psoriasis. PMID:22903787

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