J Korean Med Sci.  2016 Aug;31(8):1307-1318. 10.3346/jkms.2016.31.8.1307.

Skin Barrier Function Is Not Impaired and Kallikrein 7 Gene Polymorphism Is Frequently Observed in Korean X-linked Ichthyosis Patients Diagnosed by Fluorescence in Situ Hybridization and Array Comparative Genomic Hybridization

Affiliations
  • 1Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Korea. choieh@yonsei.ac.kr
  • 2Institute of Atopic Dermatitis, Department of Dermatology, Chung-Ang University Hospital, Seoul, Korea.
  • 3M&D, Inc. Wonju Eco Environmental Technology Center, Wonju, Korea.
  • 4Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University, Wonju, Korea.
  • 5Department of Medical Genetics, Ajou University School of Medicine, Suwon, Korea.

Abstract

X-linked ichthyosis (XLI) is a recessively inherited ichthyosis. Skin barrier function of XLI patients reported in Western countries presented minimally abnormal or normal. Here, we evaluated the skin barrier properties and a skin barrier-related gene mutation in 16 Korean XLI patients who were diagnosed by fluorescence in situ hybridization and array comparative genomic hybridization analysis. Skin barrier properties were measured, cytokine expression levels in the stratum corneum (SC) were evaluated with the tape stripped specimen from skin surface, and a genetic test was done on blood. XLI patients showed significantly lower SC hydration, but normal basal trans-epidermal water loss and skin surface pH as compared to a healthy control group. Histopathology of ichthyosis epidermis showed no acanthosis, and levels of the pro-inflammatory cytokines in the corneal layer did not differ between control and lesional/non-lesional skin of XLI patients. Among the mutations in filaggrin (FLG), kallikrein 7 (KLK7), and SPINK5 genes, the prevalence of KLK7 gene mutations was significantly higher in XLI patients (50%) than in controls (0%), whereas FLG and SPINK5 prevalence was comparable. Korean XLI patients exhibited unimpaired skin barrier function and frequent association with the KLK7 gene polymorphism, which may differentiate them from Western XLI patients.

Keyword

X-linked Ichthyosis; Skin Barrier; Kallikrein 7; Polymorphism; Korean

MeSH Terms

Adolescent
Adult
Asian Continental Ancestry Group/*genetics
Child
Chromosomes, Human, X
Comparative Genomic Hybridization
Cytokines/metabolism
Humans
Hydrogen-Ion Concentration
Ichthyosis/diagnosis/*genetics/pathology
In Situ Hybridization, Fluorescence
Intermediate Filament Proteins/genetics
Kallikreins/*genetics
Male
Polymorphism, Single Nucleotide
Proteinase Inhibitory Proteins, Secretory/genetics
Republic of Korea
Skin/metabolism/*pathology
Young Adult
Cytokines
Intermediate Filament Proteins
Kallikreins
Proteinase Inhibitory Proteins, Secretory

Figure

  • Fig. 1 Deletion in chromosome X. (A) Array CGH results for chromosome X. Arrow indicates the deletion of the steroid sulfatase deficiency critical region (Xp22.31), including the STS gene (arr[hg19] Xp22.31(7,078,532-7,676,445) × 0). (B) FISH with a Xp22.31 region-specific probe; arrow indicates a deletion of the probe (STS-) in a del(X)(p22.31p22.31) chromosome.

  • Fig. 2 Skin barrier properties of XLI patients. (A, B) Whereas basal TEWL levels do not differ significantly among these groups, SC hydration is significantly lower in lesional than in non-lesional or control skin. (C) Skin surface pH does not differ among lesional, non-lesional skin of patients and that of normal controls.

  • Fig. 3 The results of PCR-REBA in XLI patients and the control group.

  • Fig. 4 Histopathological findings. (A-C) XLI patients. (D-F) Healthy control group. H & E staining from all patients shows hyperkeratosis and a normal to a slightly increased granular layer in the epidermis, but no acanthosis. Immunohistochemical staining intensity of filaggrin and involucrin shows a slightly increased pattern in the patient as compared to the control group (magnification 200 ×).

  • Fig. 5 Immunohistochemical stains and semi-quantitative expression analysis. (A, B) KLK7 and PAR-2 in XLI patients. (C, D) Control group. The staining intensity score is (A) 3, (B) 3, (C) 0.5, and (D) 2. (E) Staining intensities of KLK7 and PAR-2 are significantly higher in XLI patients than in the control group. (F, G) KLK7 and PAR-2 in XLI patients with KLK7 polymorphism, (H, I) without the KLK7 polymorphism. The staining intensity scores are (F) 4, (G) 4, (H) 3, and (I) 3. (J) Expression of KLK7 is not significantly different, whereas expression of PAR-2 is significantly higher in XLI patients with the KLK7 polymorphism (KLK7, 200 ×; PAR-2, 200 ×).

  • Fig. 6 Cytokine expression levels in the SC of XLI patients. (A-C) IL-1α, β, and TNF-α, pro-inflammatory cytokines, show no differences in the expression level among the lesional and non-lesional skin of XLI patients and healthy control skin.

  • Fig. 7 Skin findings from an XLI patient (Case 6). (A, B) The patients in our cohort manifested thick polygonal scales on the trunk. (C, D) Most (81.3%) of the patients lacked flexure involvement.


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