Arch Dermatol Res

DOI 10.1007/s00403-015-1611-x

CONCISE COMMUNICATION

Correlation of IL36RN mutation with different clinical features

of pustular psoriasis in Chinese patients
Ting-Shun Wang1,2 • Hsien-Yi Chiu1,3,4 • Jin-Bong Hong1 • Chih-Chieh Chan1 •

Sung-Jan Lin1,4 • Tsen-Fang Tsai1

Received: 11 June 2015 / Revised: 18 October 2015 / Accepted: 5 November 2015

Ó Springer-Verlag Berlin Heidelberg 2015

Abstract Different studies have reported various values
for the percentage of patients with IL36RN mutations, and
it has also been reported that the sites of these mutations
differ among different ethnicities. The current study was a
cross-sectional study conducted to investigate the risk
factors predicting IL36RN mutation in Chinese patients
with different clinical features of pustular psoriasis. 57 Han
Chinese patients, including 32 with generalized pustular
psoriasis, 14 with palmoplantar pustulosis, 9 with plaque-
type psoriasis with pustules, and 2 with erythrodermic
psoriasis, were enrolled between March 2013 and July
2014. Blood samples were collected, genomic DNA was
extracted from leukocytes, and polymerase chain reaction
(PCR)-based Sanger sequencing was used to analyze the
coding exons and flanking introns of the IL36RN gene. The
patients with generalized pustular psoriasis exhibited the
highest IL36RN mutation rate (75 %) among the afore-
mentioned patient types, with the subgroup consisting of
those patients who had features of acrodermatitis continua
of Hallopeau exhibiting the highest c.115?6T[C mutation
rate (93.8 %). In addition, early onset, ever generalized
& Tsen-Fang Tsai
tftsai@yahoo.com
1
Department of Dermatology, National Taiwan University
Hospital and National Taiwan University College of
Medicine, #7, Chung-Shan South Road, Taipei, Taiwan
2
Division of Dermatology, National Taiwan University
Hospital, Yun-Lin Branch, Dou-Liou, Taiwan
3 and even acute generalized exanthematous pustulosis
Division of Dermatology, National Taiwan University
Hospital, Hsin-Chu Branch, Hsin-Chu, Taiwan
4 However, the reported percentage of patients with
Institute of Biomedical Engineering, College of Medicine and
College of Engineering, National Taiwan University, Taipei,
Taiwan
pustular psoriasis (more than two attacks), ever acroder-
matitis continua of Hallopeau, inverse psoriasis, and a
family history of pustular psoriasis were associated with
IL36RN mutation. The c.115?6T[C mutation was the
most common and the most important variant in all sub-
types of pustular psoriasis with IL36RN mutations among
our sample of Chinese patients.
Keywords IL36RN
Pustular psoriasis
Acrodermatitis
continua of Hallopeau
Mutation
Chinese
Introduction
Pustular psoriasis can be classified into different forms:
generalized pustular psoriasis von Zumbusch type (GPPZ),
annular pustular psoriasis (APP), impetigo herpetiformis
(IH), palmoplantar pustulosis (PPP), and acrodermatitis
continua of Hallopeau (ACH) [3, 7]. However, differenti-
ation among these various forms may be difficult because
overlaps and transitions between them are common.
In 2011, 2 independent studies identified missense
mutations of the IL36RN gene in patients with GPPZ. The
first study included 9 Tunisian families with autosomal
recessive GPPZ [13]. In the other study, IL36RN mutations
were identified in 3 out of 5 patients with GPPZ using an
exon-sequencing strategy [16]. Subsequent reports have
also shown links between IL36RN mutations and other
clinical forms of pustular psoriasis, including PPP, ACH,
plaque-type psoriasis with pustules (PsOp) [17], IH [18],
(AGEP) [15].
IL36RN mutations varies among different studies, and the
different reports also indicate that the sites of mutation

123

differ among different ethnicities. In one previous study,
for example, the c.115?6T[C mutation was the most
common IL36RN variant in Chinese and Malay patients
with ACH and GPPZ [17]. However, the role of IL36RN
mutations has not yet been studied in Chinese patients with
ACH, PPP, and APP. In this study, we tried to correlate the
clinical presentations and IL36RN mutations of Chinese
patients with different forms of pustular psoriasis.
Materials and methods
The present study was a cross-sectional study and was
approved by the Institutional Review Board of National
Taiwan University Hospital. All the patients were diag-
nosed by the same dermatologist (Tsai) on the basis of skin
biopsies and were followed up on for at least 3 months.
There might be some degree of overlap between pustular
psoriasis and AGEP. However, pustular psoriasis has a
longer disease course (usually more than 15 days) and
might lack a related drug history. In any event, patients
who met the diagnostic criteria for AGEP were excluded
from the present study [21]. We did not test for anti-nuclear
antibody because no patient had symptoms of lupus ery-
thematosus and because some psoriatic patients might also
have positive results for anti-nuclear antibody. Blood
samples were collected from 57 consecutive Han Chinese
patients between March 2013 and July 2014 after each
patient signed an informed consent form. Data were col-
lected for the clinical parameters listed in Table 1.
Definitions of clinical forms and subtypes of pustular
psoriasis
GPPZ was defined as the acute onset of generalized pus-
tules arising from previously normal appearing skin with
fever and other constitutional symptoms (Fig. 1a, case 6).
ACH was defined as chronic relapsing of pustules involv-
ing the nail beds or nail matrix resulting in permanent nail
dystrophy (Fig. 1b, case 25). APP was defined as gener-
alized or localized annular erythematous rashes with at
least occasional pustular formation and a subacute or
chronic relapsing course without significant concomitant
systemic constitutional symptoms (Fig. 1c, case 43). PPP
was defined as chronic discrete pustules on the palms or
soles with or without typical psoriatic plaques elsewhere
(Fig. 1d, case 20). PsOp was defined as pustules arising
within typical psoriatic plaques (Fig. 1e, case 27). Ery-
throdermic psoriasis was defined as generalized thin pla-
ques of psoriatic lesions covering more than 90 % of the
body surface area (Fig. 1f, case 51). Inverse psoriasis was
defined as psoriatic lesions involving the axillae or groin
presenting as shining, moist, well-defined erythematous
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Arch Dermatol Res
patches (Fig. 1g, case 2). IH was defined as pustules with
fever occurring only during or immediately after
pregnancy.
However, because of the frequent transitions between
and co-occurrences of ACH, APP, and GPPZ, we included
all the patients exhibiting those subtypes into the same
group, the generalized pustular psoriasis (GPP) group,
regardless of their current main subtype(s). Thus, we
defined 4 main current subtypes for further analysis,
including GPP, PPP, PsOp, and erythroderma, according to
the main disease patterns at the time of blood sample
collection.
While we have included sub-analysis results for GPP
with/without ACH features and GPP with/without APP
features to make the data presentation more clear, the term
‘‘GPP’’ was used when analyzing the main current subtypes
and the term ‘‘GPPZ’’ is used in our discussion of clinical
forms.
Sequencing methods
Genomic DNA was extracted from leukocytes using the
Chemagic DNA Blood Kit Special, and polymerase chain
reaction (PCR)-based Sanger sequencing was used to
analyze the five coding exons and flanking introns of the
IL36RN gene. Standard DNA sequencing reactions were
performed using fluorescence-labeled dideoxy chain ter-
minations with the Big Dye Terminator ABI Prism Kit
and the ABI PRISM 3130 DNA Analyzer (Applied
Biosystems, Foster City, California). A genomic sequence
analysis for IL36RN was performed for all the enrolled
patients, and all the mutations were numbered based on
RefSeq NM_012275.2.
Statistical analysis
Statistical analysis was performed using SPSS 17.0 soft-
ware (SPSS Inc., Chicago, IL, USA). Differences between
groups were determined by using the t test or Wilcoxon
rank sum test for continuous variables and by using the
Fisher’s exact or Chi-square test for discrete variables. The
Kolmogorov–Smirnov test was applied to test the normal
distribution of all continuous variables. A p value of less
than 0.05 was regarded as statistically significant.
Results
Demographics
Among the 57 enrolled patients, the main current subtypes
were GPP (in 32 patients), PPP (14 patients), PsOp (9
patients), and erythrodermic psoriasis (2 patients). 16 of the
 Table 1 Demographics of patients
Case Sex Age Onset Main type Initial Ever Ever GPP Ever Ever Ever Have PsA Ever Inverse Aggravation Family
no age presentation PsO (episodes) ACH PPP erythroderma aggravated APP psoriasis during pregnancy history
factorsa

1 F 34 14 PPP PPP No 1 No Yes No Yes No No No Yes PsO

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2 M 46 16 GPP ACH No 3 Yes No No No No No Yes No No

3 F 29 28 GPP GPP No 1 No No Yes Yes No No No Yes No
4 M 27 10 GPP ACH No 0 Yes No No No No No Yes No No
5 M 9 8 GPP GPP Yes 3 Yes No No No No No Yes No No
6 F 30 26 GPP GPP No 3 No No No No No Yes No Yes No
7 F 24 16 GPP GPP Yes 3 Yes Yes No No No No No No No
8 F 33 3 GPP GPP No 3 Yes Yes No No No Yes No Yes No
9 M 37 30 GPP GPP No 3 Yes Yes No No Yes Yes Yes No No
10 F 17 0 GPP GPP Yes 3 Yes No No Yes No No No No No
11 F 37 14 GPP GPP Yes 3 No Yes No Yes No No Yes No No
12 M 21 10 GPP GPP No 3 Yes No Yes No No Yes Yes No PsO
13 F 60 27 PsOp PsO Yes 2 No No No No Yes No No Yes PsO
14 F 55 30 GPP APP Yes 3 No No Yes No No No No Yes No
15 M 16 1 GPP GPP Yes 3 Yes No No Yes No No No No PsO ? PP
16 F 39 30 GPP GPP Yes 3 No No Yes Yes No No No No PsO ? PP
17b F 35 26 PsOp PPP Yes 0 No No No No Yes No No No No
18 F 7 0 GPP GPP No 2 No No Yes Yes No No No No PsO
19 F 47 46 PPP PPP No 0 No Yes No No Yes No No Yes No
20 F 46 41 PPP PPP Yes 0 No Yes No No Yes No No No No
21 M 59 39 PsOp PsO Yes 0 No No No No Yes No No No No
22 M 51 38 PPP PPP Yes 0 No Yes No No No No No No No
23 M 14 5 PsOp GPP Yes 1 Yes No No No No No No No No
24 M 56 54 PPP PPP No 0 No Yes No No No No No No No
25 M 43 42 GPP PPP Yes 0 Yes No No No Yes No No No No
26 F 29 10 PsOp PsO Yes 1 No No No No No No No No PsO
27 M 61 51 GPP GPP Yes 3 No No Yes No Yes Yes No No No
28 M 43 27 PPP PPP Yes 0 No Yes No No No No No No No
29 M 59 53 GPP ACH Yes 0 Yes No No No No No No No No
30b F 29 14 PsOp PsO Yes 0 No No No No No No No Yes No
31 M 22 6 Erythroderma Erythroderma No 1 No No Yes No Yes No No No No
32 F 23 22 GPP GPP No 1 No No No No No No No No No
33 F 36 9 GPP GPP Yes 3 No No No No No Yes No No PsO
34 F 45 44 PPP PPP No 0 No Yes No No No No No Yes No

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 Table 1 continued
Case Sex Age Onset Main type Initial Ever Ever GPP Ever Ever Ever Have PsA Ever Inverse Aggravation Family
no age presentation PsO (episodes) ACH PPP erythroderma aggravated APP psoriasis during pregnancy history

123
factorsa

35 M 55 52 PPP PPP No 0 No Yes No No No No No No No

36 M 56 50 PPP PPP No 0 No Yes No No No No No No No
37 F 60 58 GPP ACH No 0 Yes No No No No No No No No
38 F 36 33 PPP PPP No 0 Yes Yes No No No No No Yes No
39 F 50 48 PPP PPP No 0 Yes Yes No No Yes No No Yes No
40 F 39 10 GPP ACH No 0 Yes No No No No No No No No
41 F 32 20 GPP GPP No 3 No No No No Yes No No No PsO
42 F 20 12 PsOp PsO Yes 1 No No Yes No No No No No PsO
43 F 24 9 GPP APP No 0 No No No No Yes Yes No No No
44 F 35 10 GPP GPP No 3 No No No No No No No Yes No
45 F 52 42 PPP PPP No 0 No Yes No No No No No No No
46 M 9 0 GPP GPP No 3 No No No No No No No No No
47 M 55 52 PPP PPP Yes 0 No Yes No No No No No No No
48 M 42 29 PsOp PsO Yes 0 No No No No No No No No No
49 F 48 45 GPP GPP No 3 No No No No No No No No No
50 M 39 3 GPP GPP No 3 Yes No No No Yes No Yes No PsO
51 F 51 25 Erythroderma PsO Yes 1 No No Yes No Yes No No No No
52 F 46 37 GPP ACH No 0 Yes No No No No No No No No
53 F 36 20 GPP GPP No 3 No No No No No Yes No No No
54 F 52 42 PPP PPP No 0 No Yes No No No No No No No
55 M 26 21 PsOp PsO Yes 0 No No No No No No No No No
56 M 21 12 GPP ACH No 0 Yes No No No No No No No No
57 F 14 2 GPP GPP No 3 No No No No No Yes No No No
GPP generalized pustular psoriasis, APP annular pustular psoriasis, PPP palmoplantar pustulosis, ACH acrodermatitis continua of Hallopeau, PsO psoriasis vulgaris, PsOp plaque-type psoriasis
with pustules, PP pustular psoriasis, PsA psoriatic arthritis
a
Aggravation by antibiotics and/or non-steroidal anti-inflammatory agents
b
Only case 17 and case 30 have consanguineous marriage
Arch Dermatol Res
Arch Dermatol Res
Fig. 1 a Generalized pustular psoriasis (GPP) from case 6: discrete
pustules with crusted scales arising on the annular erythematous
plaques on the abdomen in a pregnant female. b Acrodermatitis
continua of Hallopeau (ACH) from case 25: Several pustules arising
on the left thumb with grossly nail dystrophy. c Annular pustular
psoriasis (APP) from case 43: annular erythematous patches along
with peripheral surrounding scales and tiny pustules on the back.
d Palmoplantar pustulosis (PPP) from case 20: discrete pustules
32 GPP patients also had features of ACH and 9 of the 32
GPP patients also had features of APP.
Sequencing results
The sequencing results revealed multiple genetic variants,
including the c.115?6T[C mutation on intron 3
(p.Arg10Argfs*1), the c.140A[G (p.Asn47Ser) and
c.227C[T(p.Pro76Leu) mutations on exon 4, and the
c.334G[A (p.Glu112Lys) mutation on exon 5 (Table 2).
Out of the total of 57 pustular psoriasis patients, 30 had at
least one of these variants. Among these mutations, one
novel mutation, the c.334G[A (p.Glu112Lys) mutation,
has not been reported before. The PolyPhen-2 software tool
predicts that this c.334G[A mutation is probably damag-
ing, while the SIFT program predicts that it is definitely
damaging. The mutation frequency for each main current
subtype of pustular psoriasis is summarized in Table 3.
IL36RN mutations in different main current
subtypes of pustular psoriasis
Among the four discovered genetic variants, the c.140A[G
(p.Asn47Ser) variant was found to be unrelated to GPP in a
previous study of the Chinese population. The allele
arising on the hyperkeratotic erythematous plaques on the right palm.
e Plaque-type psoriasis with pustules (PsOp) from case 27: some
pustules arising on the erythematous scaly plaques on the bilateral
lower legs and dorsal feet. f Erythroderma from case 51: generalized
thin scaly erythematous plaques covering whole trunk and limbs
(more than 90 % of body surface areas). g Inverse psoriasis from case
2: shining moist well-defined erythematous patches on the right
axillary region
frequencies for c.140A[G were not significantly different
between the healthy controls and GPP patients, with reported
frequencies of 6.7 and 7.4 %, respectively [10, 11]. Our
results showed the presence of heterozygous c.140A[G
(p.Asn47Ser) variant in 3 GPP patients and 1 PPP patient,
indicating its presence in 7 % of our overall study popula-
tion. Therefore, we only considered c.115?6T[C,
c.227C[T, and c.334G[A as the relevant IL36RN mutation
variants for the association analysis. As shown in Table 3,
the GPP patients had the highest mutation rate of 75 %. In
comparison, mutations of IL36RN were infrequent in the
other subtypes of pustular psoriasis, with a rate of 22.2 %
among the PsOp patients, 14.3 % among the PPP patients,
and 0 % among the erythrodermic psoriasis patients.
Among the three discovered variants, the c.115?6T[C
variant was the most common variant, having been found
in all the GPP patients with IL36RN mutations. Further
analysis results for the different subtypes of pustular pso-
riasis and the c.115?6T[C mutation are shown in Table 3.
The c.115?6T[C variant was homozygous in most cases.
The other 2 mutation variants were c.227C[T (p.Pro76-
Leu) and c.334G[A (p.Glu112Lys). Three patients had the
c.227C[T variant, and they all had homozygous
c.115?6T[C. Two patients had the c.334G[A variant,
which in both cases was compound heterozygous with the
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Table 2 The sequencing results of all patients

Sample Main Mutation Sample Main type Mutation Sample Main type Mutation
no type no no

1 PPP c.115?6T[C (HO) 18 GPP No mutation 35 PPP No mutation

2 GPP c.115?6T[C (HO) 19 PPP No mutation 36 PPP No mutation
3 GPP No mutation 20 PPP No mutation 37 GPP No mutation
4 GPP c.115?6T[C (HO) 21 PsOp No mutation 38 PPP c.115?6T[C
c. 227C [ T, (HE)
p.Pro76Leu (HE)
5 GPP c.115?6T[C (HO) 22 PPP No mutation 39 PPP No mutation
6 GPP c.115?6T[C (HO) 23 PsOp c.115?6T[C (HO) 40 GPP c.115?6T[C
c. 227C[T, (HO)
p.Pro76Leu (HE)
7 GPP c.115?6T[C(HO) 24 PPP No mutation 41 GPP c.115?6T[C
(HO)
8 GPP c.115?6T[C (HO) 25 GPP c.115?6T[C (HO) 42 PsOp No mutation
c. 227C[T, p.Pro76Leu
(HE)
9 GPP c.115?6T[C (HO) 26 PsOp No mutation 43 GPP No mutation
10 GPP c.115?6T[C (HO) 27 GPP c.115?6T[C (HE) 44 GPP No mutation
c. 334G[A,
Glu112Lys(HE)
11 GPP c.115?6T[C (HE) 28 PPP No mutation 45 PPP No mutationa
c. 334G[A, Glu112Lys
(HO)
12 GPP c.115?6T[C (HO) 29 GPP c.115?6T[C (HO) 46 GPP c.115?6T[C
c. 243?15A[G (HE)a (HO)
13 PsOp No mutation 30 PsOp c.115?6T[C (HO) 47 PPP No mutation
14 GPP c.115?6T[C (HO) 31 Erythroderma No mutation 48 PsOp No mutation
15 GPP c.115?6T[C (HO) 32 GPP No mutation 49 GPP c.115?6T[C
(HO)
16 GPP c.115?6T[C (HO)a 33 GPP No mutationa 50 GPP c.115?6T[C
(HE)
17 PsOp No mutation 34 PPP No mutation 51 Erythroderma No mutation
Sample no Main type Mutation

52 GPP c.115?6T[C (HO)

53 GPP No mutation
54 PPP No mutation
55 PsOp No mutation
56 GPP c.115?6T[C (HE)
57 GPP c.115?6T[C (HO)

GPP generalized pustular psoriasis, PPP palmoplantar pustulosis, PsOp plaque-type psoriasis with pustules, HO homozygous, HE heterozygous
a
Mutation: c.140A[G, Asn47Ser

c.115?6T[C variant. No other combination of compound
heterozygous mutations was found.
GPP patients with ACH features had the highest
c.115?6T[C mutation rate at 93.8 %, which was higher than
the 75 % overall rate for all the GPP patients and the 56.3 %
rate for the GPP patients without ACH features (Table 3).
Risk factor analysis for correlations
between IL36RN mutations and phenotypes
The risk factor analysis results for correlations between
IL36RN mutations and phenotypes are shown in Table 4.
Ever GPPZ (more than two attacks) and ever ACH were

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Table 3 The relationship between the type of pustular psoriasis and the c.115?6T[C variant of IL36RN
Main current types: GPP (=GPPZ?ACH?APP, total = 32) PsOp PPP Erythroderma Historical
control
Subanalysis of GPP with GPP without GPP with GPP without
subtypes: ACH features ACH features APP features APP features

AA 1 7 3 5 7 12 2 95
Aa 2 2  1  3  0 1 0 1
aa 13* 7 5* 15* 2* 1 0 0
Total 16 16 9 23 9 14 2 96
c.115?6T[C 93.8 % 56.3 % 66.7 % 78.3 % 22.2 % 14.3 % 0.0 % 1.04 %
frequency p = 0.014 p = 0.496
75 % (all GPP)
All variant 78.1 % (all GPP) 22.2 % 14.3 % 0.0 % 6.25 %
frequency
Odds ratio for 10.5 (all GPP) 1 0.96 0 –
c.115?6T[ C (reference)
(vs. PsOp)
p value for 0.004 (all GPP) – 1 1 –
c.115?6T[C
(vs. PsOp)
Odds ratio for 285 (all GPP) 27.1 15.8 0 1
c.115?6T[C (reference)
(vs. control)
p value for \0.001 (all GPP) 0.019 0.04 1.00 –
c.115?6T[C
(vs. control)
a
* Heterozygous c.227C[T, p.Pro76Leu;   heterozygous c.334G[A, Glu112Lys. Each symbol refers to one c.115?6T[C case with the
indicated genetic variant. With reference to APP, odds ratio is determined by comparing the mutation group (Aa and aa) versus the non-mutation
group (AA) for each type of pustular psoriasis using Fisher exact test
b
GPP generalized pustular psoriasis, GPPZ generalized pustular psoriasis von Zumbusch type, APP annular pustular psoriasis, PPP palmo-
plantar pustulosis, ACH acrodermatitis continua of Hallopeau, PsOp plaque-type psoriasis with pustules
c
For comparison between our patients and normal populations of Han Chinese, the data of 96 controls is adopted from the previous published
article of reference [12]. p value for c.115?6T[C is statistically significant and the Odds ratio for c.115?6T[C is also high. So the frequency of
c.115?6T[C is significantly higher in GPP patients and is rare in the normal populations

significantly (p \ 0.001) and positively correlated with
IL36RN mutations.
Discussion
IL36RN encodes the IL-36 receptor antagonist (IL-36Ra),
which is primarily expressed in the skin [1, 14, 20].
Therefore, an IL36RN loss-of-function mutation can lead to
the activation of IL36 signaling and its major downstream
nuclear factor-jB pathway [22]. The relationship between
GPPZ and IL36RN was first unveiled by Marrakchi et al.
who found a homozygous c.80T[C (p.Leu27Pro) mutation
in the IL36RN gene in a family with recessive GPPZ [13].
This loss-of-function mutation caused unregulated cytokine
release, which in turn caused skin inflammation [13].
In our study, the c.115?6T[C (p.Arg10Argfs*1),
c.227C[T (p.Pro76Leu), and c.334G[A (p.Glu112Lys)
variants were found. The c.334G[A (p.Glu112Lys) variant
had not been reported before, although a close variant,
c.338C[T (p.Ser113Leu), has been reported by previous
studies [8, 16, 17]. The other 2 variants that we found had
been previously reported in GPPZ patients. Among the 14
known mutations associated with GPPZ, the c.115?6C[T
(p.Arg10Argfs*1) mutation has been reported to be the
most common mutation variant in Chinese patients [4, 8,
11, 17, 19]. Farooq et al. [4] first identified the compound
heterozygous mutations of c.115?6T[C accompanied by
c.368C[G (p.Thr123Arg) or c.28C[T in 2 Japanese GPPZ
patients. Although the c.115?6T[C mutation is located
beyond the critical 2 bp of the splice junction, the tran-
script analysis revealed that the c.115?6T[C mutation
caused skipping of exon 3, resulting in a frameshift with
premature transcription termination (p.Arg10Argfs*1) [9].
Whereas heterozygous c.115?6T[C alone is seen in the
normal population and in some cases of GPPZ, a

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Table 4 The risk factor analysis for correlation between IL36RN mutation and phenotypes
IL36RN mutation (?), N = 28 IL36RN mutation (-), N = 29 Odds ratioa, b
p value

Onset age 19.11 ± 15.9 30.6 ± 16.7 0.018

Ever PsO 12 (42.9 %) 13 (44.8 %) 0.92 0.88
Ever ACH 16 (57.1 %) 2 (6.9 %) 16.6 \0.001
Ever GPPZ 20 (71.4 %) 11 (37.9 %) 6.44 0.011
Ever PPP 6 (21.4 %) 12 (41.4 %) 0.39 0.11
Ever APP 6 (21.4 %) 3 (10.3 %) 2.4 0.25
Ever erythroderma 4 (14.3 %) 5 (17.2 %) 0.80 0.76
Inverse psoriasis 8 (28.6 %) 0 (0 %) N/A 0.002
Main manifestation of pustular psoriasis
ACH 9 (32.1 %) 1 (3.4 %) 8.11 0.004
GPP 13 (46.4 %) 4 (13.8 %) 5.42 0.007
APP 2 (7.1 %) 3 (10.3 %) 0.67 0.67
PsOp 2 (7.1 %) 7 (24.1 %) 0.24 0.08
PPP 2 (7.1 %) 12 (41.4 %) 0.11 0.003
Erythroderma 0 (0 %) 2 (6.9 %) N/A 0.16
Aggravation factorsc 5 (17.9 %) 2 (6.9 %) 2.9 0.21
PsA 5 (17.9 %) 9 (31.0 %) 0.48 0.25
Aggravation during pregnancy 6/15 (40 %) 6/19 (31.6 %) 1.4 0.61
Family history of all type psoriasis 7 (25.0 %) 5 (17.2 %) 1.6 0.47
Family history of pustular psoriasis 3 (10.7 %) 0 (0 %) N/A 0.07
Consanguineous marriage 1 (3.6 %) 1 (3.4 %) 1.04 0.98
GPP generalized pustular psoriasis, APP annular pustular psoriasis, PPP palmoplantar pustulosis, ACH acrodermatitis continua of Hallopeau,
PsO psoriasis vulgaris, PsOp plaque-type psoriasis with pustules, PsA psoriatic arthritis
a
The Fisher’s exact or Chi-square test for discrete variables and t-test for continuous variables
b
Odds ratio is calculated by all IL36RN mutation
c
Aggravation by antibiotics and/or non-steroidal anti-inflammatory agents

homozygous mutation or compound heterozygous mutation
of c.115?6T[C is more strongly associated with GPPZ [5,
13, 20]. These findings suggest a dosage effect of the
mutation allele. In our study, the homozygous
c.115?6T[C variant was found to be highly enriched in
GPP while the heterozygous and compound heterozygous
mutations were infrequent.
According to two previous studies, the frequency of the
c.115?6T[C mutation in the Chinese population is lower
than 3 % [11, 12]. Other previous studies on IL36RN have
focused on patients with GPPZ, with around 80 % of those
patients showing mutations [1, 19]. The percentage of GPP
patients with IL36RN mutation found in our study (75 %)
was similar. Most of the individuals affected by GPP had
homozygous c.115?6T[C variants (75 %). The high
IL36RN single nucleotide mutation detection rates in our
study may have been due to a more homogeneous genetic
background and a more stringent characterization of the
psoriatic phenotypes. We detected an even higher IL36RN
mutation rate in patients with ACH features compared to
patients with GPP without ACH (93.8 vs. 56.3 %, odds
ratio: 11.7, p = 0.014). We speculated that in cases of
ACH, in which local pustules occur in the absence of local
or systemic inflammatory insults, IL36RN mutation is more
likely.
Hussain et al. defined a clinical triad (early onset, sys-
temic inflammation, and the absence of concurrent psori-
asis) that is useful for prioritizing patients with GPPZ for
IL36RN screening [6]. In our analysis, early onset was also
found to be a positive risk factor for IL36RN mutation. In
addition, we also found that ever GPPZ (more than two
attacks), ever ACH, inverse psoriasis, and family history of
pustular psoriasis were associated with IL36RN mutation.
There are differences between the different known
psoriasis susceptibility genes among different ethnicities.
For example, HLA-Cw6, is more prevalent in Caucasian
patients with plaque psoriasis compared to Asians [2, 23].
We included the largest series of patients with ACH and
detected c.115?6T[C as the most commonly occurring
IL36RN mutation among the different subtypes of pustular

123
Arch Dermatol Res
psoriasis. We also showed that GPP with ACH features has
the highest rate of this mutation in Chinese patients. The
higher detection rate of IL36RN mutation may be a result of
an ethnic phenotypic discrimination of pustular psoriasis.
The main limitation of the present study was the small
sample size, which made subgroup analysis difficult. More
cooperative studies are needed to better clarify the phe-
notype–genotype correlations of different subtypes of
pustular psoriasis.
Acknowledgments This study was supported by Grant NTUH
104-S2820 from National Taiwan University Hospital, Taiwan.
Compliance with ethical standards
Conflict of interest Dr. Tsai has conducted clinical trials or
received honoraria for serving as a consultant for Wyeth Pharma-
ceuticals (now Pfizer Inc.), Novartis International AG, Celgene,
Galderma and Janssen-Cilag Pharmaceuticals and received speaking
fee from Abbvie. Drs. Wang, Chiu, Hung, Chan and Lin have no
conflicts of interest to declare.
Research involving human participants and/or animals The
study was approved by local Institutional Review Board. All proce-
dures performed in studies involving human participants were in
accordance with the ethical standards of the institutional and/or
national research committee and with the 1964 Helsinki declaration
and its later amendments or comparable ethical standards.
Informed consent Informed consent was obtained from all indi-
vidual participants included in the study.
Funding sources No funding sources.
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