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jdv.14637

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Accepted Article
Article type
: Letter to Editor
First genetic analysis of atypical phenotype of pseudoxanthoma elasticum with ocular
manifestations in the absence of characteristic skin lesions
Takeshi Fukumoto1, Akira Iwanaga2, Atsushi Fukunaga1, Mari Wataya-Kaneda3, Yuta Koike2,
Chikako Nishigori1, and Atsushi Utani2
Authors? Affiliations:
1
Division of Dermatology, Department of Internal Related, Kobe University Graduate School of
Medicine, Kobe, Japan.
2
Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences,
Nagasaki, Japan.
3
Department of Dermatology, Course of Integrated Medicine, Graduate School of Medicine, Osaka
University, Osaka, Japan.
Running head: PXE without characteristic skin lesions
Key words: pseudoxanthoma elasticum, skin lesion, blind skin biopsy, ABCC6, c.2542delG
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/jdv.14637
This article is protected by copyright. All rights reserved.
Accepted Article
Corresponding author: Takeshi Fukumoto, M.D., Ph.D.
Division of Dermatology, Department of Internal Related, Kobe University Graduate School of
Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
Tel.: +81-78-382-6134
Fax: +81-78-382-6149
E-mail: fuku@med.kobe-u.ac.jp
Dear Editor:
Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease, characterized by mineralization
and degeneration of the elastic fibers in the skin, retina, and cardiovascular system.1-4 PXE is caused
by mutations in the ATP-binding cassette subfamily C member 6 (ABCC6) gene, but it remains
unknown how these mutations lead to the clinical phenotype.2-4 Although an association between
mutations and phenotypes has been postulated, no definite correlation has been established.5 Patients
with PXE usually exhibit typical skin lesions that are frequently the first diagnostic signs.1,6,7 The
atypical phenotype of PXE with ocular manifestations in the absence of characteristic skin lesions is
uncommon. To our knowledge, the genotype resulting in PXE with this atypical phenotype has not
been examined. The elucidation of possible genotype-phenotype correlations might enable us to
This article is protected by copyright. All rights reserved.
Accepted Article
predict disease possibility and develop early intervention strategies.5,8 We describe the clinical course
of two Japanese PXE patients with this atypical phenotype; the same ABCC6 gene mutation was
detected by using gene sequencing and multiplex ligation-dependent probe amplification (MLPA).8
A 27-year-old Japanese woman exhibited bilateral angioid streaks on fundoscopy (Fig. 1a). Her blood
pressure, peripheral vascular examination results, electrocardiogram (ECG), echocardiogram (UCG),
and chest radiograph findings were normal. Although skin lesions were not present, a blind skin
biopsy was performed (Fig. 1b). There were no characteristic histopathological features of
hematoxylin-eosin, elastica van Gieson, and von Kossa stains (Fig. 1c, d). Gene sequencing and
MLPA of ABCC6 using a blood sample revealed a heterozygous mutation of c. 2542delG;
p.V848CfsX83 in exon 19 and deletions of exon 2 and exon 4 (Fig. 1e). Although the parents had no
phenotype of PXE, a homozygous mutation of c. 2542delG in exon 19 and heterozygous deletions of
exon 2 and exon 4 in ABCC6 were identified in her father and her mother, respectively (Fig. 1f, g).
A 76-year-old Japanese man exhibited bilateral angioid streaks on fundoscopy (Fig. 2a). His blood
pressure, ECG, UCG, and chest radiograph findings were normal. Although skin lesions were not
present, a blind skin biopsy was performed (Fig. 2b). There were no characteristic histopathological
features of hematoxylin-eosin, elastica van Gieson, and von Kossa stains (Fig. 2c, d). A homozygous
mutation of c. 2542delG; p.V848CfsX83 in exon 19 was detected with gene sequencing and MLPA of
This article is protected by copyright. All rights reserved.
Accepted Article
ABCC6 using a blood sample (Fig. 2e).
In Japan, PXE patients with a possibility of this atypical phenotype were noted in 7 of 162 patients
from 2010 to 2013, according to the Research on Measures for Intractable Diseases of The Ministry
of Health, Labour, and Welfare. Among them, we identified only two patients who presented with no
histopathological findings by blind skin biopsies. Some reports have suggested that blind skin
biopsies may be useful when PXE is suspected despite the absence of typical skin lesions.5,9 Another
report described two patients with PXE who had neither clinical nor histological skin abnormalities.3
However, the PXE genotype with this atypical phenotype has not been reported. We detected the
same mutation, c. 2542delG; p.V848CfsX83 in ABCC6, in PXE patients with this atypical phenotype
for the first time. Our previous report revealed that c.2542delG might not regulate the severity of skin
lesions independently. These findings lead to the possibility that c. 2542delG might be involved in the
absence of skin lesions together with other modifying factors.
A limitation of this study is that we performed blind skin biopsies from one predisposed area, and we
could not perform medical examinations of the father of the patient in case 1 because he did not
consent. Although further studies are needed, our report may add new information regarding the
genotype-phenotype correlations of the uncommon PXE atypical phenotype.
This article is protected by copyright. All rights reserved.
Accepted Article
Conflicts of interest: We have no conflict of interest to disclose.
Funding sources: None declared.
References
1 Sherer DW, Sapadin AN, Lebwohl MG. Pseudoxanthoma elasticum: an update. Dermatology
1999; 199: 3-7.
2
Li Q, Jiang Q, Pfendner E, V鄏adi A, Uitto J. Pseudoxanthoma elasticum: clinical phenotypes,
molecular genetics and putative pathomechanisms. Exp Dermatol 2009; 18: 1-11.
3 Plomp AS, Toonstra J, Bergen AA, van Dijk MR, de Jong PT. Proposal for updating the
pseudoxanthoma elasticum classification system and a review of the clinical findings. Am J Med
Genet A 2010; 152: 1049-1058.
4 Uitto J, Li Q, Jiang Q. Pseudoxanthoma elasticum: molecular genetics and putative
pathomechanisms. J Invest Dermatol 2010; 130: 661-670.
5 Pfendner EG, Vanakker OM, Terry SF et al. Mutation detection in the ABCC6 gene and
genotype-phenotype analysis in a large international case series affected by pseudoxanthoma
elasticum. J Med Genet 2007; 44: 621-628.
This article is protected by copyright. All rights reserved.
Accepted Article
6 Uitto J, Jiang Q, Varadi A, Bercovitch LG, Terry SF. Pseudoxanthoma elasticum: diagnostic
features, classification, and treatment options. Expert Opin Orphan Drugs 2014; 2: 567-577.
7 Kenneth H, Neldner MD. Pseudoxanthoma elasticum. Int J Dermatol 1988; 27: 98-100.
8 Costrop LM, Vanakker OO, Van Laer L et al. Novel deletions causing pseudoxanthoma elasticum
underscore the genomic instability of the ABCC6 region. J Hum Genet 2010; 55: 112-117.
9
Lebwohl M, Phelps RG, Yannuzzi L, Chang S, Schwartz I, Fuchs W. Diagnosis of
pseudoxanthoma elasticum by scar biopsy in patients without characteristic skin lesions. N Engl J
Med 1987; 317: 347-350.
10 Iwanaga A, Okubo Y, Yozaki M et al. Analysis of clinical symptoms and ABCC6 mutations in
76 Japanese patients with pseudoxanthoma elasticum. J Dermatol 2017; 44: 644-650.
Figure legends
Figure 1 Clinical findings, histology, and ABCC6 mutations of case 1.
(a) Angioid streaks are evident on fundoscopy.
(b) A blind skin biopsy was obtained from the left axilla, where no skin lesions are observed.
(c) No evident histopathological findings are observed (hematoxylin-eosin, original magnification
�0).
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(d) Elastica van Gieson stain shows no fragmentation and no clumping of elastic fibers (�0).
(e) Gene sequencing of the ABCC6 gene and multiplex ligation-dependent probe amplification reveal
a heterozygous mutation of c. 2542delG; p.V848CfsX83 in exon 19 and deletions of exon 2 and exon
4.
(f) In her father, a homozygous mutation of c. 2542delG; p.V848CfsX83 in exon 19 is detected.
(g) In her mother, a homozygous mutation of c. 2542delG; p.V848CfsX83 in exon 19 is not detected.
Figure 2 Clinical findings and ABCC6 mutations of case 2.
(a) Angioid streaks are evident on fundoscopy.
(b) A blind skin biopsy was performed from the neck, where no skin lesions are observed.
(c) No evident histopathological findings are observed (hematoxylin-eosin, original magnification
�0).
(d) Elastica van Gieson stain shows no fragmentation and no clumping of elastic fibers (�0).
(e) Gene sequencing of the ABCC6 gene reveals a homozygous mutation of c. 2542delG;
p.V848CfsX83 in exon 19.
This article is protected by copyright. All rights reserved.
Accepted Article
This article is protected by copyright. All rights reserved.
Accepted Article
This article is protected by copyright. All rights reserved.
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