[Skip to Content]
[Skip to Content Landing]
Observation
April 2015

Homozygous Missense Mutation in IL36RN in Generalized Pustular Dermatosis With Intraoral Involvement Compatible With Both AGEP and Generalized Pustular Psoriasis

Author Affiliations
  • 1Division of Genetics and Molecular Medicine, King’s College London, London, England
  • 2Department of Dermatology, University of Bern, Bern, Switzerland
JAMA Dermatol. 2015;151(4):452-453. doi:10.1001/jamadermatol.2014.3848

Acute generalized exanthematous pustulosis (AGEP) and generalized pustular psoriasis (GPP) show multiple overlapping clinical features. Recently, mutations in the IL36RN gene encoding the interleukin (IL)-36 receptor antagonist (IL-36Ra) have been found to cause increased secretion of inflammatory cytokines in GPP and in a subset of AGEP.1,2 In both conditions, half of the patients with IL36RN variants had oral involvement.1,2

Report of a Case

Herein we report a man in his 40s who initially presented with fever, systemic inflammatory response syndrome, and generalized, sterile, nonfollicular pustules (Figure 1) accentuated in the major flexures and on the palatal mucosa 5 days after intake of amoxicillin, which he took as postoperative prophylaxis after surgery of the thumb. His family history was negative for psoriasis. Medical history and clinicopathologic findings (Figure 2) were consistent with AGEP due to amoxicillin. After obtaining a EuroSCAR AGEP validation score of 10, we considered the diagnosis definite.3 Discontinuation of amoxicillin therapy and initiation of treatment with topical and systemic corticosteroids led to rapid resolution of this episode. A patch test with amoxicillin performed 6 weeks later showed a pustular skin reaction, further implicating amoxicillin as the trigger of this AGEP.

Figure 1.
Clinical Photograph of the Head After the First-Described Acute Generalized Pustular Eruption
Clinical Photograph of the Head After the First-Described Acute Generalized Pustular Eruption

Compatible with acute generalized exanthematous pustulosis, nonfollicular pustules on confluent erythematous and edematous plaques are seen on the head.

Figure 2.
Right Thoracic Histologic Specimen Taken After the First-Described Generalized Pustular Eruption
Right Thoracic Histologic Specimen Taken After the First-Described Generalized Pustular Eruption

Numerous subcorneal pustules, necrotic keratinocytes, edema of the papillary dermis, and perivascular lymphocytic infiltrate consisting mainly of neutrophils and eosinophils (hematoxylin-eosin, original magnification ×100).

Nine months later, the patient again developed a generalized pustular reaction with systemic inflammatory response syndrome 3 days after a throat infection with β-hemolyzing group A streptococci, notably without prior drug intake. Again, intraoral pustules were observed. During this episode, clinical and histologic findings were consistent with GPP.1 The patient recalled a similar episode 20 years before with a generalized pustular eruption with systemic symptoms without prior drug intake. The patient was given oral clarithromycin (500 mg twice daily) for his throat infection and 2 infusions with infliximab (5 mg/kg of body weight), which resulted in rapid clearance of the lesions.

Discussion

Our patient presented with 2 episodes of acute generalized pustular eruptions. While the first episode was consistent with AGEP, the second occurred without a triggering drug and was consistent with GPP. However, current classification systems leave it unclear whether such cases should be diagnosed as AGEP or drug-elicited GPP.4

Since recent findings have shown that pustular forms of psoriasis are related to genetic defects involving IL-36Ra,5 we carried out genetic analysis and identified a homozygous mutation in exon 5 (c.C338T:p.S113L) of the IL36RN gene.2 This gene encodes the anti-inflammatory IL-36Ra, which blocks the proinflammatory cytokine IL-36. Mutations in IL36RN may lead to uncontrolled IL-36 signaling and enhanced production of IL-6, IL-8, and IL-1, giving rise to pustular eruptions.3

In our patient, the IL36RN mutation may predispose for and drive the generalized pustular reactions and constitutes the pathogenetic link between the overlapping presentation of AGEP and GPP. Stimulation of the immune system by either a drug hypersensitivity to amoxicillin or throat infection may thus result in uncontrolled neutrophilic skin inflammation due to a deficiency in IL-36Ra. Hence, our case supports the emerging concept that the disease taxonomy of pustular skin eruptions could in future be based on genetic profiling.

Intraoral involvement was observed in half of the patients with IL-36RN–dependent DITRA (deficiency of IL-36 receptor antagonist)1 and in 2 of 4 patients with IL-36RN-dependent AGEP.2 The observation that in our patient intraoral pustules were present during the 2 episodes of AGEP and GPP suggests that intraoral involvement during generalized pustular eruptions is a clinical clue for underlying mutations in IL36RN. Thus, intraoral involvement in cases of either AGEP or GPP should prompt clinicians to perform further testing including genetic analysis, drug-hypersensitivity tests, and detailed medical history. Further studies and review of patients’ data are needed to confirm this potential association.

Back to top
Article Information

Corresponding Author: Christoph Schlapbach, MD, PhD, Department of Dermatology, Inselspital/University of Bern, Freiburgstrasse, Bern, Switzerland (christoph.schlapbach@insel.ch).

Published Online: November 26, 2014. doi:10.1001/jamadermatol.2014.3848.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported in part by grant SNF PASMP3 140074 WGS from the Prof Dr Max Cloëtta foundation in collaboration with the Uniscientia foundation (Dr Navarini) and by the Inselspital Research Grant (Dr Schlapbach). The research was also supported by the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy’s and St Thomas’ NHS Foundation Trust in partnership with the King’s College London and King’s College Hospital NHS Foundation Trust.

Role of the Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Marrakchi  S, Guigue  P, Renshaw  BR,  et al.  Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med. 2011;365(7):620-628.
PubMedArticle
2.
Navarini  AA, Valeyrie-Allanore  L, Setta-Kaffetzi  N,  et al.  Rare variations in IL36RN in severe adverse drug reactions manifesting as acute generalized exanthematous pustulosis. J Invest Dermatol. 2013;133(7):1904-1907.
PubMedArticle
3.
Sidoroff  A, Halevy  S, Bavinck  JN, Vaillant  L, Roujeau  JC.  Acute generalized exanthematous pustulosis (AGEP): a clinical reaction pattern. J Cutan Pathol. 2001;28(3):113-119.
PubMedArticle
4.
Navarini  AA, Valeyrie-Allanore  L, Setta-Kaffetzi  N,  et al.  Generalized pustular eruptions: time to adapt the disease taxonomy to the genetic architecture? J Invest Dermatol. 2014;134(2):580-581.
PubMedArticle
5.
Stenerson  M, Dufendach  K, Aksentijevich  I, Brady  J, Austin  J, Reed  AM.  The first reported case of compound heterozygous IL1RN mutations causing deficiency of the interleukin-1 receptor antagonist. Arthritis Rheum. 2011;63(12):4018-4022.
PubMedArticle
×