1. The genetic basis for most patients with pustular skin disease remains elusive
R. Mössner*, D. Wilsmann-Theis*, V. Oji*, P. Gkogkolou*, S. Löhr*, P. Schulz, A. Körber, J.C. Prinz, R. Renner, K. Schäkel, L. Vogelsang, K.-P. Peters, S. Philipp, K. Reich, H. Ständer, A. Jacobi, A. Weyergraf, K. Kingo, S. Kõks, S. Gerdes, K. Steinz, T. Schill, K. G. Griewank, M. Müller, S. Frey, L. Ebertsch, S. Uebe, M. Sticherling, H. Sticht, U. Hüffmeier
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
DOI: /bjd.15867

2. Introduction What’s already known?
The genes IL36RN, CARD14 and AP1S3 have been implicated in pustular skin disease with IL36RN having a major role
Most studies analyzed variants in different genes separately
Significant subsets of patients with a pustular skin disease carry a single heterozygous mutation in IL36RN, leaving unanswered whether and how the variant is disease-contributing
A significantly younger age of onset in carriers of IL36RN mutations has been reported

3. Objective To better understand the disease-relevance of these genes
comprehensive screening of cohorts of patients with pustular skin diseases (primarily GPP and palmoplantar pustular psoriasis [PPP]) for coding changes in these 3 genes
thorough genotype-phenotype correlation in GPP
analysis of carriers of single heterozygous IL36RN mutations for a 2nd IL36RN mutation

4. Methods
Sequencing of coding exons of IL36RN, CARD14 and AP1S3 in 61 patients with GPP, 2 with acute generalized exanthematous pustulosis (AGEP) and 4 with acrodermatitis continua suppurativa Hallopeau (ACH)
Analysis of IL36RN and AP1S3 for intragenic copy-number-variants and 258 PPP patients for coding changes in AP1S3
Analysis of 11 heterozygous IL36RN mutations carriers for a 2nd non-coding mutation
Genotype-phenotype-correlations in carriers/ non-carriers of IL36RN mutations in GPP

5. Results
39 (64%) GPP patients without rare variant in any of the 3 genes
Bi-allelic and mono-allelic IL36RN mutations were identified in 15 (25%) and 5 (8%) GPP patients, respectively
15% of IL36RN mutations carriers with additional rare CARD14 or AP1S3 variants
Association of GPP with IL36RN variants with GPP: p<2.2*10-16, with CARD14 variants 3.1*10-04
Please include here Figure 1A) and B)

6. Mutations in IL36RN and clinical correlations in 61 GPP patients

7. Results
No non-coding rare IL36RN variants identified in heterozygous carriers
Only significant genotype-phenotype- correlation observed for IL36RN mutation carriers and early age of disease onset
No evidence for correlation with accompanying manifestations, frequency of episodic vs. continuous course of disease, positive family history for psoriatic/ rheumatic disease
7.4*10-04
mean age of onset (years)

8. Discussion and Conclusions What does this study add?
Low impact of AP1S3 and CARD14 variants on GPP and PPP
Identification of IL36RN mutation carriers with additional rare variants in CARD14 or AP1S3
Contribution of additional disease-causing genetic factors in heterozygous IL36RN mutation carriers outside IL36RN
Additional so far unknown genes contribute/ cause GPP in majority of patients
The same is true (even at higher percentage) in PPP
more complex mode of inheritance in pustular psoriasis

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